Liver involvement in the drug reaction, eosinophilia, and systemic symptoms syndrome

Table 1 RegiSCAR scoring system for classifying drug reaction, eosinophilia, and systemic symptoms syndrome/drug-induced hypersensitivity syndrome

Clinical manifestations	SCORE				Range
	-1	0	1	2	Min	Max
Fever	No/U	Yes			-1	0
Enlarged lymph nodes		No/U	Yes		0	1
Eosinophilia
Eosinophils		No/U	700-1499/μL	≥ 1500/μL	0	2
Eosinophils, if leukocytes < 4000		No/U	(10%-19.9%)	(≥ 20%)	0	2
Atypical lymphocytes		No/U	Yes		0	1
Skin involvement
Skin rash extent, % BSA		No/U	> 50%		-2	2
Skin rash suggesting DReSS	No	U	Yes
Biopsy suggesting DReSS	No	Yes/U
Organ involvement1
Liver		No/U	Yes		0	2
Kidney		No/U	Yes		0	2
Lung		No/U	Yes		0	2
Muscle/heart		No/U	Yes		0	2
Pancreas		No/U	Yes		0	2
Other organ(s)		No/U	Yes		0	2
Resolution ≥ 15 d	No/U	Yes			-1	0
Evaluation other potential causes: ANA; blood culture; serology for HVA/HVB/HVC/Chlamydia-/ Mycoplasma pneumonia; other serology/PCR.
If none positive and ≥ 3 of above negative			Yes		0	1
Total score					-4	9
Final score meaning: < 2: no case; 2-3 possible case; 4-5: probable case; and > 5: definite case

¹After exclusion of other explanations: 1 = 1 organ, 2 = ≥ 2 organs. Adapted from Kardaun et al[21]. U: Unknown/unclassifiable; DReSS: Drug reaction, eosinophilia, and systemic symptoms syndrome; ANA: Antinuclear antibody; PCR: Polymerase chain reaction.

Table 2 Liver involvement reported in drug reaction, eosinophilia, and systemic symptoms syndrome/drug-induced hypersensitivity syndrome case series

Ref.	N	Liver, n (%)	Presentation, n (%)	Blood work,n (%)	Drug, n (%)	Associations	Treatment	Mortality,n (%)	Follow-up,n (%)
Chiou et al[32]	30 (M: 15 F: 15)	26 (86.6)	Jaundice 5 (16.6); Mild LI to FH; Toxic liver 6 (20)	Eos (> 1500/ μL) 14 (48); Serology HHV-6: 7/11 (63); CMV, EBV, HSV IgM: all negative; HIV 3	Allopurinol 11 (37); CBZ 6 (20)	RI 16 (53.3); ATL 13 (45)	HC/PDN: 22 (76); TS + Anti-H: 7 (23)	3 (10) (acute RF, sepsis, and GA bleeding)	DM type 1: 2 patients
Mansur et al[56]1	31 (M: 15; F: 16)	22 (71)	2LI: > 2 fold of UNP to 20 –fold of increase; Hepatitis 16 (51); Hepatomegaly 7 (22.6)	ALT: 2–5 fold increase 3 (10.0); ≥ 5 fold increase 4 (13.3); AST: 2–5 fold increase 1 (3.3); ≥ 5 fold increase 4 (13.3); GGT: 2–5 fold increase 6 (20.7); ≥ 5 fold increase 9 (31); Eos (> 350) 18/28 (64.3)	CBZ 11 (48); Phenytoin 11(35.4); Lamotrigine 3 (9.6)	RI 2 (6.45)	MTP: 27; TS + anti-H: 3	One TEN patient died of sepsis	6 (19.4) developed a blister dermatitis: 3 SJS and 3 TEN. All the hepatitis recovered well
Ben m’rad et al[34]	24 (M: 12; F: 12)	22 (91.6)	Cholangitis or non-lithiasis cholecystitis	ALT increased in 22 patients; ≥ 5N 13 (54); Eos (> 500 μ/L) 12 (50); Serology/PCR for HHV6, HHV8, CMV, and EBV were negative	Allopurinol 4; SSE 3; SMX-TMP 3	RI 4 (17); Heart 5 (21); ATL 14	PDN: 11 (45)	0	No relapses occurred; Sequelae: myocarditis 1; Steroid dependent: 1
Eshki et al[45]	15 (M: 5; F: 10)	9 (60)	HP of FH: massive hepatic necrosis + eosinophilic and lymphocytic inflammatory infiltrates	DNA PCR HHV-6: serum 6/7 patients; liver 1/7; CNS: 1/7; HHV-6-IgM and IgG1 patient with FH (reactivation); HIV+ I patient	Allopurinol 4; Minocycline 3; Antiepileptics 3	FH + HHV-6: 1: Hypertensive encephalitis (HHV-6 DNA CSF): 1 RI: 6	Non-AT: 5; SS: 10; + IVIG: 3; LT: 1	3 (20); MOF + DIC: 1	14 were admitted to the ICU where 3 died; 1 Flared twice when tapering of SS
Picard et al[57]	40 (M: 19 F: 21)	39 (99)		Eos 32 (80); EBV react 16 (42); HHV-6 react 17 (45); HHV-7 react 12 (32)	Anticonvulsants 12 (30); Antibiotics 11 (27)	RF 10 (25); FH 2 (5)	LT: 1	3 (7.5); Endocarditis (1) septicemia (1) stroke (1, unrelated to DReSS)	17 (42) symptoms were still present at 180 d
Chen et al[31]	60 (M: 26, F: 34)	48 (80)	LI > 2 UNL	Eos (> 700/μL) 31 (52) EBV and CMV IgG + 9 patients; HHV-6-IgG + 1 patient, but negative PCR (only patient tested)	Allopurinol (32); Phenytoin (18); Dapsone (17)	RI 24 (40); RF 5 (8); HF 4; ATL (63)	SS: 45 (75); + IVIG: 2; Non-AT: 6	6 (10) (1 MOF; 3 septic shock; 1 cardiogenic shock; 1 shock)	Hyperthyroidism
Ang et al[58]	27 (M: 12 F: 15)	26 (96.3)		Liver enzymes > 10 UNL: 13 (48); Eos 22 (%); Serology was not done	Phenytoin 5; CBZ 4	RI 4 (15); RF 2	SS: 25 (93); TS: 2 (7); LT: 0	0	8 (32) flared while SS tapering; 17 completed SS treatment (7 to 160 d, mean of 50); Sequelae: RI 3; AT 1, and myocarditis 1
Um et al[47]	38 (M: 18, F: 20)	38 (100)		ALT (mean 383.39 IU/L, range 26-3633); AST (mean 382.73 IU/L, range 28-2360); Eos (> 500/μL) 35 (91); Serology negative to CMV, EBV, or HSV	Anticonvulsants 18 (47); Antibiotics 7 (18); NSAIDs 5 (13)	RI 6 (16); ATL 18 (47)	TS + anti-H: 22 (58); SS: 16 (42)	1 (3) LF + opportunistic infection	36 (95) recovered completely; 1 (2.6) LI was lost at FU
Wongkitisophon et al[59]	27 (M: 14; F: 13)	26 (96.3)	LI > 2 UNL; Hepatomegaly (7.4)	ALT mean 188 IU/L (r 132–1708); AST 132 IU/L (r 89–857); TB 9 (33.3) mean 32.7 μmol/L (r 18.9–244.2 μmol/L); Eos (> 700/μL) 19 (70)	Phenytoin 9 (33) Allopurinol 4 (15) Nevirapine 4 (15)	RI 2 (7); ATL (19)	Non-AT: 4; SS (DMT/PDNL): 23 (85.2)	1 (4) died from MOF	5 (19) relapse of DReSS during tapering of SS; 21 (77.8) recovered well; Sequelae: 5 (19) that recovered within 6 mo
Kardaun et al[35]	117 (M: 52; F 65)	86/114 (75)	Transiently disturbed; liver function tests; Hepatomegaly and coagulopathy	Eos (≥ 1500 μL-1) 92 (81); (700–1499 μL-1) 16 (14); HIV 1; HHV-6 react 21/58 (36)	Anticonvulsants 41 (35); Allopurinol 21 (18); Sulfonamide 14 (12)	RI 40/108 (37); ATL 68/102 (67); SJS, TEN or AGEP features were seen in 8 patients	NA	2 (2)	1 overlap with SJS/TEN; and 1 overlap with AGEP
Walsh et al[51]	27 (M: 10; F: 17)	27 (100); TRC of HPB	LI before rash 4 (14.8); Significant LI: 20; Mild LI: 7; Cholestatic pattern was associated with interface dermatitis (P = 0.036)	AST mean 970 IU/L, median 250 (31-5183); GGT mean 522 IU/L, median 379 (9-1903); ALP mean 295 IU/L, median 266 (57-819); Eos (> 0.4 × 109/ L) 25 (93)	Anticonvulsants 12; Antimicrobials 10; Anti-rheumatics 5	RI 2 (7); Pericarditis (1 patient); GA (1 patient) MOD 3 patients	LT: 2	3 (11) All had severe liver injured. Two after failed LT	18 patients completed FU and normalized liver function
Lee et al[36]	23 (M: 12; F: 11)	23 (100)	Significant LI 23 (100)	ALT 186 IU/L (114.0-458.0); AST 207 IU/L (90.0-766.0); ALP 147 IU/L (116.0-338.0); TB 1.1 (0.8-13.3); Eos 17 (74)	Beta-lactams 7 (54); Allopurinol 3 (13); Sulfonamide 2 (15)	RI 13 (56); If LI higher risk of RI (P < 0.001); and of LN (P = 0.005)	LT: (2 patients; 1 died); IVIG: 1 (4); PDNL	4 (17.39)	Duration of the disease in survivors on steroids: 25.3 ± 14.8 d
Uhara et al[60]	12 (M: 4; F: 8)	11 (92)	Peak of LI appeared 7 d after the rash (range 3-22); ALT mean 176 (range 91- 311)	Eos (>1.5 × 109 ⁄ L) 4; HHV-6-IgG 12 (100)	CBZ 6; Salazosulfapyridine 4	ATL 8 (66)	Non-AT on the first weeks of examination Hydration: 7; TS: 5 PDN: 1 patient had RA; DMT (single dose): 1	0	All patients recovered; 7 to 37 d (median, 18) after withdrawal of the drug
Sultan et al[61]	17 (M: 8 F: 9)	17 (100)	LI defined as ALT > 100 IU/L; Hyperbilirubinemia 11 (64.7); Hepatomegaly 5 (29.4)	ALT (> 100 IU/L) 17 (100); AST (> 100 IU/L) 7 (41); HF 1 (5.9); Eos (> 1.5 9 109 cells/ ) 15 (88.2)	Anti-convulsivants (65); Phenytoin 6 (35.3); Phenobarbitone 2 (12)	RI 11 (64.7); RF 1 (5.9) requiring dialysis; ATL 2 (11.7)	SS (DMT switched to PDNL): 17 (100)	1 (6) died of HF	13 (76.5) recovered without complication 1 (5.9) DReSS recurrence after withdrawal of steroids
Avancini et al[62]	27 (M: 17; F: 10)	23 (85.1)	LI defined as liver enzyme level > 3 UNL	ALT 569 ± 911.5 U/L (mean ± SD; 46–4347 U/L); AST 474 ± 743 U/L (mean ± SD; 38–2662 U/L); Eos 26 (96); HCV + 1 patient	Phenytoin 12 (44); CBZ 8 (30)	ATL 17 (62.9); Associated to and higher ALT (r = 0.62; P < 0.001)	PDN: 27 (100); LT: (1 patient)	1 (4) due to HF	1 AT
Funck-Brentano et al[33]	38 (M: 19; F: 19)	29 (76)	Cytolysis 27 (71). Duration of 47 d (12-120); Cholestasis 26 (68); No HF was observed	Eos (> 7-1.5) 8 (21); (>1.5 × 109/L) 26 (68); PCR HHV-6 11/28 (39); EBV 3/28 (11); CMV 2/29 (7)	Allopurinol 13 (34); CBZ 4 (11); Sulfonamide 4 (11)	RI 21 (55); ORF 16 (42); FRF 8 (21); ATL 21 (55)	SS (MTP/PDN): 13 (34); TS: 25 (66)	1 (3); Hypovolemic shock few weeks post-discharged	Treatment duration 40 d (15-360); Relapses 15 (39)
Lin et al[37]	72 (M: 34; F: 38)	62 (86.1)	LI before rash 6 (9.7); Pattern: Cholestasis 23 (37.1); Mixed 17 (27.) Hepatocellular 12 (19.4); Unknown 10 (16.1)	Eos (> 700/ml) 49 (58.3); ALT values as high as 3806 U/L or ALP values of up to 2616 U/L	Anticonvulsants (30.6); Phenytoin 13 (18); Allopurinol; 19 (26.4)3; Sulfonamides 14 (19.4)	ATL (79.2): related to LI (P = 0.010) and with fever (P = 0.026).	PDNL + IVIG: 1; NAC: 0	0	22 (35.5) recovered in 30 d; 40 (64.5) recovered after
Lee et al[63]	25 (M: 11; F: 14)	20 (80)	LI if liver enzymes > 2 UNL	BT increased 6 (24); Eos (> 0.7 × 109/L), 20 (80), 7 of them had (> 1.5 9 109/L). PCR HHV-6 tested in 1 patient: negative	CBZ (28); Allopurinol (16); Anti-tuberculosis drugs (12)	RI 7 (28); ATL 12 (48); Pulmonary involvement 5 (20)	SS (MTP or PDN): 13 (52); + IVIG: 2 (8); TS + anti-H: 12 (48)	3 (12); 1 Septic shock + LI; 1 septic shock + LI +RF; 1 septic shock + LI+ RI + Pneumonia	The remaining patients had fully recovered. No significant cutaneous sequelae
Wang et al[64]	104 (M: 38; F: 66)	94 (90.4)	Jaundice 5 patients	Eos 72 (69.2): (0.7 × 109/L-1.499 × 109/L) 37 (35.6); (≥ 1.5 × 109/L) 35 (33.7); HIV 1 (1); Serology for HVA/HBV/HCV 18 (17.3)	Antibiotics 37 (35.6); CBZ 7 (6.7); TCMs 14 (13.5)	RI 9 (8.7) ATL 26 (25); MOD 19 patients	PDN: 58 (58) + IVIG: 1 patient; + Cy: 1 patient; Anti-H: 45 (43); IVIG: 1 patient	1 (< 1) had progression of his previously renal disease + Acinetobacter baumannii	103 were successfully discharged
Ichai et al[16]	16 (M: 5 F: 11)	(100) TTC	ENC: 7 (43.75) Admission 3 (Grade I: 1; III: 2); After admission 4 Liver necrosis (10%-90% of parenchymal surface) 7: panlobular 1; central; 3; periportal 1; spotty 2. Kupffer cell hyperplasia: 6; and Erythrophagocytosis	ALT 1693 IU/L (1252-2256); PCR HHV6 5/6 (83); HIV+ 4 (25)	Allopurinol 2; CBZ 2 Anti-tuberculosis drugs 3	RI 5 (31.2)	NAC: 16 (100); PDNL: 9 (56); LT: 5 (31.2)	4 (25): 2 MOF; 1 LR 4 yr after LT; 1 systemic fungal infection + HF 4 d after LT	LT survival: 60%; DReSS recurrence 75 ± 91 d after LT in 3/5 patients. LR was rule out. DReSS recurrence in 1 patient 2 months after spontaneously recovery
Wu et al[65]	52 (M: 34; F: 18)	43 (83)	LI if ALT >2 UNL	Eos (> 700/μL) 42 (81); DNA HHV-6 17 (33); DNA EBV 10 (19)	Allopurinol 18 (35); SSP 11 (21); CBZ 5 (10)	RI 2 (4)	MTP: 52 (100); + IVIG: 32 (62)	3 (6) MOF + sepsis within 3 months post-discharge.	3 (6) AT

¹Case series with Anticonvulsant hypersensitivity syndrome.

²Authors reported that DReSS induced by phenytoin appeared sooner after the drug intake compared to carbamazepine (P = 0.01).

³Allopurinol was related to cholestatic pattern. Hepatocellular-type pattern was seen in younger people while the cholestatic-type was seen in elderly (P = 0.044). Patients treated with SS had more ATL and Eos than those treated with TS (P < 0.05), but no differences in liver involvement. AGEP: Acute generalized exanthematous pustulosis; Anti-H: Antihistamines; AHA: Autoimmune hemolytic anemia; AT: Autoimmune thyroid; ATL: Atypical lymphocytosis; BT: Bilirubin total; CBZ: Carbamazepine; CMV: Cytomegalovirus; CNS: Central nervous system; CSF: Cerebrospinal fluid; Cy: Cyclosporine; DIC: Disseminated intravascular coagulation; GA: Gastrointestinal; ICU: Intensive care unit; DMT: Dexamethasone; EBV: Epstein Barr virus; Eos: Eosinophilia; ENC: Encephalopathy; FH: Fulminant hepatitis; FU: Follow-up; HC: Hydrocortisone; HSV: Herpes simplex virus; HHV-6: Herpes virus type 6; HPB: Hepatobiliary disease; LN: Lymphadenopathies; LT: Liver transplant; LR: Liver rejection; MOD: Multi-organ damage; MOF: Multi-organ failure; MTP: Methylprednisolone; NA: Not-available; NAC: N-acetylcysteine; Non-AT: Non-active treatment; NSAIDs: Non-steroidal anti-inflammatory drugs; PCR: Polymerase chain reaction; PDN: Prednisone; PDNL: Prednisolone; RI: Renal injury; RF: Renal failure (ORF: Organic RF; FRF: Functional RF); SJS: Stevens–Johnson syndrome; SMX-TMP: Sulfamethoxazole-trimethoprim; SS: Systemic steroids; SSE: Sulfasalazine; SSP: Salazosulphapyridine; TEN: Toxic epidermal necrolysis; TMCs: Traditional Chinese Medicines; TRC: Tertiary Referral Center; TS: Topical steroids; TTC: Tertiary Transplant Center.