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Introduction
Patients with herb-induced liver injury (HILI) and druginduced liver injury (DILI) usually have a good prognosis,
but acute liver failure with a lethal outcome or the
requirement for a liver transplant rarely may occur [15]. As
a specific and valid diagnostic laboratory marker is lacking,
the diagnosis of HILI and DILI requires a thorough clinical
assessment and an appropriate diagnostic algorithm that
considers specific hepatotoxicity characteristics [6,7].
In case series of initially assumed DILI, alternative diagnoses
are common [822] and may account for up to 47.1% in one
study evaluating the accuracy of hepatic idiosyncratic
adverse drug reactions initially identified in 138 patients of
an English health region [10]. In this report, primary
underlying diagnoses included common bile duct stone,
ischemic hepatitis, autoimmune hepatitis, sepsis, alcoholic
liver disease, Gilberts syndrome, hepatitis because of
cytomegalovirus and Epstein Barr virus infections, steatosis,
postictal state, lymphoma, paracetamol overdose, cholangitis,
thyrotoxicosis, hepatitis C cirrhosis, and cryptogenic cirrhoc 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
0954-691X
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Publication selection
Assessment approach
Results
Initially suspected herb-induced liver injury cases with
alternative causes
Frequency of specified and unspecified alternative causes in initially suspected herb-induced liver injury cases
Herbs
Herbal drugs
Herbal supplements
Kava
Kava
Kava
Kava
Kava
Greater Celandine
Black cohosh
Herbalife products
Herbalife products
Kava
Black cohosh
Green tea
Black cohosh
Black cohosh
Kava
Hydroxycut
Black cohosh
Greater Celandine
Herbalife products
Various herbs
Greater Celandine
Pelargonium sidoides
Pelargonium sidoides
Study cohort
Initially suspected
HILI cases (n)
20
30
20
36
80
23
31
12
12
26
30
34
4
9
31
17
22
22
20
45
21
15
13
573
(40)
(53)
(50)
(67)
(58)
(30)
(65)
(33)
(33)
(50)
(37)
(27)
(75)
(89)
(58)
(12)
(46)
(41)
(15)
(40)
(57)
(93)
(87)
(48.5)
Causality
assessment methods
Ad hoc
WHO
Ad hoc
CIOMS
WHO
Ad hoc
CIOMS
WHO
WHO
CIOMS
Naranjo
Naranjo
CIOMS
CIOMS
CIOMS
DILIN
CIOMS
CIOMS
K&L
CIOMS
CIOMS
CIOMS
CIOMS
References
BfArM [23]
Denham et al. [24]
Teschke et al. [25]
Stickel et al. [26]
Schmidt et al. [27]
BfArM [28]
EMA [29]
Elinav et al. [30]
Schoepfer et al. [31]
Teschke et al. [32]
Mahady et al. [33]
Sarma et al. [34]
Teschke and Schwarzenboeck [35]
Teschke et al. [36]
Teschke [37]
Fong et al. [38]
Teschke et al. [39]
Teschke et al. [40]
Manso et al. [41]
Chau et al. [42]
Teschke et al. [43]
Teschke et al. [44]
Teschke et al. [45]
BfArM, Bundesinstitut fur Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medicinal Products in Germany); CIOMS, Council for International
Organizations of Medical Sciences; DILIN, Drug-Induced Liver Injury Network; EMA, European Medicines Agency; HILI, herb-induced liver injury; K&L, Karch and
Lasagna.
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Table 2
Hepatitis B
1/12 cases [30], 7/45 cases [42]
Hepatitis C
1/17 cases [38], 1/45 cases [42]
Hepatitis E
1/45 cases [42], 1/8 cases [31]
CMV hepatitis
1/20 cases [23], 1/26 cases [32], 1/31 cases [37]
EBV hepatitis
2/26 cases [32], 2/31 cases [37]
HSV hepatitis
1/26 cases [32], 2/4 cases [35], 1/31 cases [37]
VZV hepatitis
1/31 cases [37]
Adenovirus hepatitis
1/22 cases [40]
Giant cell hepatitis
1/10 cases [31], 1/9 cases [36]
Ischemic hepatitis
1/45 cases [42]
Mallory bodies hepatitis
1/22 cases [41]
Autoimmune hepatitis
1/20 cases [23], 1/23 cases [28], 3/31 cases [29], 3/26 cases [32],
1/4 cases [35], 4/31 cases [37], 1/22 cases [39], 1/22 cases [40],
1/13 cases [45]
LKM-positive autoimmune hepatitis
1/31 cases [37]
SMA-positive autoimmune hepatitis
1/31 cases [37]
Primary biliary cirrhosis
1/20 cases [25], 1/12 cases [30], 2/26 cases [32], 3/31 cases [37]
Overlap syndrome
2/26 cases [32], 2/31 cases [37]
Fatty liver
2/12 cases [30], 1/9 cases [36], 1/22 cases [39]
Nonalcoholic steatohepatitis
1/26 cases [32], 1/31 cases [37], 1/15 cases [44]
Nonalcoholic liver cirrhosis
1/9 cases [36]
Alcoholic liver disease
2/30 cases [24], 4/36 cases [26], 2/22 cases [39], 1/15 cases [44]
Alcoholic hepatitis: 1/31 cases [29]
Alcoholic liver cirrhosis: 1/9 cases [36]
Liver injury by comedication
DILI 6/20 cases [23], 16/30 cases [24], 9/20 cases [25], 20/36 cases [26],
20/80 cases [27], 3/23 cases [28], 2/31 cases [29], 4/26 cases [32],
3/34 cases [34], 2/9 cases [36], 8/31 cases [37], 1/22 cases [40],
2/20 cases [41], 4/45 cases [42], 3/21 cases [43], 4/15 cases [44],
8/13 cases [45]
DILI by interferon: 1/22 cases [39]
DILI by fluoxetine: 1/22 cases [39]
DILI by flupirtin: 1/22 cases [40]
DILI by roxithromycin: 1/21 cases [43]
HILI: 1/20 cases [41], 2/21 cases [43], 1/15 cases [44]
Liver abscess
1/45 cases [42]
Infection with hepatic involvement
1/9 cases [36], 8/15 cases [44], 3/13 cases [45]
Biliary diseases
Biliary disease 1/22 cases [40], 1/21 cases [43]
Biliary disease with cholecystitis: 1/21 cases [43]
Biliary tract infection, symptomatic cholecystolithiasis: 1/22 cases [40]
Cholecystolithiasis: 3/9 cases [36], 1/22 cases [40]
Cholecystitis: 1/31 cases [37], 1/45 cases [42], 1/13 cases [45]
Cholecystitis with cystic duct obstruction: 1/22 cases [40]
Cholecystitis with microcalculi in the gallbladder, choledocholithiasis
requiring endoscopic stenting, diffuse bowel inflammation: 1/21 cases [45]
Cholangitis: 1/23 cases [28], 1/31 cases [37]
Cholangitis, possibly transient choledocholithiasis: 1/13 cases [45]
Extrahepatic bile duct obstruction because of excessive hilar adenopathy:
1/21 cases [43]
Pre-existing biliary stone disease with cholecystolithiasis: 1/22 cases [40]
Pre-existing biliary stone disease: 4/21 cases [43]
Sludge in the gallbladder with cystic duct obstruction: 1/23 cases [23]
Table 2 (continued)
Pancreatitis
1/26 cases [32], 3/31 cases [37], 2/22 cases [40], 1/13 cases [45]
Pancreas carcinoma
2/45 cases [42]
Celiac disease
1/15 cases [44]
Previous gastric bypass operation
1/9 cases [36]
Cardiac hepatopathy
1/22 cases [39], 1/13 cases [45]
Hyperthyroid hepatopathy
1/26 cases [32], 1/31 case [37]
Rhabdomyolysis by statin
1/22 cases [39]
Myelodysplastic syndrome
1/31 cases [37]
Polytrauma
1/13 cases [45]
Stevens Johnson syndrome
1/31 cases [29]
Pre-existing liver diseases
2/31 cases [29], 1/26 cases [32], 1/34 cases [34], 6/9 cases [36],
1/17 cases [38], 1/22 cases [39], 1/22 cases [40], 4/15 cases [44],
2/13 cases [45]
Pre-existing liver cirrhosis
1/20 cases [23], 1/31 cases [29], 1/26 cases [32], 1/22 cases [39]
CMV, cytomegalovirus; DILI, drug-induced liver injury; EBV, Epstein-Barr virus;
HILI, herb-induced liver injury; HSV, herpes simplex virus; LKM, liver kidney
microsomes; SMA, smooth muscle antibodies; VZV, varicella zoster virus.
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Discussion
This study shows possible or likely alternative diagnoses in
278/573 cases (48.5%) of suspected HILI (Table 1);
causality assessment was impeded in 165/573 patients
(29.0%) (Table 4), resulting in diagnostic problems in
Table 3
Cases (n)
Frequency (%)
8
2
2
3
4
4
1
1
2
1
1
16
1
1
7
4
4
3
1
11
123
1
12
23
7
2
1
1
2
2
1
1
1
1
22
5
280
2.9
0.7
0.7
1.1
1.4
1.4
0.4
0.4
0.7
0.4
0.4
5.7
0.4
0.4
2.5
1.4
1.4
1.1
0.4
3.9
43.9
0.4
4.3
8.2
2.5
0.7
0.4
0.4
0.7
0.7
0.4
0.4
0.4
0.4
7.9
1.8
100
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; LKM,
liver kidney microsomes; SMA, smooth muscle antibodies; VZV, varicella zoster
virus.
Table 4
Assessability of assumed herb-induced liver injury cases of the study group (n = 573)
Parameter
Questionable liver disease
2/31 cases [29], 3/22 cases [39], 1/13 cases [45]
Lack of temporal association
1/20 cases [23], 1/23 cases [28], 3/31 cases [29], 4/26 cases [32], 2/22 cases [39]
Unassessable or poorly assessable cases
22/41 cases [23], 21/30 cases [24], 15/20 cases [25], 31/80 cases [27], 11/31 cases [29], 1/4 cases [35],
15/32 cases [38], 4/22 cases [39], 8/22 cases [40], 8/22 cases [44], 9/13 cases [45]
Slightly increased ALT: 2/22 cases [39]
Raised g-glutamyltransferase: 2/22 cases [39]
Total
1.1
11
1.9
149
26.0
166
29.0
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Acknowledgements
Conflicts of interest
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References
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