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Review Article


                                 CONVENTIONAL DRUGS AND HERBAL
                                MEDICINES-INDUCED HEPATOTOXICITY

                 Kamal E. H. EL-Tahir 1*, Othman A. Gubara 2 and AbdulRahman M. Ageel1



            ‫ُزٍ الوشاجعة جِذف إلٔ جٌْٗش كل هي األطباء ّالص٘ادلة ّجو٘ع العاهل٘ي فٖ الوِي الطب٘ةة نةي رةذسع عةط األدّٗةة‬
            ‫الوش٘ذع هعول٘ا ّالوصٌعة هي عط الٌباجات الطب٘ة الوحْاجةذع فةٖ األاةْاأ الةصاد نة٘ذمً٘ة هوحةاصع ّٗةحن ااةحعوالِا‬
            ٍ‫فٖ الدًا ّالبالد األخشٓ صثشع. ّجبذأ ُزٍ الوشاجعة إنطاء القاسئ فصشع ني اًحشاس الحسووات الصبذٗة الوحذثة ِةز‬
                                                                                                ‫ا‬
            ‫األدّٗة فٖ عط األرطاس ثن جعطٖ ّنفً ني هخحلف ّظائف الصبذ ّهي ثن جحةْلٔ هٌارشةة يل٘ةات فعةل عةط األدّٗةة‬
            ‫ّالٌباجات الطب٘ة ّالزٕ هي خاللَ جقْم ُزٍ الص٘واّٗةات حفةض ّإاةذاخ جسةون كبةذٕ جحسسةٖ ّإصناجةات أخةشٓ هثةل‬
            ‫داء الصفشاء ّالحِا ات الصبذ الحب٘ب٘ة ّالحشةحن الفسةفْسٕ ّالحِا ةات الصبةذ الذٌُ٘ةة ّالحل٘ةف ّالحشةوع الصبةذٕ ّاألّسام‬
            ‫الخب٘ثة. اُحوث ُزٍ الوشاجعة إنطاء أهثلة هحعذدع لألدّٗة الوش٘ذع هعول٘ةا ّللٌباجةات الطب٘ةة رات القةذسع نلةٔ إاةذاخ‬
            ‫ًةْ أّ أًةْا هحعةذدع هةةي الحسةووات الصبذٗةة. ّنٌةذ ركةةش الٌباجةات الطب٘ةة جةن ركةةش األاةواء الالجٌ٘٘ةة ّالحجاسٗةة للٌبةةات‬
            .‫ّنائلحةةَ الٌباج٘ةةة ّااةةحعوامجَ الطب٘ةةة ّالوصًْةةات الفعالةةة فةةٖ الٌبةةات الوس ة ْلة نةةي إاةةذاخ ّافةةض الحسةةووات الصبذٗةةة‬
            ‫ّألةةاست ُةةزٍ الوشاجعةةة أٗ ةةا إلةةٔ الطةةشأ الوحبعةةة الوحةةْفشع لحشةةخ٘ أاةةبا الحسةةون الصبةةذٕ ّاكهصاًةةات الوحااةةة‬
            ‫لعالجَ. ّجلفث ُزٍ الوشاجعة الوصغشع امًحباٍ إلٔ أى احب ّهٌع جةذاّد ُةزٍ األدّٗةة ّالٌباجةات الطب٘ةةت ّالحةٖ لةذِٗا‬
            ٍ‫القذسع نلٔ إاذاخ جسووات كبذٗة هي الحسج٘ل الص٘ذلٖت م ٗع٘ق هس٘شع نالج األهشاض الحٖ جسحعول هي أجلِةا ُةز‬
                                                                                                                  .‫األدّٗة ّالٌباجات الطب٘ة‬


            This review deals mainly with enlightening physicians, pharmacists and all those who are
            involved in the medical field with the abilities of various synthetic drugs and medicinal plants-
            that are formulated in various elegant pharmaceutical forms-that are circulating in both our own
            countries and abroad. It initially gives an idea about the prevalence of drugs-induced
            hepatotoxicity in some countries and then it describes the various physiological functions of the
            liver. It also discusses the various mechanisms through which chemicals induce toxic and allergic
            hepatotoxicity and other disturbances such as cholestasis, granulomatous hepatitis,
            phospholipidosis, steatohepatitis, fibrosis, cirrhosis and tumors. For each of these diseases
            numerous examples of synthetic drugs and medicinal plants are given. With regard to medicinal
            plants, the Latin and Trade names, botanical families, uses and active constituents responsible for
            the induction of the hepatotoxicity are also given. The possible methods available for diagnosis
            and treatment of such diseases are given. The review then draws the attention to the fact that
            withdrawal of these drugs and medicinal plants from the pharmaceutical register does not limit
            the effective treatments of the various diseases for which these chemicals are indicated.

                         Introduction                                           storage of vitamins, minerals and regulation of blood
                                                                                glucose. It consists of four main types of cells. The
    The liver performs numerous functions including                             hepatocytes are the biosynthetic engines of the liver.
bile formation and secretion, synthesis of a range of                           Their important Golgi system and rough
proteins including clotting factors, detoxification of                          endoplasmic reticulum allow them to synthesize and
drugs, xenobiotics and endogenous compounds,                                    secrete an array of proteins and metabolic enzymes.
                                                                                The endothelial cells line the sinusoids and serve as
1*
 Department of Pharmacology, College of Pharmacy, King Saud                     a barrier between the blood and hepatocytes. Two
University, Riyadh, Kingdom of Saudi Arabia. 2Department of                     additional cell types line the sinusoids: They include
Clinical Pharmacy, College of Pharmacy, King Saud University,                   Kupffer’s cells, which are capable of removing and
Riyadh, Kingdom of Saudi Arabia.                                                phagocytizing old and defective blood cells, bacteria
*To whom correspondence should be addressed.                                    and other foreign materials, and Stellati cells, which

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CONVENTIONAL DRUGS AND HERBAL MEDICINES-INDUCED HEPATOTOXICITY                                               129

store fat and vitamin A (1).                                and hydrolysis) mediated by various cytochrome
     According to literature surveys several drugs          P450 isozymes, and/or phase II conjugation (i.e.
have been implicated in cases of hepatic injury (2).        glucuronidation,    acetylation,    sulphation and
Among the therapeutic classes most often involved           methylation), mediated by a variety of transferases.
in hepatotoxicity are neurological drugs, followed by       For highly polar drugs such metabolism is
cardiovascular drugs, antibacterial drugs and those         unnecessary. Some drugs may break down
affecting metabolism and musculoskeletal system             spontaneously. In most instances, metabolites
(3).                                                        generated by means of these reactions are either
     Reports in the literature showed that incidences       pharmacologically inactive or highly reactive. Based
of hepatotoxicity associated with drug use accounted        on their chemical character these metabolites may
for 10.7% in USA (4), 2.85% in United Kingdom               bind covalently to cellular macromolecules resulting
(5), 4.2% New Zeland (6) and 9.7% in France (3).            in the formation of toxic oxygen species or react
Nowadays complementary alternative medicine is              with membrane lipids to form lipid peroxides (9).
increasingly used in various parts of the word. It              Other metabolic pathways for biotransformation
includes dietary, nutritional and life styles changes       of many compounds involve glutathione and
together with a separately mind and body control            possibly other antioxidants (e.g. vitamin E and
measures, cauterization, manual healing and                 ascorbic acid). Glutathione is a thiol-containing
biological treatments with animal, sea and herbal           tripeptide capable of binding to potentially harmful
products. The latter are produced in various                electrophillic compounds through glutathione-s-
pharmaceutical forms including pills, capsules,             transferase, and thus plays an important role in
tablets, powders, syrups and suppositories. Of all the      protecting the cell from these toxic species (10).
alternative medicines, herbal products are gaining          Likewise, altered pharmacokinetics variables
wide spread popularity for two reasons. Firstly, their      resulting from genetic influences, sex, age, and other
production and presentation to the public in elegant        conditions such as diabetic, hepatic and renal
pharmaceutical forms that resemble the synthetic            diseases may influence the metabolic outcomes, and
and well-studied pharmaceutical products, and               predispose patients to toxic reactions to many drugs
secondly to the purported mistaken belief that herbal       (11-13). Multiple factors are also often implicated,
medicines are natural and bear no harm or toxicity to       the most frequently being enzyme induction.
the human body. However, it should always be                Common inducing agents of certain P450 enzymes
remembered that some herbal therapies are really            include phenobarbital, phenytoin, rifampicin as well
toxic and can induce hepatotoxicity or even death. It       as cigarette smoking.
should be noted that, for instance, in Asiatic
countries, where some statistics are reported, herbal       Pathogenesis of hepatotoxicity:
medicines-induced hepatotoxicity reached 30% of all            Drug or herbal medicines-induced hepatic
reported drug-induced liver diseases (7). This review       damage is divided into several types that include:
will present some evidence regarding this aspect.
                                                            a. Toxic hepatic damage:
Biotransformation of drugs in the liver:                        This type of damage is initiated via the
    The liver’s unique metabolism makes it an               interaction of the drug or the active component(s) of
important target of the toxicity of drugs and               the herb with hepatic cytochrome P450 enzymes to
xenobiotics. Most of these compounds enter the              produce electrophilic molecules or oxygen radicals
body through the gastrointestinal tract with minority       that interact with the hepatic cells membranes and/or
absorbed directly through the lung or skin or by            enzymes leading to the damage and necrosis of the
parenteral route. The greater part of drugs and             hepatocytes (10,14). In addition, the drug may act to
xenobiotics are lipophillic, and can easily cross the       elevate the intracellular Ca2+ concentration resulting
membrane of intestinal and the hepatocyte cells.            in damage of the hepatic mitochondria and the
Drugs are rendered more hydrophilic by enzymatic            membranes integrity (10).
action in the hepatocyte, yielding water-soluble                The classical example of such hepatic damage is
products that are excreted in the urine or bile (8).        that produced by high doses of paracetamol
The pathways of drug metabolism can be classified           (acetaminophen) (15). The normal metabolism of the
as either phase I reactions (i.e. oxidation, reduction      therapeutic doses of paracetamol involves sulphate



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130                                                                                             ELTAHIR ET AL

conjugation via glutathione and excretion in the            cells that initiate the immune response that involves
urine (16). However, following acute or chronic             both humoral and cellular immunities. The produced
consumption of high doses of paracetamol, the               antibodies then bind to the membranes of the
normal conjugation pathway is exhausted due to the          hepatocytes. The antigen antibody reaction then
depletion of glutathione and another cytochrome             results in hepatic damage that is accompanied by
P450-pathway operates to produce a toxic highly             skin rash, urticaria, fever, gastrointestinal upset,
reactive metabolite N-acetyl-p-benzoquinoneimine            jaundice and hepatomegaly (10,36).
(NABQI). The latter interacts covalently with                   Several drugs are shown to induce allergic
protein molecules in the hepatocytes leading to cell        hepatic damage. These include the combination of
degeneration and death (15-17). Paracetamol-                amoxicillin-clavulanate (42), sulphonamides (42),
induced hepatotoxicity is characterized by very high        diphenylhydantoin (44) and the anti HIV-I drug
elevation of blood alanine and aspartate                    nevirapine (45,46).
aminotransferases levels- over 3500 I.U per liter               With regard to herbal medicines some plants
(18). Other symptoms include severe hepatocytes             have been shown to induce their hepatotoxicity via
damage, metabolic acidosis, renal insufficiency and         this allergic reaction. These include Iillicium
damage, coma, thrombocytopenia and pancreatitis             lanceolatum (or Mang Cao), Lycopodium serratum
(19,20). Such type of hepatotoxicity is aggravated by       (or Jin Bu Huan), Tripterygium wilfordii and the
concomitant use of phenytoin, isoniazid, starvation         Germander herb Teucrium chamaedrys (30,31,37,
or chronic alcohol consumption (19,20). The                 38). (For constituents and use see also Table-1)
standard antidote for such hepatoxicity is N-
acetylcysteine which is highly effective in                 c. Idiosyncratic Hepatotoxicity:
replenishing the depleted glutathione stores and                Some of the well established drugs have been
preventing further hepatic injury even when                 reported to induce non-allergic hepatotoxicity that
administered 10 hours following paracetamol                 is unpredictable. It is believed to result from
ingestion (16,21). Similar glutathione depletion-           metabolic aberrations. The reaction latent period
induced hepatotoxicity is observed following                takes from weeks up to months following use of the
excessive consumption of mescaline and cocaine              drug. It can be differentiated from allergic
(22). Other drugs that are shown to induce toxic            hepatotoxicity by the absence of fever, rash or
hepatic damage included the selective serotonin             eosinophilia. Some of the drugs that have been
reuptake inhibitor and antidepressant citalopram (23,       shown to induce such hepatotoxicity are: isoniazid,
24), the macrolide erythromycin analogue                    valporic acid, ketoconazole, methyldopa and
roxithromycin (25,26) and the anthraquinone                 diclofenac (47,48). No reports concerning medicinal
laxatives (27).                                             herbs are revealed.
    With regard to the herbal medicines, many plants
have been shown to induce toxic hepatic damage.             d. Hepatic cholestasis:
Table 1 depicts some of the most famous plants that             As mentioned above, one of the liver functions is
are available as herbal medicines in various                synthesis of bile salts and their passage into the gall
pharmaceutical forms. The Table also shows the              bladder to be secreted into the duodenum. These
generic and Latin names of the plant, its active            comprise the salts of the primary bile acids such as
constituents and its purported uses.                        cholic and chenodeoxy cholic acids which are
                                                            conjugated with glycine or taurine and from which
b. Allergic hepatic damage:                                 the secondary bile acids such as deoxycholic acid,
    Allergic hepatic damage is usually caused by the        lithocholic acid and urosedeoxycholic acid are
antigen formed via the combination of a hapten of           formed by the action of the resident bacteria (49).
the drug or the active constituent of a herb with a         Some drugs have the ability to interrupt bile flow
specific liver protein (10,36). The efficacy of such        and secretion from the hepatocytes into the gall
combination to culminate in an active antigen               bladder via binding of the bile salts in the liver or by
depends upon the human leukocyte antigen (HLA)              interaction with the bile salts transporting proteins.
configuration which is genetically determined (42,          This results in the accumulation of the bile inside the
43). The newly formed antigen is then processed by          liver with the concomitant cholestasis and
the human macrophages and presented to the CD4              appearance of high level of bilirubin in the blood and



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CONVENTIONAL DRUGS AND HERBAL MEDICINES-INDUCED HEPATOTOXICITY                                                    131

precipitation of jaundice (10,36). The hepatocytes                  Many synthetic widely used drugs are known for
are usually undamaged. However, if such cholestasis            their ability to induce hepatic cholestasis of the non-
is accompanied by failure of canalicular and other             mixed type. These include chlorpromazine, hydro-
intracellular processes, the toxic bile acids will             chlorothiazide, tenoxicam, estrogens, erythromycin,
accumulate within the hepatocytes leading to their             ibuprofen, captopril, prochlorperazine, clarithro-
damage. The damage may also extend to the bile                 mycin, ticlopidine, terfenadine, amoxicillin-
ducts (50). Thus, mixed hepatotoxicty can ensue                clavulanate, co-trimoxazole, tetrahydrocanabinol and
(10). In normal hepatic cholestasis, the patient               parenteral nutrition (16,22,51,51-54), metformin
suffers from jaundice together with fever, skin rash           (55), cyproterone (56), pravastatin (57,58).
and arthralgia with an elevation of ALT enzyme and             However, both lovastatin (59) and atrovastatin (60,
prolongation of prothrombin time. In the mixed                 61) induce toxic acute hepatitis. Drug-induced mixed
hepatotoxicity     one    can    observe      capillary        hepatic damage is observed following use of
cholangiectasis, reduction in microvilli, formation of         metformin, carbamaze-pine, cyclosporine, amoxi-
microbiliary thrombosis, liver cells degeneration,             cillin-clavulanate, fenofibrate and methimazole (9,
necrosis and bile sedimentation (10).                          10).


Table 1: Medicinal plants that induce toxic liver damage.

 Generic or           Latin name          Botanical              Constituents          Purported uses       Reference
 Trade names                              family
 Milkwort; Da        Polygala             Polygalaceae      Chinensin, chnensina       Sedative.             (28,29)
 gin niu cao.        chinensis                              pathol
 Germander           Teucrium             Labiatae          Iridoid glycosides:        Antiobesity           (30,31)
                     chamaedrys                             furanoditerpenoids,
                                                            Celerodane,
                                                            Neocelerodane,
                                                            Phenylpropanoids,
                                                            Teucrin A
 Kava tubers         Piper                Piperaceae        Kava pyrones, Kavaine      Antianxiety           (32,33)
                     methysticum                            alkaloids                  Antipsychotic
 Impila              Callilepsis          Asteraceae        Atracytoloside;            Anthelmentic           (34)
                     laureola                               Carboxyatracytoloside      Antitussive
                                                                                       Antiimpotence
 Comfrey             Symphytum            Boraginaceae      Pyrrolizidine alkaloids:   Antigastrointes-       (35)
                     officinale                             Symphytine;                tinalailments
                                                            Intermedine, Echimidine,
                                                            symglandine
 Colts foot          Tussilago            Asteraceae        Pyrrolizidine alkaloids:   Treatment of lung      (36)
                     farfara                                Senkirkine; Senecionine    and       gastric
                                                                                       diseases
 Lycopodii           Lycopodium           Lycopodiaceae     Tetrahydropalmatine        Analgesic              (37)
 herb, Jin Bu        serratum
 Huan


 Tripterygium        Tripterygium         Celasteraceae     Wilforgine; Triptolide     Male                   (38)
 Roots, leaves       wilfordii                                                         contraceptive
 and flowers
 Polygonum           Polygonum            Polygonaceae      Anthraquinones             Treatment of          (39-41)
 herb; Shou Wu       multiflorum                                                       prostate cancer,
 Pian                                                                                  hair loss and re-
                                                                                       blackening of gray
                                                                                       hair


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132                                                                                                  ELTAHIR ET AL



Table 2. Medicinal plants that induce cholestatic hepatitis.

 Generic or            Latin name                Botanical           Constituents      Purported uses      References
 Trade names                                     family
 Chaparral leaves;     Larrea tridenta;          Zygophyllaceae      Nordihydro-       Anti-psoriasis;       (63-65)
 Creosote bush         (Larrea divaricata                            guaiaretic acid   Anti-amoebic;
                       Covillea tridentate)                                            Diuretic;
                                                                                       Antioxidant
 Cascara               Rhamnus purshiana         Rhamnaceae          Free              Laxative               (66)
                                                                     Anthraquinones,
                                                                     anthraquinone
                                                                     glycosides
 Rhubarb               Rheum cultorum            Polygonaceeae       Anthraquinones    Laxative               (67)
 Senna leaves          Cassia senna              Fabaceae            Anthraquinone     Laxative               (68)
                                                                     glycosides
                                                                     (Sennosides A
                                                                     and B)
 Polygonum             Polygonum                 Polygonaceae        Anthraquinones    Treatment of          (39-41)
 Shou Wu Pian          multiflorum                                                     prostate cancer


Table 3. Medicinal plants that induce mixed hepatic necrosis and cholestatic hepatitis.

  Generic or Trade            Latin name          Botonical           Constituents     Purported uses       References
  names                                           family
  Kava Ka tubers              Piper               Piperaceae           Alkaloids       Antianxiety,           (32,33)
                              methysticum                             (Kavaine)        Antipsychotic
  Coutarea herb               Coutarea            Rubiaceae                            Treatment of            (69)
  Copalchi, Copaltra          latiflora                                                diabetes mellitus
                                                                                       Type II
  Ephedra, Ma-Huang           Ephedra sinica      Ephedraceae         Ephedrine &      Anorexigenic to        (70,71)
                                                                      related          decrease body
                                                                      alkaloids        weight; Treatment
                                                                                       of asthma
  Polygonum                   Polygonum           Polygonaceae        Anthraquinones   Treatment of          (39-41)
  Shou Wu Pian                multiflorum                                              prostate cancer
  Aristolochia                Aristolochia        Aristolochiaceae    Aristolochic     Abortificient           (72)
                              bracteata                               acid
                                                                      Magnoflorine



   With regard to medicinal herbs several plants                  changes in the hepatic parenchyma and the portal
have been implicated in the induction of cholestatic              region. There are small rounded foci of epitheloid
hepatitis. These are shown in Table 2. Others have                cells and round cells with multi-nucleated giant cells
been shown to induce mixed hepatic damage                         which may be surrounded by eosinophils. It may be
necrosis and cholestasis. Some of these are shown in              accompanied by low grade fever and chronic fatigue.
Table 3. In contrast some plants can suppress or treat            These symptoms are also present in cases of
cholestatic hepatitis. An example of these is                     sarcoidosis and tuberclosis (73). It is now known
Balanitis aegyptica bark extract (62).                            that chronic use of various drugs induces this type of
                                                                  hepatotoxicity. These include: ticlopidine (74),
e. Granulomatous Hepatitis:                                       allopurinol (75), carbamazepine (76,77), aspirin
    Granulomatous hepatitis is characterized by                   (78), paracetamol (79), dicloxacillin (80),
infiltration of inflammatory cells and granulomatous              glibenclamide (81), rosiglitazone (82), norfloxacin


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CONVENTIONAL DRUGS AND HERBAL MEDICINES-INDUCED HEPATOTOXICITY                                               133

(83), nitrofurantoin (84), procainamide (85),               no reports about medicinal plants causing this
mebendazole (86), methimazole (87), phenytoin               hepatic disturbance.
(88), hydralazine (89), diltiazem (90), methyldopa
(91), sulfonamides (92), and amoxicillin-clavulanic         h. Non- Alcoholic Steatohepatitis:
acid (93).                                                      Non- alcoholic steatohepatitis is usually
    With regard to the natural products it has been         described as fatty liver with inflammation and
reported that intake of quinine (94) and quinidine          necrosis in absence of alcohol consumption. It is
(95) or consumption of ground and squeezed young            believed to be due to excessive release of free fatty
leaves of barley used as a supplementary nutrient           acids released from the accumulated hepatic
under the generic name “Green juice “ induced               triglycerides. It is accompanied by a decrease in S-
granulomatous hepatitis with excessive elevation in         adenosyl methionine that protects the liver against
both AST and ALT enzymes (96)                               fatty degeneration (103,104). It is accompanied by
.                                                           an elevation in hepatic aminotransferases and
f. Hepatic Veno-occlusive disease:                          hepatomegaly and may predispose to liver fibrosis
    Hepatic Veno-occlusive disease results from             and cirrhosis (105,106). It is usually observed in
closure or obliteration of the small intrahepatic veins     patients with obesity, diabetes mellitus type 2 or
by loose connective tissues in absence of thrombi. It       hyperlipidemias and mostly in patients with insulin
is a progressive disease that leads to massive              resistance (104). Various drugs have been shown to
hepatocellular necrosis (97). It is usually observed as     induce this disease. These include: amineptine and
hepatomegaly, ascites, jaundice and weight gain             valproate (107); olanzapine and risperidone (108);
(97).                                                       tamoxifen (109), corticosteroids [prednisolone (110)
    With regard to drugs it is usually induced by           and methylprednisolone (111)], amiodarone (106),
high doses of some anticancer drugs such as                 zidovudine (112), didanosine (2, 3-dideoxyinosine)
azathioprine, cyclophosphamide, thioguanine and             (113) and high doses of tetracycline and aspirin
combination of cis-platinum-cyclophosphamide and            (106) and parenteral nutrition (53). There are no
dicarbazine (98).                                           reports for herbal medicines, to induce this
    Concerning the medicinal herbs, two of them             condition.
have been reported to induce hepatic venooclussive
disease. The first is the herbal medicine which is          i. Liver Fibrosis and Cirrhosis:
known as “Black Cohosh” which composed of an                     Some drugs have been shown to induce direct
infusion of the herbs Heliotropium, Senecio and             liver fibrosis and cirrhosis without inducing any
Crotalaria species. The major constituents of these         elevation in hepatic aminotransferases or blood
herbs are pyrrolizidine alkaloids (99). The second          bilirubin. However, portal hypertension may be
one is the medicinal tea which is known in trade as         precipitated. These include high doses of
the Jamaican “Bush Tea”. It is composed of an               methotrexate (114), methyldopa (115), and vitamin
infusion of the medicinal herb Comfrey that is              A (116).
claimed to be an effective treatment for                         With regard to plants, however, various plants
gastrointestinal pain (100). It is known by the Latin       that belong to the genus Senecio, family Asteraceae
name Symphytum officinale and contains various              e.g. Senecio aureus, S. bicolor and S. vulgaris have
pyrrolizidine alkaloids such as symphytine,                 been observed to induce liver cirrhosis (117).
intermedine, echimidine and symglandin (35).
                                                            j. Liver Tumors:
g. Hepatic phospholipidosis:                                    Sporadic reports point to the involvement of
    Phospholipidosis is a minor hepatic disease that        some drugs in inducing hepatic carcinogenicity but
is induced by some amphophillic drugs that have a           there is controversy in this aspect. The accused drugs
tendency to accumulate within the lyposomes and             are methotrexate (118), cyclosporine (119) and
interact with their phospholipids resulting in              nitrofurantoin (120). However, in herbal medicines
suppression of lysosomal function. It also induces          most of the plants that contain pyrrolizidine
hepatomegaly (101). Amiodrone is one of the drugs           alkaloids e.g. heliotrine and indicine have been
known to induce such disturbance (102). There are           positively linked with induction of hepatic cancer.




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134                                                                                            ELTAHIR ET AL

These include those herbs that belong to the genus             vii. Anti-mitochondrial
Heliotropium, family Boraginaceae such as                      Besides these, the presence or absence of
Heliotropium araborescens, H. popvii, H.                       hepatitis B surface antigen and hepatitis C RNA
lasiocarpium, H. eichwaldii, H. indicum and H.                 should be examined.
bacciferum (121) and those plants that belong to the        f- Performance of ultra-sound guided percutaneous
genus Senecio, family Asteraceae which are                     liver biopsy.
medicinally used for inducing diuresis and                  g- If possible the response to re-challenge with
diaphoresis. Such as Senecio aureus, S. bicolor, S.             the suspected drug should be performed.
jacobaco, S. vulgaris, S. douglasii and S. dofonicum.
This Senecio genus of herbs contains various                           Treatment of Hepatotoxicity
pyrrolizidine alkaloids such as senecionine,
riddeline, retrorsine, floridanine, monocrotaline and           Generally there is no established treatment for
otosenine (121). Other medicinal plants that also           drugs- or herbs-induced hepatotoxicity. The best that
induce liver cancer include Aristolochia bracteata          can be done is the withdrawal of the offending drug
that belongs to the botanical family Aristolochiaceae       or herb. Beside these, it can be pointed that some
and contains aristolochic acid and magnoflorine             benefits have been observed with corticosteroids in
(72). Others are Lingularia dentate, L. intermedia,         allergic hepatotoxicity (10) and with betaine (103),
Crotalaria albida and C. tetragona which belong to          clofibrate and ursodeoxycholic acid (122,123) and
the botanical family Asteraceae (121).                      metformin (124,125) for non-alcoholic steatohe-
                                                            patitis. Of all of drugs-induced hepatotoxicities, the
            Diagnosis of the hepatotoxicity                 only one that can be effectively treated is that of
                                                            paracetamol via use of N-acetylcysteine (16, 21).
   The initial steps in diagnosis of the drugs and
medicinal herbs-induced hepatic damages are (96,                           Concluding Remarks
103):
a- Thorough grasping of the patient's medical                   This review clearly attempted to reveal the
   history that include the types of drugs and/or           seriousness of the problems of drugs and herbal
   herbal medicines used together with their doses          medicines-induced hepatotoxicity and pin pointed
   frequency and duration of their use.                     the limitations of its treatment. Thus, it remains for
b- The medical health of the patient should be              the health authorities in various countries to re-
   considered.                                              consider the registration of all those drugs and all
c- Various biochemical parameters should be                 approved medicinal herbs that have been shown in
   measured. These include measurement of blood             this review and others to induce or even predispose
   levels of bilirubin, hepatic transaminases e.g.          to hepatotoxicity. All of the medications mentioned
   aspartate aminotransferase (AST) and alanine             in this review are not unique. Several of their better
   aminotranferase (ALT) together with γ-glutamyl           substitutes are already registered in various parts of
   transpeptidase     and    alkaline   phosphatase         the world. Thus care must be taken when these drugs
   enzymes.                                                 are used for long times. This should be under the
d- All diseases known to induce hepatotoxicity              direction of physicians with careful monitoring of
   similar to drugs and medicinal herbs-induced             liver function.
   hepatotoxicity such as sarcoidosis and tuberculo-            On a broad basis we as drug informers we have
   sis should be excluded.                                  to enlighten the public with the real facts that
e- Performance of serological tests to check the            medicinal herbs do contain both harmful and
   presence and absence of the following anti-              beneficial chemicals but unfortunately some of them
   bodies:                                                  are not well studied, regarding their toxicities and
   i. IgM antihepatitis A virus                             useful doses. Thus we have to advice all those
   ii. Antihepatitis B/and C viruses                        patients who suffer from hepatic renal and
   iii. IgM anticytomegalovirus                             cardiovascular diseases to avoid the use of not well
   iv. IgM anti Epstein-Bar virus capsid antigen            studied herbs and all those which are not clearly
   v. Herpes simplex virus                                  labeled for their active constituents, accurate doses
   vi. Anti-nuclear                                         and uses.



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CONVENTIONAL DRUGS AND HERBAL MEDICINES-INDUCED HEPATOTOXICITY                                                                 135

                        References                                 22.   ElTahir KEH. Narcotics and Mind-manifesting drugs.
                                                                         Alfrazdag Publishing Co. Riyadh, 2002, pp 70-90.
                                                                   23.   Fredriscon OK and Svendsen O. Hepatotoxicity of
1.    Porth CM. Pathophysiology: concepts of altered health              citalopram in rats and first pass metabolism. Archiv
      states 3 rd ed. J.B Lippncott Company, Philadelphia, 1992,         Toxicol Suppl 1978; 1: 177-180.
      p 720.                                                       24.   Lopez-Torres E, Lucena MI, Seoane J, Verge C, Andrade
2.    Young LY and Koda-Kimble (eds). Applied Therapeutics:              RJ. Hepatotoxicity related to citalopram. Am J Psyciatry
      the clinical use of drugs 6 th ed. 1995, P 26-1.                   2004; 161: 932-4.
3.    Begaud B. The liver as the target organ for idiosyncratic    25.    Vial T, Biour M, Descotes J, Trepo C. Antibiotic
      reactions In: Idiosyncratic drug reactions: Impact on drug         associated hepatitis updated from 1990.. Ann Parmacother
      development and clinical use after marketing (Naranjo CA           1997; 31: 204 220.
      and Jones JK (eds). Elsevier Science, Amsterdam, 1990 pp     26.   Akeay A, Kanbay M, Sezer S and Ozdemir F. Acute renal
      85-98.                                                             failure and hepatoxicity associated with roxithromycin.
4.    Faich GA. US adverse drug reaction surveillance 1989-              Ann Pharmacother 2004; 38: 721-722.
      1994. Pharmacoepidemiol Drug Safety 1996; 5; 393-8.          27.   Beuers U, Spengler U and Pape GR. Hepatic hepatitis after
5.    Bem JL, Breckenridge AM, Mann RD and Rawlins MD.                   chronic use of senna. Lancet 1991; 337: 372-373.
      Review of yellow card (1986): a report to the Committee      28.   Ghosal S, Chauhan RPS, Srivastava RS. Chemical
      on Safety of Medicines. Br J Clin Pharmacol 1988; 26:              constituents of polygalaceae III. Two aryl naphthatide
      679-90.                                                            lignans from polygla chinensis. Phytochemistry (Elservier)
6.    Pillans PL. Drug associated hepatic reaction in New                19974; 13: 1933-6.
      Zeland: 21 years of experience. N Z Med 1996; 109: 315-9.    29.   Ghosal S, Chauhan RPS, Srivastava RS. Chemical
7.    Wang YZ and Fei JH. Chinese herb-induced liver damage.             constituents of polygalacea III. Structure of chinensin a
      J Clin Int Med 1998; 15: 179-181.                                  new     lignan    lactone from       polygala    chinensis.
8.    Meyer UA. Overview of enzymes of drug metabolism. J                Phytochemistry 1994; 13; 2281-4
      Pharmacokinet Biopharm 1996; 24: 449-459.                    30.   Lalibere L and Villeneuve JP. Hepatitis after use of
9.    Shah RR. Drug-induced hepatotoxicity: pharmacokinetic              germander: an herbal remedy. Can Med Assoc J 1996; 154:
      perspectives and strategies for risk reduction. Adverse            1689-1692.
      Drug React Toxicol 1999; 18: 181-233.                        31.   Stickel F, Egerer G and Seitz HK. Hepatotoxity of
10.   Lee WM. Drug-induced hepatotoxcity. N Engl J Med 1995;             botanicals. Pub Health Nutr 2000; 3: 113-124.
      333: 1118-1127.                                              32.   Russmann S, Lauterbury BH and Helbling A. Kava
11.   Hunt CM, Westerkam WR, and Stave GM. Effect of age                 hepatotoxicity. Ann Intern Med 2001; 135: 68-69.
      and gender on the activity of human hepatic CYP3A.           33.   Moulds RF and Malani J. Kava: herbal panacea or liver
      Biochem Pharmacol 1992; 43: 2407-12.                               poison? Med J Aust 2003; 178: 451-3.
12.   Barent CR, Abbot RA, Bailey CJ, Flatt PR and Ioannides       34.     Popat A, Shear NH, Malkiewicz I, Stewart MJ,
      C. Cytochrome P-450-dependent mixed-function oxidase               Steenkamp V, Thomson S and Neuman MG. The toxicity
      and glutathione S-transferase activities in spontaneous            of Callilepis Laureola: a South African traditional herbal
      obesity-diabetes. Biochem Pharmacol 1992; 43: 1868-71.             medicine. Clin Biochem 2001; 34: 229-36.
13.   Nolin TD, Frye RF and Matzke GR. Hepatic drug                35.   Yuan JL. Current studies on Chinese herb-induced liver
      metabolism and transport in patients with kidney disease.          diseases. Chinese Herbs 1999; 30: 711-726.
      Am J Kideny Dis 2003; 42: 906-925.                           36.   Ridker PM, Ohkuma S, Mcdermott MV, Trey C and
14.   Farrel GC. Mechanism of halothane induced liver injury. J          Huxtable RJ. Hepatic venoocclusive disease associated
      Gastroenterol Hepatol 1988; 3: 465-482.                            with the consumption of pyrolizidine-containing dietary
15.   Mitchell JR, Thorgeirsson SS, and Potter WZ.                       supplements. Gastroentrology 1985; 88: 1050-1054.
      Acetaminophen induced-hepatic injury, protective role of     37.   Picciotto A, Campo N and Brizzolara R. Chronic hepatitis
      glutathione in man and rationale for therapy. Clin                 induced by Jin Bu Huan. J Hepatology 1998; 28: 165-167.
      Pharmacol Ther 1997; 18: 676-684.                            38.   Liao LQ. Tentative analoges of Chinese-herb-induced liver
16.   ElTahir KEH. The Pharmacology of Essential Drugs,                  damage. J Integrated Chinese Western Medicine on Liver
      Alfrazdag Publishing Co. Riyadh 2004, pp 97-8.                     disease 2001; 11: 60-62.
17.   Prescott LF, and Crtchley JA. Drug interactions affecting    39.   But PP, Tomlinson B and Lee KI. Hepatitis related to
      analgesic toxicity. Am J Med 1983; 75: 113-116.                    Chinese medicine Shou-Wu-Pian manufactured from Poly-
18.   Schiodt FV, Rochling FJ, Casey DL and Lee WM.                      gnum multiflorum. Vet Hum Toxicol 1996; 38:280-282.
      Acetaminophen toxicity in an urban county hospital. N        40.   Park GJ, Mann SP and Ngu MC. Acute hepatitis induced
      Engl J MED 1997; 337: 1112-7.                                      by Shou-Wu-Pia, a herbal product derived from Polygum
19.   Sceff LB, Cuccherini BA, Zimmerman HJ, Alder E and                 multiflorum. J Gatroenterol Hepatol 2001, 16: 115-117.
      Benjamin SB. Acetaminophen hepatotoxicity in alcoholics:     41.   Battinelli L, Danuele C, Mazzant G, Mastroianni CM,
      a therapeutic misadventure. Ann Intern Med 1986; 104:              Lichtner M, Coletta S and Costantini S. New case of acute
      399-404.                                                           hepatitis following the consumption of Sou-Wu-Pian, a
20.   Whitcomb DC and Block GD. Association of                           Chinese herbal product derived from Polygnum
      hepatotoxicity with fasting and alcohol use. JAMA 1994;            multiflorum. Ann Internal Med 2004; 140: 589-590.
      272: 1845-50.                                                42.   Hautekeete MI, Horsmans Y, Van Waey-enberge C ,
21.   Prescott LF, IIIingworth RN, Crtchley JAH, Stewart MJ,             Demanet C, Henrion J, Verbist L, Brenard R, Sempoux C,
      Adam RD and Proudfoot AT. Intravenous N-acetylcystine:             Michielsen PP. Yap PS, Rahier J and Geubel AP. HLA
      the treatment of choice for paracetamol poisoning. BMJ             association of amoxicillin-clavulanate-induced hepatitis.
      1979; 2: 1097-100                                                  Gatroentrology 1999; 117: 1181-6.



Saudi Pharmaceutical Journal, Vol. 13, No. 4 October 2005
136                                                                                                              ELTAHIR ET AL

43.   Pohl LR. Drug-induced allergic hepatitis. Semin Liver Dis       65.   Batchelor WB, Heathcote J and Wanless IR. Chaparral-
      1990; 10: 305-15.                                                     induced hepatic injury. Am J Gastroenterol 1995; 90: 831-
44.   Kleckner HB, Yakulis V and Heller P. Severe                           832.
      hypersensitivity to diphenhydantoin with circulating            66.   Nadir A, Reddy D and Van Thiel DH. Cascara sgarada-
      antibodies to drug. Ann Intern Med 1975, 83: 522-3.                   induced      intrahepatic     cholestasis  causing     portal
45.   Baylor MS and Johann-Liang R. Hepatoxicity associated                 hypertension. Case report and review of herbal
      with nevirapine use. Acquir Immune Defic Synd 2004; 35:               hepatotoxicity. Am J Gastroenterol 2000; 95: 3634-37.
      538-539.                                                        67.   Streicher G. Acute renal failure and jaundice following
46.   WHO. Regulatory and safety action. Drug information                   rhubarb leaf poisoning. Dtsch Med Wochenschr 1994; 89:
      2004; 18:31.                                                          2379-2381.
47.   Garibaldi RA, Drusin RE, Fercbee SH and Gregg MB.               68.   D' Arcy PF. Hepatitis after chronic use of senna. Int Pharm
      Isoniazid-associated hepatitis, report of an out-break. Am            J 1991; 5: 106.
      Rev Respir Dis 1972; 106: 357-65.                               69.   Wurtz AS, Vial T, Isoard B and Saillard E. Possible
48.   Ramakrishana B and Viswanath N. Diclofenac-induced                    hepatotoxicity from Copaltra an herbal medicine. Ann
      hepatitis: case report and literature review. Liver 1994; 14:         Pharmacother 2002; 36: 941-942.
      83-4.                                                           70.   Nadir A., Agarwal S, King PD and Marshall JB. Acute
49.   Diem K and Lentener C (eds). Scientific Tables; Seventh               hepatitis associated with the use of a Chinese herbal
      edition. Ciba-Geigy Limited, Basle, Switzerland 1970, pp              product Ma-Huang. Am J Gastroenterol 1996; 91: 1436-
      653-56.                                                               1438.
50.   Trauner M, Meler PJ and Boyer J. Molecular pathogenesis         71.   US Food and Drug Administration. Dietary supplements
      of cholestasis. N Engl J Med 1998; 339: 1217-27.                      containing ephedrine alkaloids. Withdrawal in part, 65
51.   Chitturi S, and Farrell GC. Drug-induced cholestasis.                 Fedral Register 17477 year 2000.
      Semin Gastrointest Dis 2001; 12: 113-4                          72.   ElTahir KEH. Pharmacological actions of magnoflorine
52.   Velayudham LS, and Farrell GC. Drug-induced cholestasis.              and aristolochic acid-1 isolated from seeds of Aristolochia
      Expert Opin Drug Saf 2003; 2: 287-304.                                bracteata. Int J Pharmacogn 1991; 29: 1-11.
53.   Fulford A, Scolapio JS and Aranda-Michel J. Parenteral          73.   McMaster KR 3rd and Henniger GR. Drug-induced
      nutrition-association hepatotoxicity. Nutr Clin Pract 2004;           granulomatous hepatitis. Lab Invest 1981; 44: 61-73.
      19: 274-283.                                                    74.    Ruiz-Valverde P, Zafon C, Segarra A, Ribera R and Piera
54.   Mindikoglu AL, Anantharaju A, Hartman GG, Li SD,                      L. Ticlopidine-induced granulomatous hepatitis. Ann
      Villanueva J and Van Thiel DH. Prochloperazine-induced                Pharmacother 1995; 29: 633-4.
      cholestasis in patients with alpha-1-antitrypsin deficiency.    75.   Swank LA, Chejfee G and Nemchausky BA. Allopurinol
      Hepatogastroenterology 2003; 50: 1338-40.                             induced granulomatous hepatitis with cholangitis and
55.   Desilets D J, Shorr AF, Moran KA and Holtzmuller KC.                  sarcoid-like reaction. Arch Intern Med 138: 997-998.
      Cholestatic jaundice associated with use of metformin. Am       76.   Forbes GM, Jeffery GP, Shilkin KB and Reed WD.
      J Gastroenterol 2001; 96: 2257-2258.                                  Carbamazepine hepatotoxicity: another cause of vanishing
56.   Anon. High dose cyproterone and hepatotoxicity. Aust Adv              bile duct syndrome. Gastroentrology 102: 1385-8.
      Drug Reactions Bull 2004; 23: 3.                                77.    Swinburn BA, Croxson MS, Miller MV and Crawford KB.
57.   Hartleb M, Rymerczyk G, and Januszewski K. Acute                      Carbamazepine induced granulomatous hepatitis. N Z Med
      cholestatic hepatitis associated with pravastatin. Am J               J 1986; 99: 167.
      Gastroenterol 1999; 94: 1388-1390.                              78.   Elzouki AN and Lindgren S. Granulomatous hepatitis
58.   Bolego C, Baetta R, Bellosta S, Corsini A, and Paolettc R.            induced by aspirin-codeine analagesics. J Intern Med 1996;
      Safety consideration for statins. Current Opinion Lipidol             239: 279-81.
      2002; 13: 637-44.                                               79.   Lindgren A, Aldenborg F, Norkrans G, Olaison L and
59.   Gimbert S, Pessayre D, Degott C and Benhamou JP. Acute                Olsson R. Paracetamol-induced cholestatic and granuloma-
      hepatitis induced by MG-Co-A reductase inhibitor,                     tous liver injuries. J Intern Med 1997; 241: 435-9.
      lovastatin. Dig Dis Sci 1994; 39: 2032-33.                      80.   Saab S, Venkataramani A and Yao F. Possible
60.   Nakad A, Bataille L, Hamoir V, Sempoux C, Horsmans Y.                 granulomatous hepatitis after dicloxacillin therapy. J Clin
      Atrovastatin-induced acute hepatitis with absence of cross-           Gastroentrol 1996; 22: 163-4.
      sensitivity with simvastatin. Lancet 1999; 353: 1763-1764.      81.   Saw D, Pitman E, Maung M, Savasatit P, Wasserman D
61.   Chalsani N, Aljadhey H, Kesterson J, Murray MD and Hall               and Yeung CK. Granulomatous hepatitis associated with
      SD. Patients with elevated liver enzymes are not at higher            glyburide. Dig Dis Sci 1996; 41: 322-5.
      risk for statin hepatotoxity. Gastroenterology 2004; 126:       82.   Dhawan M, Agrawal R, Ravi J, Gulati S, Silverman J,
      128-1292.                                                             Nathan G and Raab S. Rosiglitazone-induced
62.   Mohamed AH, ElTahir KEH, Ali MB, Galal M, Ageel IA                    granulomatous hepatitis. J Clin Gastroenterol 2002; 34:
      and Hamid OA. Some pharmacological and toxicological                  582-4
      studies on Balanitis aegyptica bark. Phytotherapy Res           83.   Bjorusson E, Olsson R and Remotti H. Norfloxacin-
      1999; 13: 1-3.                                                        induced eosinophilic necrotizing granulomatous hepatitis.
63.   Alderman S, Kailas S, Goldfarb S, Singaram C and Malone               Am J Gastroenterol 2000; 95: 3662-4.
      DG. Cholestasis hepatitis after ingestion of chaparral leaf:    84.   Sippel PJ and Agger WA. Nitrofurantoin-induced
      Confirmation by endoscopic retrograde cholangiopan-                   granulomatous hepatitis. Urology 1981; 18: 177-8.
      creatography and liver biopsy. J Clin Gastroenterol 1994;       85.   Rotmensch HH, Yust I, Siegman-Igra Y, Liron M, IIie B
      19: 242-247.                                                          and Vardinon N. Granulomatous hepatitis: a hyper-
64.   Sheikh NM, Philen RM, and Love LA. Chaparral-                         sensitiveity response to procainamide. Ann Intern Med
      associated hepatitis.Archiv Intern Med 1997; 157: 913-919.            1978; 89: 646-7.



Saudi Pharmaceutical Journal, Vol. 13, No. 4 October 2005
CONVENTIONAL DRUGS AND HERBAL MEDICINES-INDUCED HEPATOTOXICITY                                                                     137

86.    Colle I, Naegels S, Hoorens A and Hautekeete M.                 109. NemotoY, Saibra T, Ogawa Y, Zhang T, Xu W, Ono M,
       Granulomatous hepatitis due to mebendazole. J Clin                   Akisawa N, Iwasaki S, Maeda T and Onishi S. Tamoxifen-
       Gastroenterol 1999; 28: 44-5.                                        induced nonalcoholic steatohepatitis in breast cancer
87.    Di Gregorio C, Ghini F and Rivasi F. Granulomatous                   patients treated with adjuvant tamoxifen. Intern Med 2002;
       hepatitis in a patient receiving methimazole. Ital J                 41: 345-50.
       Gastroenterol 1990; 22: 75-7.                                   110. Dourakis SP, Sevastianos VA, and Kaliopi P. Acute severe
88.    Cook IF, Shilkin KB and Reed WD. Phenytoin induced                   steatohepatitis related to prednisolone therapy. Am J
       granulomatous hepatitis. Aust N Z Med 1981; 11: 539-41.              Gastroenterol 2002; 97: 1074-75.
89.    Rice D and Burdick CO. Granulomatous hepatitis from             111. Candelli M, Nista EC, Pignataro G, Zannoni G, de Pascalis
       hydralazine therapy. Arch Intern Med 1983; 143: 1077.                B, Gasbarrini G and Gasbarrini A. Steatohepatitis during
90.    Toft E, Vyberg M and Therkelsen K. Diltiazem-induced                 methylprednisolone therapy for ulcerative colitis. J Int
       granulomatous hepatitis. Histopathlogy 1991; 18: 474-5.              Med 2003; 253: 391-392
91.    Mirada Canals A, Monteagudo Jimenez M, Sole Villa J and         112. Gardon JD, Chapnick EK, Sepkowitz DV. Zidovudine-
       Rodriguez Moreno C. Methyldopa-induced granulomatous                 induced hepatitis. J Intern Med 1992; 231: 317-8.
       hepatitis. DICP 1991; 25: 1269-70.                              113. Lai KK, Gang DL, Zawack JK and Cooly TP. Fulminant
92.    Fich A, Schwartz J, Braverman D, Zifroni A and                       hepatic failure associated with 2,3 dideoxyinosine (ddI).
       Rachmilewitz D. Sulfasalazine hepatotoxicity. Am J                   Ann Intern Med 1991; 115: 283-4.
       Gastroenterol 1984; 79: 401-2.                                  114. Gilbert SC, Klintmalm G, Menter A, and Silverman A.
93.    Silvain C, Fort E, Levillain P, Labat-Labourdette J and              Methotrexate-induced cirrhosis in three patients with
       Beauchant M. Granulomatous hepatitis due to combination              psoriasis: a word of caution in light of expanding use of
       of amoxicillin and clavulanic acid. Dig Dis Sci 1992; 37:            this ”steroid sparing” agent. Arch Intern Med 1990; 150:
       150-2.                                                               889-891.
94.    Katz B, Weetch M and Chopra S. Quinine-induced                  115. Lee WN and Dalton WT. Chronic hepatitis and indolent
       granulomatous hepatitis. Br Med J 1983; 286: 264-5.                  cirrhosis due to methyldopa: the bottom of iceberg? JSC
95.    Geltner D, Chajek T, Rubinger D and Levij IS. Quinidine              Med Assoc 1989; 85:75-9.
       hypersensitivity and liver involvement: A survey of 32          116. Geubal AP, Galocsy C, Alves N, Rahier J and Dive C.
       patients. Gastroenterology 1976; 70: 650-2.                          Liver damage caused by therapeutic vitamin A
96.    Mifuji R, Iwasa M, Tanaka Y, Hori Y, Araki J, Kaito M                administration: estimate of dose-related toxicity in 41
       and Adachi Y. “Green juice “ associated granulomatous                cases. Gastroenterology 1991; 100; 1701-9
       hepatitis. Am J Gasteroenterol 2003; 98: 2334-2335.             117. Wilmot FC and Robertson GW. Senecio disease or
97.    Rollins BJ. Hepatic veno-occlusive disease. Am J Med                 cirrhosis of liver due to senecio poisoning. Lancet 1920; 2:
       1986; 81: 297-306.                                                   848-9.
98.    Lemley DE, Delacy LM, Seeff LB, Ishak KG and Nashel             118. Mehdi A, Marteau P, Lavergne A, Molho-Sabatier P,
       DJ. Azathioprine induced hepatic veno-occlusive disease in           Cochand-Priollet B, Caen J, and Rambaud JC.
       rheumatoid arththritis. Ann Rheum Dis 1989; 48: 342-346.             Hepatocellular carcinoma in a patient with psoriasis and
99.    Whiting PW, Clouston A and Kerlin P. Black cohosh and                methotrexate-induced cirrhosis. Gastroenterol Clin Biol
       other herbal remedies associated with acute hepatitis. Med           1991; 15: 464-465.
       J Aust 2002; 177: 440-443.                                      119. Honda H , Franken EA Jr, Barloom TJ and Smith JL.
100.   Bach N, Thung SN and Schaffner F. Comfrey herb tea-                  Hepatic lymphoma in cyclosporine-treated transplant
       induced hepatic veno-occlusive disease. Am J Med 1989;               recipients sonographic and CT findings. Am J Roentgenol
       87: 97-99.                                                           1989; 152: 501-3.
101.   Halliwell WH. Cationic amphiphilic drug induced                 120. Anttinen H, Ahonen A, Leinonen A, Kallioinen M and
       phospholipidosis. Toxicol Pathol 1997; 25: 53-60.                    Heikkinen ES. Diagnostic imaging of focal nodular
102.   Reasor MJ, and Kacew S. Drug-induced phospholipidosis:               hyperplasia of the liver developing during nitrofurantoin
       are those functional consequences. Exp Biol Med 2001;                therapy. Acta Med Scan 1982 211: 227-32.
       226: 825-30.                                                    121. Fu PP, Yang YC, Xia QS, Chou MW, Cui YY and Lin G.
103.   Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB                  Pyrrolizidine alkaloids-tumorigenic components in Chinese
       and Lindor KD. Betaine, a promising new agent for                    herbal medicines and dietary supplements. J Food and Drug
       patients with non-alcoholic steatohepatitis: Results of Pilot        Analysis 2002; 10 (4): 198-211.
       Study. Am J Gasteroenterol 2001; 96: 2711-14.                   122. Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ,
104.   Lee RG. Non-alcoholic steatohepatitis. A study of 49                 Ludwig J, Rakela J, and McGill DB. Ursodeoxycholic acid
       patients. Hum Pathol 1989; 6: 594-598.                               or clofibrate in the treatment of non-alcoholic-induced
105.   Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu                 steatohepatitis: a pilot study. Hepatology 1996; 23: 1464-
       YC and McCullough AJ. Non-alcoholic fatty acid disease:              1467.
       a spectrum of clinical and pathological severity.               123. Bauditz J, Schmidt HH, Dippe P, Lochs H and Pirlich M.
       Gastroentrology 1999; 116: 1413-19.                                  Non-alcoholic induced steatohepatitis in non-obese
106.   Stravitz RT, and Sanyal AJ. Drug-induced steatohepatitis.            patients: treatment with ursodeoxycholic acid Am J
       Clin Liver Dis 2003; 7: 435-51.                                      Gastroenterol 2004; 99: 959-60
107.   Lonardo A. Fatty liver and non-alcoholic steatohepatitis:       124. Marchesini G, Brizi M, Bianchi g, Tomassetti S, Zoli M
       where do we stand and where are we going. Dig Dis 1999;              and Melchionda N.            Metformin in non-alcoholic
       17: 80-89.                                                           steatohepatitis. Lancet 2001; 358: 893-894.
108.   Haberfellner M and Honsig T. Non-alcoholic                      125. Urso R and Visco-Comandini U. Metformin in non-
       steatohepatitis: a possible side effect of atypical                  alcoholic steatohepatitis. Lancet 2002; 359: 355-356.
       antipsychotics. J Clin Psychiatry 2003; 64; 851.



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