Drug induced liver disorders

1. Definition
• The liver disease/disorder resulting from the inhalation,
ingestion or parenteral administration of any pharmacological
or chemical agent is called as drug induced liver disease or
drug induced liver disorder (DILD).
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2. Risk Factors
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3. PATTERNS/TYPES OF DILD The most common and serious drug induced liver
disorders are as follows:
1. Idiosyncratic reactions
2. Allergic hepatitis
3. Toxic hepatitis
4. Chronic active hepatitis
5. Toxic cirrhosis
6. Liver vascular disorders
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4. For some drugs, a genetic or acquired
abnormality must exist in a particular metabolic pathway for a toxic reaction to
take place. In other cases, the reactions are typically associated with a drug
concentration and often respond to simply lowering the dose of the drug.
Idiosyncratic reactions tend to occur without association to particular blood
concentrations or specifically identified metabolic abnormalities.
• e.g. sulfonylureas like glipizide and antibiotics like ciprofloxacin. Idiosyncratic
reactions are rare and are sometimes described as liver hypersensitivity to a
drug.
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5. 2. ALLERGIC HEPATITIS: Allergic reactions in the liver can be caused by many
drugs and result in many different kinds of hepatic damage. It is marked by
fever, pruritus, rash, eosinophilia, arthritis, and haemolytic anaemia. The
formation of granulomas within the liver is often seen on biopsy. The reaction
reverses with discontinued therapy and reappears upon rechallenge.
e.g. Most antibiotics have been associated with this type of reaction, including
the fluoroquinolones, macrolides, B-lactams, trimethoprim- sulfamethoxazole,
penicillinase-resistant Penicillins such as dicloxacillin and allopurinol.
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6. CONTD...
SIGNS & SYMPTOMS: i) The onset of symptoms is 1 to 6 weeks after
initiation of therapy.
ii) The incidence, like all the allergic liver reactions, is low, estimated
at less than 1%. ill) The clinical presentation includes eosinophilia,
fever, rash, and arthritis. The biopsy may show a pattern of fibrin-ring
granulomas similar to those seen in Q fever.
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7. 3. TOXIC HEPATITIS: Toxic reactions are predictable, often dose-related effects
in the liver due to specific agents.
e.g. Paracetamol (acetaminophen). When taken in overdose, acetaminophen
becomes bioactivated to a toxic intermediate known as N-acetyl-p-
benzoquinone imine (NAPQI). NAPQI is very reactive, with a high affinity for
sulfhydry! groups and requires glutathione for further metabolism to non-toxic
metabolites. After glutathione supplies are exhausted, the toxic metabolite binds
to sulfhydryl-containing proteins in the liver cell and causes lipid peroxidation
disrupting the cell membrane. These events eventually lead to cell death.
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8. CONTD...
SIGNS & SYMPTOMS:
i) Early in the process of Reye's syndrome, mitochondrial dysfunction leads to the depletion of acyl
coenzyme A and carnitine.
¡i) Fatty acids accumulate and gluconeogenesis is impaired, resulting in hypoglycaemia.
iii) A concurrent disruption of the urea cycle occurs, leading to a decrease in the removal of
ammonia and a slowing of protein use.
iv) A threefold rise in the blood ammonia level and an increase in the prothrombin time are common
findings.
v) In advanced stages of Reye's syndrome, many patients develop intracranial hypertension that
can be life threatening and refractory to therapy.
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9. Patients experience periods of
symptomatic hepatitis followed by periods of convalescence, only to repeat the
experience months later. It is a progressive disease with a high mortality rate
and is more common in females than males. Antinuclear antibodies appear in
most patients. These drugs appear to form anti-organelle antibodies. The exact
identification of a causative agent is sometimes difficult since diagnosis
requires multiple episodes occurring long after exposure to the offending drug.
e.g. Dantrolene, isoniazid, phenytoin, nitrofurantoin, and trazodone have been
reported in association with a type of autoimmune mediated disease in the liver.
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10. The scarring effect of hepatitis in the liver leads
to the development of cirrhosis. Some drugs tend to cause such a mild
case of hepatitis that it may not be detected. Mild hepatitis can be
easily mistaken for a more routine generalized viral infection. If the
offending drug or agent is not discontinued, this damage will continue
to progress. The patient eventually presents not with hepatitis, but with
cirrhosis.
e.g. Methotrexate and vitamin A toxicity.
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11. CONTD...
i) Methotrexate causes periportal fibrosis in most patients who experience
hepatotoxicity. The lesion results from the action of a bioactivated metabolite
produced by cytochrome P450. This process has most commonly been noted in
patients treated for psoriasis and arthritis. The extent of damage can be reduced
or controlled by increasing the dosage interval to once weekly or by routine use
of folic acid supplements. il) Vitamin A is normally stored in liver cells, and
causes significant hypertrophy and fibrosis when taken for long periods in high
doses. Hepatomegaly is a common finding, along with ascites and portal
hypertension. In patients with vitamin A toxicity, gingivitis and dry skin are also
very common. This is accelerated by ethanol, which competes with retinol for
aldehyde dehydrogenase.
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12. Focal lesions in hepatic venules, sinusoids,
and portal veins occur with various drugs. e.g. Cytotoxic agents used to treat
cancer, the pyrrolizidine alkaloids, and the sex hormones.
A centralized necrosis often follows and can result in cirrhosis. Azathioprine
and herbal teas that contain comfrey (a source of pyrrolizidine alkaloids) are
associated with the development of veno- occlusive disease. The exact
incidence is rare and may be dose related.
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13. CONTD... "Peliosis hepatitis" is a rare type of hepatic vascular lesion
that can be seen as both an acute and a chronic disease. The liver
develops large, blood-filled lacunae within the parenchyma. Rupture
of the lacunae can lead to severe peritoneal haemorrhage. e.g.
Peliosis hepatitis has been associated with exposure of the liver to
androgens, ostrogens, tamoxifen, azathioprine, and danazol.
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14. MECHANISMS OF DILD: The common mechanisms involved in drug induced
liver disorders are:
1. Centro lobular necrosis
2. Steatohepatitis
3. Phospholipidosis
4. Generalized hepatocellular necrosis
5. Cholestatic jaundice
6. Mixed hepatocellular necrosis and cholestatic disease
7. Neoplastic jaundice
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15. 1. CENTRO TUBULAR NECROSIS: Centro lobular necrosis is often a dose-
related, predictable reaction secondary to drugs such as acetaminophen.
However, it also can be associated with idiosyncratic reactions, such as those
caused by halothane. It is also called as "direct or metabolite-related
hepatotoxicity". Centro lobular necrosis is usually the result of the production
of a toxic metabolite. The damage spreads outward from the middle of a lobe
of the liver. More severe forms of Centro lobular necrosis are accompanied by
nausea, vomiting, upper abdominal pain, and jaundice.
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16. 2. STEATOHEPATITIS: Steatohepatitis (also known as steatonecrosis) is a
specialized type of acute necrosis resulting from the accumulation of fatty
acids in the hepatocyte. Drugs or their metabolites that cause steatonecrosis
do so by affecting fatty-acid oxidation within the mitochondria of the
hepatocyte. Hepatic vesicles become engorged with fatty acids, eventually
disrupting the homeostasis of the hepatocyte. The liver biopsy is marked by a
massive infiltration by polymorphonuclear leukocytes, degeneration of the
hepatocytes, and the presence of Mallory bodies.
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17. CONTD... Alcohol is the drug that most commonly produces steatonecrotic
changes in the liver. When alcohol is converted into acetaldehyde, the
synthesis of fatty acids is increased. When the hepatocyte has become
completely engorged with micro vesicular fat, it often breaks open, spilling into
the blood. If enough hepatocytes break open, an inflammatory response
begins. If the offending agent is withdrawn before significant numbers of
hepatocytes become necrotic, the process is completely reversible without
long-term sequelae. In non-alcoholic steatohepatitis the same endpoint is often
achieved through oxidation of lipid peroxidases. e.g. Tetracycline, sodium
valproate produces non-alcoholic steatohepatitis.
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18. 3. PHOSPHOLIPIDOSIS: Phospholipidosis is the accumulation of phospholipids
instead of fatty acids. The phospholipids usually engorge the lysosomal bodies of the
hepatocyte.
e.g. Amiodarone Patients treated with amiodarone who develop overt hepatic disease
tend to have received higher doses of the drug. These patients also have higher
amiodarone to N-desethyl-amiodarone ratios, indicating a greater accumulation of the
parent compound. Amiodarone and its major metabolite N-desethyl-amiodarone
remain in the liver of all patients for several months after therapy is stopped. Usually
the phospholipidosis develops in patients treated for more than 1 year. The patient
can present with either elevated transaminases or hepatomegaly; jaundice is rare.
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19. 4. GENERALISED HEPATOCELLULAR NECROSIS: Generalized hepatocellular necrosis
mimics the changes associated with the more common viral hepatitis. The onset of
symptoms is usually delayed as much as a week or more after exposure to toxin.
Bioactivation is often important for toxic hepatitis to develop, but may not be the immediate
cause of damage. Many drugs that are that are associated with toxic, hepatitis produce
metabolites that are not inherently toxic to the liver. Instead, they act as haptens, binding to
specific cell proteins and inducing an autoimmune reaction. The rate of bioactivation can
vary between males and females and between individuals of the same sex. The vtochrome
P450 system (CYP) tends to metabolize lipophilic substrates which are actively pumped into
the hepatocyte by an organic anion (or cation) transporting protein. The CYP subspecies 1A,
2B, 3A, and 4A are regulated by the highly inducible xenobiotic receptor on complementary
DNA.
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20. CONTD... The receptor is found in the liver, and to a lesser extent in the cells lining
the intestinal tract, and is responsible for cholesterol catabolism and bile acid
homeostasis. The activity of this receptor is subject to genetic polymorphism as
well. This results in a wide variation in the sensitivity of the population to
"generalized hepatocellular necrosis" and other forms of hepatic damage.
e.g. The long-term administration of isoniazid can lead to hepatic dysfunction in
10% to 20% of those receiving the drug. ii) Ketoconazole produces generalized
hepatocellular necrosis or milder forms of hepatic dysfunction in 1% to 2% of
patients treated for fungal infections
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21. 5. CHOLESTATIC JAUNDICE: Cholestatic jaundice, or cholestasis, can be classified by
the area of the bile canalicular or ductal system that is impaired. Canalicular cholestasis
is very often associated with long-term high-dose estrogen therapy. Clinically, these
patients are often asymptomatic and present with mild to moderate elevations of serum
bilirubin. e.g.
i) An, intravenous form of vitamin. E,, a-tocopherol acetate, causes cholestatic jaundice
primarily involving the canalicular duct in premature infants.
il) The administration of total parenteral nutrition for periods greater than 1 week induces
cholestatic changes and nonspecific enzyme elevations in some patients.
iii) This reaction also has been reported to occur rarely with sulfonamides, sulfonylureas,
erythromycin estolate and ethyl succinate, captopril, lisinopril, and other phenothiazines.
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22. 6. MIXED HEPATOCELLULAR NECROSIS & CHOLESTATIC JAUNDICE: Patients
infrequently present with a purely hepatocellular necrosis or cholestatic damage,
but rather with a mixed picture of damage.
e.g. Flutamide causes a mix of lesions that appear at or about the 48th week of
treatment. il) Niacin in doses greater than 3 g/day, or in doses greater than 1 g/day
of sustained-release formulations, causes the same mixed pattern of damage. ili)
These patients often present with only a few signs or symptoms at first, but can
progress rapidly to fulminant hepatic failure. Additionally, niacin- induced and other
drug-induced mixed hepatocellular disease can be misinterpreted as hepatobiliary
cancers.
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23. 7. NEOPLASTIC JAUNDICE: A large body of the current literature on adverse reactions
and the liver addresses the development of neoplasms following drug therapy. Both
carcinoma- and sarcoma-like lesions have been identified. Fortunately, hepatic tumours
associated with drug therapy are usually benign and remit when drug therapy is
discontinued. Except in rare instances, these lesions are associated with long-term
exposure to the offending agent.
e.g. i) Androgens, ostrogens, and other hormonal-related agents are the most
frequently associated causes of neoplastic disease.
ii) The model for drug-induced hepatic cancer is polyvinyl chloride exposure. Used in
the production of many types of plastic products, polyvinyl chloride induces
angiosarcoma in exposed workers after as few às 3 years of exposure.
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24. ASSESSMENT: Assessment and monitoring of DILD is important. DILD may cause death
if they are not treated. Assessment done based on various factors like patient's clinical
presentation and patient history.
1. Patient history:
- Social habits like alcohol consumption
• Previous medications or reactions
• Occupational and environment factors
* Alternative/non drug therapy
2. Liver enzyme levels: - Serum proteins: increased albumin indicates impaired liver
function " Prothrombin time
3. Liver biopsy
4. Nutritional status
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25. TREATMENT:
• Current therapy should be stopped.
• Rechallenge - if rechallenge is negative then continue the
treatment. • Management with drugs include antidote (if
available), corticosteroids,
supportive treatment.
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26. N-Acetylcysteine and Glutathione
• NAC is an N-acetylated derivative of L-cysteine (L-Cys) and a
precursor of Glutathione (GSH), and has the pharmacological effects
of anti-oxidation, anti-inflammation, dilatation of microvessels and
protection of DNA molecules (Dekhuijzen, 2004). It is the only
antidote approved by the US Food and Drug Administration (FDA) in
2004 for acetaminophen (APAP)-induced DILI.
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27. Glycyrrhizin Acid Preparation
Glycyrrhizin acid, extracted from the roots of the plant Glycyrrhiza
glabra, is a triterpenoid compound, also known as glycyrrhizin for its
sweet taste. It is hydrolyzed in vivo by glucuronidase to glucuronic
acid and glycyrrhizin acid. At present, Glycyrrhizin acid preparation
have been commonly used in the treatment of DILI in clinical
application around the world, mainly including compound glycyrrhizin
tablets, magnesium isoglycyrrhizinate (MgIG) and other drugs. It plays
an anti-oxidation, anti-inflammation and hormone-like role in DILI
treatment and protects liver against inflammatory damage.
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28. Polyene Phosphatidylcholine
PPC is refined from phospholipids, which is extracted from soybeans.
Accounting for about 52%, diacylphospholipidcholine (DLPC) is the
main active ingredient. It can provide endogenous phospholipids to
repair damaged liver cell and organelle membrane, so as to restore
membrane function and increase the fluidity and stability of cell
membrane, which protects from liver diseases caused by a variety of
factors
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29. Bicyclol
Bicyclol (4, 40-dimethoxy-5, 6, 50, 60-dimethylene-dioxy-2, 20-dicarboxylate
biphenyl) is the first chemical new drug independently developed by China
and used to treat inflammatory liver injury. It has been recommended by
Russian physicians’ clinical guidelines for the treatment of DILI (Expert
Committee on Clinical Application of Bicyclol, 2020). Its pharmacological
activity mainly lies in its inhibition of the expression and activity of NF-κB, IL-
1β, IL-18, TNF-α, TGF-β1 and other inflammatory regulatory factors induced
by liver injury, as well as the production of reactive oxygen species (ROS) and
nitric oxide (NO), reducing consumption of antioxidants such as GSH
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30. Silymarin
Silymarin is a flavonoid isolated for the first time in 1968 from the seed
extract of milk thistle plant which is mainly a mixture of lignin-derived
flavonols, including silybin, silydianin, silychristin, and isosilybin with
silybin is the most potent constituent. Such drugs can maintain the
fluidity of liver cell membrane through anti-lipid peroxidation and
enhance the resistance of liver cell membrane to various injury factors,
so as to protect against drug-induced liver injury
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31. Ursodeoxycholic Acid
UDCA, a naturally occurring hydrophilic bile acid, which main mechanism is to
reduce the cholesterol saturation index of bile and inhibit the absorption of
cholesterol in intestine, has been reported to have a variety of hepatoprotective effect,
such as cell protective, anti-apoptotic, immunomodulatory and cholagogues effects.
It was the only FDA approved drug for treatment of primary biliary cholangitis (PBC)
and has also been successfully used in various cholestatic liver diseases. Both
European Association for the Study of the Liver (EASL) and Asia Pacific Association
of Study of Liver (APASL) guidelines indicated that it was commonly used for DILI
with cholestasis,
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32. S-Adenosylmethionine
SAMe is the active form of methionine in the body. It is formed from
substrate L-methionine and ATP catalyzed by s-adenosylmethionine
synthetase. Due to its transformation of methyl, sulfur and
aminopropyl groups, SAMe is involved in the detoxification of bile
acid metabolism and the generation of glutathione, improves cell
membrane fluidity, promotes the synthesis and secretion of bile acid
in many aspects, and prevents liver cell injury and necrosis
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33. Cholestyramine
Cholestyramine, also known as Calleenamine, is a non-absorbable styrene anion
exchange resin. After oral administration, it binds with intestinal cholic acid,
hindering the reabsorption of cholic acid and increasing the excretion of cholic
acid by 3∼15 times compared with normal. In clinical practice, cholestyramine
was often used to relieve itchy skin symptoms in patients with cholestasis. As
specific therapy, it was recommended by EASL and APASL guidelines that
administration of cholestyramine may be used to decrease the course of
hepatotoxicity induced by very selected drugs, such as leflunomide and
terbinafine
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34. Immunosuppressants
Adaptive immune attack may be the final common event of DILI. Inflammatory
responses are mainly a combination of immune activation and a series of
related cellular and molecular events . Intrahepatic inflammation caused by
non-drug factors is an independent predisposing factor for DILI and also a
factor that promotes the progression of DILI. Adaptive immune responses can
mediate DILI and also lead to extrahepatic immune injury and then produce
s y s t e m i c m a n i f e s t a t i o n s i n c l u d i n g f e v e r a n d r a s h e s . T h u s ,
immunosuppressants and anti-inflammatory drugs such as glucocorticoids
(GCs) are also helpful in DILI treatment.
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35. Glucocorticoids
As steroids, glucocorticoids (GCs) have been widely used in clinic practice, due
to its anti-inflammatory, immunosuppressive, anti-allergic and anti-shock
effects. GCs was recommended for severe DILI patients in cases where the
patients’ serum TBIL levels are exacerbated under regular therapy, regardless
of whether serum ALT level decreases or not. In addition, GCs could be
empirically given to patients with marked signs of hypersensitivity or
autoimmunity, and patients without remarkable improvement or even
aggravation of biochemical indicators after withdrawal offending drug(s). A
step-down therapy with gradually tapering off the dose of steroid seems to be
used most often in clinical practice. Prednisone ranging from 15 to 20
mg/kg/day for 3 days was reported to treat successfully patients with severe
DILI without obvious side effects. Abrupt withdrawal of the corticosteroids is
not recommended because it may sometimes result in the rebound of liver
injury.
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