Drug-Induced Acute Liver Failure in Children and Adults

Results of a Single-Centre Study of 128 Patients

Harshad Devarbhavi; Mallikarjun Patil; Vishnu V. Reddy; Rajvir Singh; Tarun Joseph; Deepak Ganga

Liver International. 2018;38(7):1322-1329.

Conclusion

The result of our study has something in common and something at odds with other reported series; antimicrobials largely driven by antituberculosis drugs are the commonest causes of idiosyncratic DIALF. Mortality depends on the causative agent with a higher mortality in those with antituberculosis DIALF and lesser mortality in those with anti–epileptic drugs and dapsone both of which are associated with hypersensitivity features in a majority of patients. MELD score rather than KCC predicts outcome.

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Abbreviations
AGA, American Gastroenterology Association; ALF, acute liver failure; ACLF, acute on chronic liver failure; AED, anti-epileptic drugs; ALFSG, acute liver failure study group; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AP, alkaline phosphatase; APAP, acetaminophen; ATD, antituberculosis drugs; CAM, complementary and alternative medicines; DIALF, drug-induced acute liver failure; DILI, drug-induced liver injury; FeSO₄, ferrous sulphate; GGT, gamma glutamyl transferase; INR, International normalized ratio; IQR, interquartile range; ITU, intensive therapy unit; ICU, intensive care unit; KCC, King's College criteria; MELD, Model for end-stage liver disease; OTC, over the counter; ROC, Receiver operating characteristic; RUCAM, Roussel Uclaf Causality Assessment Method; TB, tuberculosis; UNOS, united network organ sharing; WBC, white blood cells.

Table 1. Baseline characteristics of all patients with drug–induced ALF
Variable	N = 128
Age in years	38 ± 19
Gender	M:60 (47%); F:68 (53%)
Jaundice	118 (92%)
Skin rashes	27 (21.3%)
Ascites	61 (47%)
Primary drug (anti–TB drugs)	92 (72%)
Duration of treatment	70 ± 117
Serum protein (g/dL)	5.6 ± 1.4
Serum albumin (g/dL)	2.5 ± 0.8
Total bilirubin (mg/dL)	15 ± 9.7
Direct bilirubin (mg/dL)	9.4 ± 6
AST(U/L), Median (IQR)	343 (155–867)
ALT(U/L), Median (IQR)	334 (153–699)
AP(U/L), Median (IQR)	224.5 (152–412)
GGT(U/L), Median (IQR)	90 (45–223)
INR	4 ± 3
Serum creatinine (mg/dL)	1.6 ± 1.6
MELD score	30 ± 11.7
Haemoglobin (g/dL)	11 ± 2
Log_e WBC (10³/dL)	9.2 ± 1.0
Platelets (10⁵/dl)	2 ± 1.2
Eosinophils (%)	2.3 ± 4.4

AST, aspartate aminotransferase; ALT, alanine aminotransferase; AP, alkaline phosphatase; GGT, gamma glutamyl transferase; INR, International normalized ratio; MELD, Model for end stage liver disease; TB, tuberculosis; WBC, white blood cells.

Table 2. Baseline characteristics in children (≤ 18 years) and adults with drug–induced ALF
	Children (≤ 18 years)	Adults(>18 years)
Variable	N = 21	N = 107
Age in years	13.7 ± 4.3	44 ± 16.7
Age, Median (IQR)	16 (9.5–17)	42 (30–55)
Gender	M:10 (47.6%); F: 11 (52.4%)	M:50 (46.7%), F:57 (53.3%)
Encephalopathy	21 (100%)	107 (100%)
Jaundice	17 (81%)	101 (94.4%)
Skin rashes	7 (33.3%)	20 (18.7%)
Ascites	6 (28.6%)	55 (51.4%)
Primary drug (anti–TB drugs)	13 (62%)	9 (73.8%)
Duration of treatment	75 ± 94	72 ± 128
Serum protein (g/dL)	5.5 ± 1.4	5.7 ± 1.2
Serum albumin (g/dL)	2.7 ± 0.7	2.4 ± 0.8
Total bilirubin (mg/dL)	10.6 ± 8	15.6 ± 9.7
Direct bilirubin (mg/dL)	6.7 ± 5	10 ± 5.8
AST(U/L), Median (IQR)	576 (229–1852)	330 (150–867)
ALT(U/L), Median (IQR)	513 (215–1338)	332 (140–681)
AP(U/L), Median (IQR)	285 (177–480)	203 (145–386)
GGT(U/L), Median (IQR)	137 (48–233)	80 (45–222)
INR	5.4 ± 4	3.6 ± 2.7
Serum creatinine (mg/dL)	1.0 ± 0.6	1.7 ± 1.8
MELD score	29 ± 13	30 ± 10
Haemoglobin (g/dL)	10 ± 2	11 ± 2.2
Log_e WBC (10³/dL)	9.2 ± 0.8	9.2 ± 1.0
Platelets (10⁵/dL)	2.5 ± 1.3	2.1 ± 1.1

AST, aspartate aminotransferase; ALT, alanine aminotransferase; AP, alkaline phosphatase; GGT, gamma glutamyl transferase; INR, International normalized ratio; MELD, Model for end–stage liver disease; TB, tuberculosis; WBC, white blood cells.

Table 3. Difference between survivors vs non–survivors
Variable	Non–survivors (n = 84; 66%)	Survivors (N = 44; 34%)	P value
Age in years	41 ± 19	35 ± 17.5	.08
Gender Female	50 (59.5%)	18 (39.5%)	.03
Jaundice	77 (92%)	41 (93%)	.77
Skin rashes	15 (18%)	12 (28%)	.19
Ascites	48 (58%)	12 (29%)	.002
Anti–TB drugs	66 (79%)	26 (61%)	.03
Treatment duration (days)	74 ± 86	62 ± 163	.58
Serum protein (g/dL)	5 ± 1.4	6 ± 1.1	.01
Serum albumin (g/dL)	2.4 ± 0.7	2.7 ± 0.8	.01
Total bilirubin (mg/dL)	18 ± 10	9 ± 6	.001
AST(U/L), Median(IQR)	317 (141–585)	360 (168–1098)	.13
ALT(U/L), Median(IQR)	329 (153–661)	336 (157–1033)	.42
AP(U/L), Median(IQR)	202 (154–431)	274 (142–406)	.66
INR	4.3 ± 3	3 ± 2.5	.02
Serum creatinine (mg/dL)	1.5 ± 1.2	1.7 ± 2.3	.67
Haemoglobin (g/dL)	11 ± 2.3	10.8 ± 1.8	.86
LogeWBC(10³/dL)	9.3 ± 1.1	9.1 ± 0.6	.48
Platelets (10⁵/dl)	2.21 ± 1.1	2.1 ± 1.18	.87
MELD score	33 ± 10	24 ± 9	.001
Non–acetaminophen King's College Criteria Score	33 (41%)	21 (49%)	.40

Table 4. Drugs implicated in causing ALF
Drugs	Frequency
Atorvastatin	1
Anti–TB drugs	92
Augmentin	2
Ayurvedic	1
Anti–chemotherapeutic (BEP (1) + adriamycin (1) + cisplatin(1))	3
Complementary	1
Carbamazepine	4
Dapsone	7
Duloxetine	1
Efavirenz	1
Iron (FeSO₄)	2
Lamotrigine	1
Nevirapine	1
Norethisterone	1
Paracetamol	2
Phenytoin sodium	6
Progesterone	1
Valproate	1
Total	128

ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BEP, bleomycin– etoposide– cisplatin; FeSO₄, Ferrous sulphate; GGT, gamma glutamyl transferase; INR, International normalized ratio; MELD, Model for end–stage liver disease; TB, tuberculosis; WBC, white blood cells.

Table 5. Comparison between anti–TB DIALF and non–anti–TB DIALF groups
Variable	Anti –TB DIALF	Non–anti –TB DIALF	P value
Age in years	41 ± 19	33 ± 19	.06
Gender Female	49 (53.3%)	19 (52.7%)	.86
Jaundice	87 (97%)	26 (79%)	.001
Skin rashes	12 (13%)	14 (42%)	.001
Ascites	50 (56%)	9 (28%)	.006
Dead	64 (71%)	18 (54.5%)	.08
Duration of treatment	66 ± 79	84 ± 194	.47
Serum protein (g/dL)	5.6 ± 1.4	5.5 ± 1.1	.73
Serum albumin (g/dL)	2.4 ± 0.8	2.7 ± 0.7	.07
Total bilirubin (mg/dL)	16.2 ± 10	12 ± 8.6	.03
Direct bilirubin (mg/dL)	10 ± .6	8.2 ± 6.2	.13
AST(U/L), Median(IQR)	335 (135–86)	360 (189–984)	.30
ALT(U/L), Median(IQR)	297 (119–672)	453 (235–1096)	.04
AP(U/L), Median(IQR)	197 (145–358)	279 (156–586)	.10
GGT(U/L), Median(IQR)	58 (43–183)	192 (72–309)	.003
INR	4.2 ± 3	3.4 ± 2.8	.21
Serum creatinine (mg/dL)	1.6 ± 1.4	1.8 ± 2.3	.53
Haemoglobin (g/dL)	11 ± 2.2	11.5 ± 1.9	.06
Log_eWBC(10³/dL)	9.2 ± 1	9.3 ± 0.5	.43
Neutrophils (%)	77 ± 18	71±	.08
Lymphocytes (%)	16 ± 13	20 ± 13	.16
Eosinophils (%)	1.6 ± 2.3	4.6 ± 7.6	.05
MELD score	31 ± 11	28 ± 9.6	.18
Platelets (10⁵/dL)	2.2 ± 1.2	2 ± 1	.43

AST, aspartate aminotransferase; ALT, alanine aminotransferase; AP, alkaline phosphatase; GGT, gamma glutamyl transferase; INR, International normalized ratio; MELD, Model for end–stage liver disease; TB, tuberculosis; WBC, white blood cells.

Table 6. Demographical, clinical, laboratory and liver histopathology characteristics of the 2 patients with ALF from APAP overdose
Variable	Patient 1	Patient 2
Age	16	24
Gender	Male	Female
Height/weight	165 cm/70 kg	152 cm/54 kg
Risk factor	Drug abuse	14 weeks pregnant
APAP dose ingested (grams)	8	6
Concomitant drugs	Propoxyphene napsylate, dicyclomine hydrochloride	Aspirin
Serum total protein	5.8	5.5
Serum albumin	3.2	3.2
Serum total bilirubin	2.5	5.2
Direct bilirubin	1.5	3.2
AST	1857	210
ALT	1259	340
ALP	258	649
GGT	478	23
Serum creatinine	2.1	1.1
INR	>12	6.2
Prothrombin time (min)	>3	>1
Haemoglobin	13.6	12.3
WBC count	9800	40 700
Platelet count	21 000	120 000
Admission PH (ABG)	7.2	7.1
Post–mortem liver biopsy	Hepatocellular necrosis with marked sinusoidal congestion	Extensive massive necrosis

APAP, acetaminophen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; AP, alkaline phosphatase; GGT, gamma glutamyl transferase; INR, International normalized ratio; WBC, white blood cells.

Table 7. Multivariate analysis for mortality risk factors
Variable	Adjusted OR	95% C.I.	P value
Age in years	0.98	0.95–1.0	.11
Gender Female	0.64	0.23–1.79	.39
Ascites	0.41	0.15–1.17	.10
Antituberculosis drugs	0.96	0.31–3.0	.95
Serum protein	1.85	1.1–3.0	.02
Serum albumin	0.77	0.35–1.73	.54
Total Bilirubin	0.87	0.72–1.05	.14
Direct bilirubin	1.01	0.77–1.33	.92
Log_e INR	0.31	0.12–0.8	.01

Table 8. Receiver operating characteristic curve comparing MELD, non–acetaminophen KCC and ALFSG prognostic index for survival
Test Results	Area	95% CI
King's College Criteria Score	0.51	0.38–0.63
MELD Score	0.76	0.66–0.86
ALFSG prognostic score	0.76	0.67–0.85

ALFSG, acute liver failure study group; MELD, Model for end–stage liver disease.

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