Comprehensive Research Journal of Biological Science (CRJBS) Vol.1(1) pp.

001 - 005 December, 2013

Available online http://crjournals.org/CRJBS/Index.htm
Copyright © 2013 Comprehensive Research Journals

Review

Hepatotoxicity: mini review

Saim Jamil M1, Akram M*2, Halima Nazar1, Khan Usmanghani1, Asif M. H2, Osama Alam1,
Tasneem Qureshi1, Mohiuddin E1
1
Faculty of Eastern Medicine and Surgery, Hamdard University Karachi, Pakistan
2
Department of Eastern Medicine and Surgery, Faculty of Medical and Health Sciences, The University of Poonch,
Rawalakot, Azad Jammu and Kashmir, Pakistan
Accepted 12 December, 2013

There are limited data regarding the frequency and proportionality of drug-induced hepatotoxicity.
We sought to determine the scope of drug-induced hepatitis as seen in a community-based
hepatology referral service. The present work constitutes a review of the drug induced hepatitis in
literature. We performed PUBMED, EMBASE, and CENTRAL searches for research papers of drug
induced hepatitis. Due to lack of reliable markers it is very difficult to diagnose drug-induced liver
injury. Similarly it is very difficult to differentiate between drug-induced hepatotoxicity and any
idiosyncratic reaction caused by a toxin. Complexity increases by the simultaneous use of multiple
drugs. Liver function returns to normal in most of the cases when the offending drug is stopped. The
manuscript plays an important role in the field of hepatotoxicity. This is focused review referring
different published article on this topic.

Keywords: Hepatitis, drug induced hepatitis, literature review

INTRODUCTION

Hepatotoxicity implies chemical-driven liver damage.
The term also applies to radioactive materials and drugs
of synthetic origin which may cause liver damage. The
most susceptible organ to toxicity from foreign agents is
liver, due to its major role in transforming and clearing
chemicals. Certain medicinal agents may injure the liver
when taken in therapeutic range. A lot of chemicals used
in laboratories, industries, drugs or even herbal
remedies can induce hepatotoxicity. Thus chemicals or
drugs which have the tendency to induce liver injury are
called Hepatotoxins. Medical world faces with the
serious problem of the development of safe and effective
drug in hepatitis. Modern drugs either lose effects or
cause one or another side disease of any pathway.
Drug-induced liver injury is one of the major concerns
pertaining to drug design for curative and preventive
health care function. Therefore it creates problem in the
liver in its proper function and also poses threat for its
injury leading to the manifestation of drug toxicity.
Objective of this paper is to review the published papers
on cases of hepatotoxicity.
Pathophysiology

Antituberculosis drug-induced hepatotoxicity is

Correspondence Author E-mai: makram_0451@hotmail.com presented by Jaimer and co-workers where in the age
Tel: 923343367632 greater than 35 years was the target factor for the drug-

induced hepatitis in patients who were treated with
antituberculosis. A study was conducted to determine
whether infection with either the hepatitis C virus or
human immunodeficiency virus was to be treated with
antituberculosis drugs material. The treatment of
tuberculosis in patients who were suffering with drug
induced liver injury as well as suffering from hepatitis C
and HIV. The patients with hepatitis C who were positive
and who developed drug-induced hepatitis on repeated
reintroducing of the TB drugs were offered a liver biopsy.
If inflammation that cause with hepatitis C, the sample
was presented for biopsy, treatment with interferon alpha
started and was the anti TB drugs. During the 18 month
of the study, 22 patients were found having drug induced
liver injury.
The relative risk of hepatitis C or HIV positive was
determined as fivefold and fourfold, (p <0,05). Partially,
four patients were treated with alpha-interferon and anti-
TB resurgence therapy was shown having liver injury
(Koziel and Peters, 2007). Although statins are well
tolerated medications, recent cases of autoimmune
hepatitis (AIH) associated with statins use have been
documented (Nasil, 2004). Satoshi Nakayama studied
the overlap syndrome of autoimmune hepatitis and
primary billiary cirrhosis induced by Fluvastatin. A 59-
year old man reported with liver damage, which occur 1
month after initiation of therapy with fluvastatin and
continued after stopping the drug. Although drug-
induced liver damage could have a positive antibody test
(antinuclear antibody>1/ 1280, anti-mitochondrial
antibodies M2 21 price index) point that autoimmune
liver disease is generated. Liver biopsy findings were
consistent with overlapping autoimmune hepatitis and
primary biliary cirrhosis. Treatment with prednisone and
ursodeoxycholic acid resulted in a better clinical
response. In patient the exhibition of autoimmune
hepatitis and primary biliary cirrhosis overlap syndrome
was triggered by statin one year later as the onset
(Satoshi and Naoya, 2011).
Literature review
Over the last five years, two drugs have been
withdrawn from the market which can cause severe liver
damage, potential risks that were not fully recognized
during the pre-approval clinical tests. Drug-induced
hepatic injury is the most common reason given for
withdrawal, representing more than 50 percent of cases
of acute liver failure in different countries around the
world. The recent endeavor has been directed toward a
better understanding of these facts in order to improve
results and contain drug induced liver injury (Dienstag,
2008). Acute liver failure is a rare disorder with high
mortality and resource cost (William and George, 2010).
In the developing countries, viral causes dominated by
infection with hepatitis C are recognized as a common
Akram et al. 002
cause in many countries. In the developed countries, the
incidence of virally induced disease has declined
significantly in recent years, with most cases now arising
from drug-induced liver damage, often from
paracetamol. However, results have clearly showed that
use of liver transplantation emergency (William, 2003).
A study on Ceftriaxone induces toxic hepatitis actively
in the liver system. Toxic hepatitis or drug-induced liver
injury include manifestation of clinical illness which range
from mild to moderate as well as biochemical
abnormalities in acute liver failure. There is advantage of
a long half life, wide spectrum, high tissue penetration as
well as a good safety profile of ceftriaxone which is
regarded as third generation cephalosporin. The choice
for the treatment of childhood infections which is
regarded in previous studies have shown that few cases
of high aspartate and alanine aminotransferases, with
three cases of hepatitis have been caused by
ceftriaxone. It has been brought to the notice to cite a
case of drug-induced toxic hepatitis in a patient who was
treated with ceftriaxone for acute tonsillitis (Erdal and
Eren 2009).
Schapira (1986) cited the diclofenac-induced
hepatotoxicity as of paramount importance. Clinical and
laboratory action of non-steroidal anti-inflammatory
drugs are mentioned in great detail in text.
Hepatotoxicity is one of the rare side effects of aspirin,
indomethacin, naproxen, phenylbutazone, sulindac and
other drugs. Diclofenac sodium is a potent and widely
used non-steroidal anti-inflammatory and analgesic
composite. It ranks among the strongest of this type of
medications while among the better tolerated diclofenac
metabolites excreted in urine and into bile. Experiments
displayed that the main route of drug life is different in
different species, urinary excretion is most important to
humans. The lack of enterohepatic in human being
accounts for the reduced gastrointestinal toxicity of this
drug. Side effects of liver function are very rare. Seaman
et al. has reported and these has also been verified in
experimental and are extensively cited in medical
literature. In one study, two patients developed acute
hepatotoxicity soon after initiating treatment with
diclofenac sodium.
Furthermore, HLA association of amoxicillin
clavulanate-induced hepatitis has been pinpointed.
Drug-induced hepatitis immune allergic effects of
patients are caused by the drug in clinical settings of
adverse stage of development. This could be due to
metabolic or immunologic idiosyncrasy. The presence of
an immunologic idiosyncrasy may be thought due to
HLA associated. An investigation was conducted where
in 35 patients with biopsy-documented amoxicillin-
clavulanate-induced hepatitis were clinically and
biochemically monitored. HLA-A and B were typed
using alloantisera along with 300 controls. Amoxicillin-
clavulanate-induced hepatitis associated with DRB1*
1501-DRB5 * 0101-DQB1 * 0602 haplotype yielded
003 Compr. Res. J. Biol. Sci
results that temper immune-mediated HLA class II
antigens, is found to exert its activity on the
pathogenesis of drug-induced hepatitis immunoallergic
(Marc, 1996). Minocycline as a cause of drug-induced
autoimmune hepatitis reported by (Neal and Naseer,
2000) where in clinical and liver biopsy morphological
characteristics of four patients described with
minocycline autoimmune hepatitis (group 1). Serum
laboratory values were compared with liver biopsy
findings from group 1 with those from 10 patients with
sporadic autoimmune hepatitis (group 2). All patients in
group 1 were assessed having positive serum
antinuclear antibodies, but no one observed having
positive serum anti-smooth muscle antibodies. The
morphological determination of the biopsy group 1 was
the response with those of autoimmune hepatitis in all 4
patients. However, 1 of these biopsy specimens shown
scattered eosinophils, in comparison with autoimmune
hepatitis. The mean histological activity index scores for
patients in Groups 1 and 2 was respectively, 6.7 and 5.4
and not patient in group 1 mark bridging fibrosis or
cirrhosis, compared with 4 of 10 patients in group 2.
Minocycline clinical prevention with autoimmune
hepatitis is alike autoimmune hepatitis. The absence of
eosinophils cannot be predicted as an attribute the
possibility a minocycline cause. If the drug is unmasking
latent autoimmune hepatitis then morphological
differentiation cannot be considered as diagnostic
approach.
Acute liver failure with concurrent Bupropion and
Carbimazole treatment plan has been communicated.
Bupropion is an antidepressant and has been in use as
an aid for smoking cessation. It also inhibits dopamine
neurons and norepinephrine and enhances the effect of
norepinephrine and dopamine, with no appreciable effect
on monoamine oxidase activity. Till date the studies
given in the literature reveal that bupropion is found
connected with hepatotoxicity. However case reports
are available where in the patients made a smooth
recovery during 8 weeks period after the initial
presentation by the patients. The hepatotoxicity of
carbimazole has been quite amply proved in which acute
liver failure showed concurrent treatment with
carbimazole and bupropion (Khoo and Tham, 2003).
Horng and Chia, (2011), detailed delineation on the
hepatic insufficiency by using Itraconazole as compared
with Corticosteroids treatment. Itraconazole have shown
risk of hepatotoxicity because of its low affinity for
human P-450 enzyme. Although, hepatic failure caused
by itraconazole is rather rare. The case of a 46-year old
woman was investigated who developed liver failure with
itraconazole that was administered for the treatment of
onychomycosis. Treatment with corticosteroids found
effective for itraconazole-induced hepatitis, especially in
those patients not responding to conventional treatment.
A study conducted based on Halothane-induced
hepatitis in developing countries shows that Halothane
as an anesthetic was introduced in 1950 and thus
proved its effectiveness in surgery. Two types of
halothane associated hepatotoxicity have been cited:
type 1, or mild hepatitis, related with elevated
transminase levels and self-limiting symptoms and type
2 or severe hepatotoxicity connected with acute fatal
liver failure and its fatality in many cases. Hepatotoxicity
is most likely found with the immune system, based on
many elements. The free radicals generated by
metabolism of halothane in the liver may alter cellular
proteins and introduce neo-antigens to the immune
system. These neo-antigens produce a more severe
reaction after multiple exposures. Majority cases of
hepatitis type 2 occur after repeated contact. It is
interesting to note here that new halogenated
anesthetics such as enflouranio, and desflurane are not
metabolized in the liver that led to the concern (Pieman
and Nastran, 2011). Raquel and co-workers have
worked on the genetic polymorphism of NAT2, CYP2E1
and GST enzymes and the appearance of
antituberculosis drug-induced hepatitis in tuberculosis
patients. The drug used was isoniazid which is used in
antituberculosis treatment plan is also the drug
implicated in hepatotoxicity. The differences in INH-
induced toxicity have been attributed to genetic
variability more posts as NAT2, CYP2E1, GSTM1 and
GSTT1, that code for enzymes that metabolize drugs.
The polymorphism was studied in these enzymes as
susceptibility factors in anti-TB drug-induced hepatitis
suffering patients. In a case control having active
tuberculosis participated in this clinical trial. Patients with
a history of anti-TB drug-induced acute hepatitis (cases
with up to 3 times the upper limit of normal serum
transaminases and symptoms of hepatitis) and patients
without evidence of TB effects liver function (controls)
were genotyped for NAT2, CYP2E1, GSTM1 and
GSTT1 polymorphism. With slow onset having a higher
incidence of hepatitis from intermediate/rapid acetylators
[22% (18/82) versus 9,8% (6/61), odds ratio (OR),2,86,
95% confidence interval (CI), 1,06 – 7,68, p= 0,04).
Logistic regression showed that the slow acetylation
status was the independent risk factor (OR 3.59, 95%
CI, 2,53 4, 64, p=0,02) for the appearance of anti-
tuberculosis drug-induced hepatitis during treatment for
TB with INH systems containing patients (Raquel and
Renata, 2011). Ashima (2010), have put forward a study
to deal with autoimmune hepatitis diagnosis and
treatment in order to make it easy for the health officials
to differentiate between autoimmune or drug-induced
hepatitis. Autoimmune hepatitis is an acute inflammatory
natured position by inflammation around the gate,
elevated immunoglobulins, auto-antibodies, and
response to immunosuppressant. One environmental
factor (tropical) is assumed to cause immune-mediated
attack against liver antigens in genetically predisposed
individuals. A variety of clinical presentations have been
observed ranging from chronic indolent disease to

fulminant hepatic failure, and diagnosis requires the
exclusion of other causes of liver disease. Treatment
with corticosteroids should be executed promptly.
Treatment decision is usually complicated by the diverse
clinical manifestations and its clinical efficacy plan for
multitude immunosuppressive agents. Achieving normal
liver test and tissue is the ideal indicator for treatment
point. Compensated patients may benefit from liver
transplantation. Long-term prognosis is excellent, with
early and aggressive initiation of therapy. The research
work carried out on autoimmune hepatitis gives detailed
clinical findings of the risk factors, immune-
pathogenesis, diagnostic parameter, treatment with in
pregnancy, and long term effects on cirrhosis and
hepato-cellular carcinoma in patients (Jou and Muir,
2008). The differentiation between drug-induced
hepatitis, drug-induced autoimmunity or classical
autoimmune hepatitis was the subject that was
presented by Altintas et al. It was the subject of the
debate that Dydrogesterone which is natural
progesterone for women has been utilized in
gynecological complaints and disorders. But the
dydrogesterone-induced hepatotoxicity and
dydrogesterone-induced hemolytic anemia has been
dealt extensively in literature findings. The authors have
proposed a case of hepatitis and warm antibody
hemolytic anemia due to dydrogestrone and given its
assessment for the possible differentiation in the
diagnosis of hepatitis induction and drug induced
immunity (Altintas, 2004).
Kazuto (2008), have cited a default study and
furnished the practical guidelines to combat drug-
induced liver injury. The range of the drug induced liver
injury is both diverse and complex in its onset on liver
function. Neil Kaplawitz has given detailed description on
drug-induced liver injury. The predominant clinical
picture is acute hepatitis or cholestasis with clinical
pathological parameter of acute or chronic liver disease
appears as a core commitant outcome. The
pathogenesis of drug-induced liver disease involves the
participation of the parent drug or metabolite that either
directly affects the biochemistry of cells or to elicit an
immune response. Each hepatotoxin is associated with a
distinctive signature on the pattern of loss and latency.
Unpredictable, low frequency, reactions occur in the
background by a higher rate of mild asymptomatic liver
injury and these are difficult to detect by monitoring
serum alanine aminotransferase levels. The
investigation on development in toxicogenomics and
proteomics could improve the determination of risk
factors and exploration of idiosyncratic hepatotoxicity
(Neil, 2011).
The recent view of research undertaken on drug-
induced liver injury describe that liver metabolizes
foreign substances and also functionally insert between
site of absorption and systemic circulation (Tainin,
2008). These parameters fulfill the liver with the
Akram et al. 004
detoxification of foreign material but also become a
target for toxicity. More than 1000 drugs are utilized with
idiosyncratic hepatotoxocoty and drug-induced liver
injury. This has created an awareness as well as point
for removing viable drugs from the market. Drug-induced
hepatotoxicity involved in half of cases of acute liver
failure, with paracetamol as the main factor responsible
for the violation. The liver damage caused by the drug in
2.3% of patients hospitalized for jaundice. However,
drugs used in drug-induced toxicity could not be figured
out because of the difficulty in diagnosis and the low
frequency of furnishing the data on pharmacovigilance.
Therefore drug-induced toxicity represents a clinical
challenge due to the large number of reported
hepatotoxic drugs in use, the wide range of liver damage
because of absence of clinical findings and the diagnosis
on the effect on liver. Therefore the assessment of drug-
induced liver injury should be the first priority while
developing dosage form design (Ryder, 2008).
Drug-induced liver injury is a growing problem along
with complication of drugs prescribed, because the liver
is for the metabolic disposal of drugs and foreign
material. Although drugs are supposed to metabolize
without damage, the liver damage has been constantly
observed an adverse event. Drugs produce metabolites
causing liver damage in a single dose fashion. Most drug
material is a toxic byproduct only in rare individuals.
Injury to hepatocytes results either directly by the
disruption of intracellular function or membrane integrity
or indirectly by immune-mediated membrane damage.
Genetic alterations in enzymes harmful metabolite
competition in drugs, and depletion of substrates
required to detoxify the metabolite in the liver so that it
can be prevented. Drug-induced hepatotoxicity clearly
spelled out the withdrawal of many drugs that produced
severe liver damage, a potential risk that was not
recognized in the pre-approval clinical trials. Drug-
induced liver injury is the leading cause for more than 50
percent of cases of acute liver failure. More than 75
percent of cases of idiosyncratic drug reactions have
given way to option for liver transplantation that has lead
to death in some cases. In order to improve the drug not
to resort to drug-induced liver damage the pathogenesis
of drug-induced liver damage, common adverse drug
reactions is to be understood in a better experimental
and clinical findings and this should be monitored
exclusively to check the types of malaise (William,
1995).
Mechanism of drug-induced liver injury is the choice of
research in many findings and has depicted the
idiosyncratic nature and poor prognosis of drug-induced
liver damage exhibit drug reaction and safety and the
cause of withdrawal of drugs. Drug-induced toxicity is
generated by direct hepatotoxic effects of a drug or its
metabolites. Parenchymal cell damage create the
activation of innate and / or adaptive immune cells,
which combat inflammatory and tissue hepatotoxic
005 Compr. Res. J. Biol. Sci
mediators and propel immune responses against drug-
related antigens. Understanding the molecular and
cellular components with different mechanisms can
identify risk factors and eventually develop of a working
methodology to predict and prevent drug-induced liver
injury (Michael and Cynthia, 2006).
Diagnosis
The first step in diagnosis of drug-induced liver injury is a
suspicion based on careful consideration of recent
comprehensive reports on the disease. There are some
cases where the suspicion of drug-induced liver injury is
particularly strong. Exclusion of other possible causes,
according to the model of the liver injury is necessary for
diagnosis.
Management
Early management of drug-induced liver injury will mean
immediate removal of the used drug suspected to be
responsible, in accordance with serum level of Alanine
aminotransferase, Alkaline phosphates, and total
Bilirubin (Sjogren and Cheatham, 2010).
CONCLUSION
Fulminant liver failure by drug-induced hepatotoxicity
may require liver transplant. Drugs mostly associated
with drug-induced liver injury include paracetamol, non-
steroidal anti-inflammatory drugs, antibiotics,
immunosuppressants and psychiatric drugs. Articles
used in this study showed that the major cause of drug-
induced hepatotoxicity was due to paracetamol, drug
induced toxicity required liver transplants or withdrawal
from the drug known to have caused the effects.
Conflict of interest declaration
There is no conflict of among authors
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