Systematic Review: Ibuprofen-induced Liver Injury

Miguel E. Zoubek; María Isabel Lucena; Raúl J. Andrade; Camilla Stephens

Aliment Pharmacol Ther. 2020;51(6):603-611.

Methods

A systematic literature review was conducted in accordance with the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) guidelines, in order to identify all preexisting studies on ibuprofen-induced liver injury to date.

Systematic Database Search

Systematic electronic searches of PubMed, Cochrane and Web of Science were performed to obtain case reports and case series of ibuprofen-induced liver injury published up to December 2018. The searches were conducted using the terms "hepatotoxicity", "drug-induced liver injury" and "ibuprofen". An elevated number of ibuprofen-induced hepatotoxicity events related to the term "vanishing bile duct syndrome" was also observed. Thus, this term was included in a new search. Only articles published in English were considered. No other restrictions were applied.

Eligibility Criteria

After removing duplicates, titles and abstracts were screened independently for eligibility by two reviewers (MEZ and CS). Any disagreements were resolved by discussion between the two reviewers. Full articles corresponding to the selected abstracts and/or titles were obtained and assessed against eligibility criteria. Only cases where ibuprofen was judged as the single culprit drug causing a liver reaction were considered for our analysis. References cited by the selected articles were also reviewed to identify other potentially eligible studies not captured in the initial electronic database search.

Data Collection

Demographic, clinical, histological, laboratory and outcome information corresponding to exposure to ibuprofen resulting in hepatotoxicity was retrieved from the articles and analysed. The pattern of liver injury was classified based on R value calculations from the first available blood test after DILI recognition.^[38] For those cases without complete analytical information at DILI recognition, histological findings from liver biopsies were carefully reviewed. Presentations considered as hypersensitivity features included fever, rash, eosinophilia and lymphopenia.

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Table 1. Prevalence of NSAID hepatotoxicity in large prospective DILI cohorts worldwide
	Spanish DILI Registry¹²	Latin DILI Network¹²	US DILIN¹¹	Iceland¹⁰	India¹⁴	Italy¹³
Year	1994–2015	2012–2015	2004–2013	2010–2011	1997–2008	2000–2016
Type of registry	National	Multinational	National	Population-based study	Single-center study	Single-center study
Total number of DILI cases, n	871	200	1221	96	313	185
Musculo-skeletal drugs, n (%)	96 (11)	36 (18)	N/A (N/A)	N/A (N/A)	N/A (N/A)	N/A (N/A)
NSAIDs, n (%)	73 (9)	29 (10)	30 (3)	6 (6)	8 (3)	65 (36)
Most frequent NSAIDs, n (% of total NSAIDs)	Ibuprofen 21 (29) Diclofenac 13 (18) Nimesulide^a 9 (12) Piroxicam 5 (7) Droxicam 4 (5) Naproxen 4 (5)	Nimesulide^a 11 (38) Diclofenac 10 (34) Ibuprofen 5 (17) Piroxicam 1 (3) Ketorolac 1 (3) Ketoprofen 1 (3)	Diclofenac^b 16 (53) Meloxicam 3 (10) Celecoxib 3 (10) Ibuprofen 2 (7) Etodolac 2 (7) Oxaprozin 2 (7) Sulindac 1 (3) Valdecoxib 1 (3)	Diclofenac 6 (100)	Nimesulide 2 (25) Ibuprofen 2 (25) Celexocib 2 (25) Diclofenac 1 (13) Piroxicam 1 (13)	Nimesulide 25 (39) Ketoprofen 22 (34) Diclofenac 10 (15) Ibuprofen 4 (7)

Abbreviations: N/A, not available; NSAID, nonsteroidal anti-inflammatory drug.
^aWithdrawn from the market in Spain in 2002 and Argetina in 2009, but still commercialized in other countries.
^bAlone or in combined formulation.

Table 2. Biochemical parameters (at the time of peak ALT), liver injury pattern and additional information on ibuprofen-induced liver injury (n = 25)
Case	TBL (mg/dL)	AST (IU/L)	ALT (IU/L)	ALP (IU/L)	Type of injury^a	Additional information	References
Idiosyncratic DILI cases
1	2	6200	N/A	760	Hep	ANA+ (1:4096)	16
2	1	2200	1245	N/A	Hep	—	17
3	14	N/A	441	238	Chol	Developed acute-onset SJS	18
4	6.5	404	488	309	Mix	Developed VBDS and severe progressive xanthomatosis	19
5	3.3	582	649	519	N/A	Developed acute-onset VBDS and SJS; ANA+ (1:40)	20
6	N/A	459	1209	N/A	Hep	—	21
7	N/A	523	1238	N/A	Hep	—	21
8	N/A	597	1577	N/A	Hep	—	21
9	30	2260	2099	N/A	Hep	—	22
10	N/A	N/A	N/A	N/A	N/A	—	23
11	5.4	333	639	1697	Hep	Developed acute VBDS	24
12	8.5	879	723	890	N/A	Developed acute VBDS and TEN	25
13	0.4	383	464	36	Hep	Developed meningitis; ASMA+ (1:20)	26
14	3.9	99	182	N/A	Chol	ASMA+ (1:80)	27
15	15	1492	1860	323	Hep	Developed multiform exudative erythema; DLST+ for ibuprofen	28
16	6	247	207	1598	Chol	Developed VBDS and hyperlipidemia; ANA+ (1:320)	29
17	N/A	105	255	155	Mix	ANA+	30
18	N/A	185	N/A	N/A	N/A	—	30
19	N/A	355	1093	N/A	Hep	—	31
20	8.1	186	419	700	Mix	Developed VBDS and TEN	32
21	N/A	147 U/mL^b	N/A	N/A	N/A	ANA+ (1:80)	33
22	2.9	1168	2154	90	Hep	Developed DRESS syndrome	34
Mean (range)	7.6 (0.4–30)	986 (99–6200)	968 (182–2154)	610 (36–1697)
Intrinsic DILI cases
23	5	>717	1873	135	Hep	ANA+, ASMA+	35
24	19	N/A	2301	109	Hep	—	36
25	N/A	291	N/A	245	N/A	—	37

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Chol, cholestatic; DLST, drug lymphocyte stimulation test; DRESS, drug rash with eosinophilia and systemic symptoms; Hep, hepatocellular; Mix, mixed; N/A, not available; Ref, bibliographic reference; SJS, Stevens-Johnson syndrome; TBL, total bilirubin; TEN, toxic epidermal necrolysis; VBDS, vanishing bile duct syndrome.
^aType of liver injury was deduced from R values based on initial blood analysis values when presented, or biopsy findings in the absence of analytical information.
^bNormal, <47 U/mL.

Supplementary Table 1. Demographic, clinical, histological and outcome information of ibuprofen-induced liver injuryevents reviewed in the literature (n=25)
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

Abbreviations: APAP, acetaminophen; d, days; DILI, drug-indcued liver injury; GSH, glutathione; HCV, hepatitis C virus infection; LTx, liver transplantation; mo, months; N/A, not available; Ref, bibliographic reference;UDCA, ursodeoxycholic acid; w, weeks.
^#Treatment cessation due to maculopapular skin rash appearing 2 hours after ibuprofen intake. Jaundice appeared 7 days later; *7-month-old infant;**a single-dose of ibuprofen, 10mg/kg, was given three months earlier; ^§Last follow-up; ^§§two days after ibuprofen re-exposition during hospitalization (day 8)

Supplementary Table 2. Description of demographic and clinical characteristics in 25 Spanish Latin American ibuprofen-induced liver injury cases
Patient	Gender	Age, y	Time to onset, d	Comorbid conditions	Type of liver injury	Additional information	Severity
1	F	21	15*	None	Hep	-	Mild
2	M	43	25	None	Mix	Jaundice	Moderate
3	M	77	4	Osteoarthritis, arteritis, COPD, peptic ulcer	Mix	Jaundice, rash	Moderate
4	M	30	66	None	Mix	Jaundice	Moderate
5	M	75	3	COPD, pneumothorax	Mix	Jaundice	Moderate
6	F	69	21	Diabetes mellitus	Hep	Jaundice, eosinophilia	Moderate
7	M	43	8	None	Hep	Jaundice	Moderate
8	M	18	3	None	Mix	Jaundice, lymphopenia	Moderate
9	F	47	68	None	Mix	Eosinophilia	Mild
10	F	41	3	None	Hep	-	Mild
11	F	64	11	Diabetes mellitus, hypertension	Mix	Jaundice, ASMA+	Moderate
12	F	59	4	osteoarthritis, peripheral vascular disease	Hep	Jaundice, lymphopenia, ANA+	LTx
13	F	44	8	Depression, breast cancer	Mix	Jaundice	Fatal
14	F	49	10	None	Hep	Jaundice, eosinophilia	Moderate
15	F	57	31	Goitre, diabetes mellitus, dyslipidemia, psoriasis	Chol	Jaundice	Moderate
16	F	71	30	Diabetes mellitus, dyslipidemia, hypertension	Mix	Jaundice, lymphopenia	Moderate
17	M	40	1767^§	None	Chol	Eosinophilia	Mild
18	F	60	27	Obesity, depression	Hep	Eosinophilia, ANA+, ASMA+	Mild
19	M	40	38	Sclerosing cholangitis, ulcerative colitis, pancreatitis	Hep	Jaundice	Moderate
20	M	56	15	None	Hep	Jaundice, ASMA+	Moderate
21	F	48	14	Diabetes mellitus, rheumatoid arthritis	Hep	Eosinophilia	Mild
22	F	42	40	Hypothyroidism, depression	Hep	Lymphopenia	Mild
23	M	62	11	None	Hep	Jaundice, ASMA+	Fatal
24	M	37	96	None	Hep	-	Mild
25	M	64	6	Colorectal cancer, diabetes mellitus, hyperlipidemia, myocardial infarction	Hep	Jaundice, ASMA+	Moderate

*Asymptomatic episode, time to onset is based on first detection in routine blood analysis, ^§on-demand intake
Abbreviations:Chol, cholestatic; ANA+, positive antinuclear antibody titers; ASMA+, positive anti-smooth muscle antibody titers;COPD, chronic obstructive pulmonary disease; d, days; F, female; Hep, hepatocellular; LTx, liver transplantation; M, male; Mix, mixed; y, years

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Systematic Review: Ibuprofen-induced Liver Injury

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Systematic Review: Ibuprofen-induced Liver Injury

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