BAB I

PREFACE
Drugs are an important cause of liver injury. More than 900 drugs, toxins, and herbs have
been reported to cause liver injury, and drugs account for 20-40% of all instances of
fulminant hepatic failure. Approximately 75% of the idiosyncratic drug reactions result in
liver transplantation or death. Drug-induced hepatic injury is the most common reason cited
for withdrawal of an approved drug. Physicians must be vigilant in identifying drug-related
liver injury because early detection can decrease the severity of hepatotoxicity if the drug is
discontinued. The manifestations of drug-induced hepatotoxicity are highly variable, ranging
from asymptomatic elevation of liver enzymes to fulminant hepatic failure. Knowledge of the
commonly implicated agents and a high index of suspicion are essential in diagnosis (Mehta,
2012).
The liver metabolizes virtually every drug or toxin introduced in the body. Most drugs are
lipophilic (fat soluble), enabling easy absorption across cell membranes. In the body, they are
rendered hydrophilic (water soluble) by biochemical processes in the hepatocyte to enable
inactivation and easy excretion. With such a function, it is not surprising that the liver has a
significant possibility also for ravaged by drug. Drug-induced liver damage (Drugs Induced
Liver Injury) generally does not cause permanent damage, but sometimes it can last long and
fatal (Mehta, 2012).
Tuberculosis is a contagious infectious disease remains a public health problem in the
world. This disease is one of the national priorities for communicable disease control
programs have the greatest impact on quality of life and economic and often result in death
(Riset Kesehatan Dasar, 2008).
According to the World Health Organization (WHO), Tuberculosis (TB) is one of the
leading causes of death for men. In 2011, there were approximately 8.7 million cases of TB
globally or 125 cases per 100,000 inhabitants and 1.4 million people died from TB. In the
world, there were 22 countries with the highest number of TB cases, and 22 countries are
referred to as high-burden countries. Indonesia is one country which include high burden
countries (Global Tuberculosis Report, 2012). And drugs that used in the treatment of
tuberculosis is one of the causes of drug induced liver injury.

BAB II
LITERATURE REVIEW
1. Drug Induced Liver Injury
Drug induced liver injury (DILI) is an abnormalities of liver function due to the
use of hepatotoxic drugs. In this case, due to the drugs that being used for latent TB
infection treatment, such as Isoniazid, Rifampicin and Pyrazinamide. (Aditama, 2006)
DILI may result from direct toxicity of the primary compound, a metabolite, or
from an immunologically mediated response, affecting hepatocytes, biliary epithelial
cells,and/or liver vascula-ture. In many cases, the exact mechanism and factors contributing to liver toxicity remain poorly understood. Predictable DILI is generally characterized
by certain dose-related injury in experi-mental animal models, has a higher attack rate, and
tends to occur rapidly. Injurious free radicals cause hepatocyte necrosis in zones farthest
from the hepatic arterioles, where metabolism is greatest and antioxidant detoxifying
capacity is the least.
Unpredictable or idiosyncratic reactions comprise most types of DILI. These
hypersensitivity or metabolic reactions occur largely independent of dose and relatively
rarely for each drug, and may result in hepatocellular injury and/or cholestasis. Hepatocyte necrosis is often distributed throughout hepatic lobules rather than being zonal, as is
often seen with predictable DILI. In hypersensitivity reactions, immunogenic drug or its
metabolites may be free or covalently bound to hepatic proteins, form-ing haptens or
neoantigens. Antibody-dependent cytotoxic, T-cell, and occasionally eosinophilic
hypersensitivity responses may be evoked. Released tumor necrosis factor- , interleukin
(IL)-12, and IFN- promote hepatocellular programmed cell death (apoptosis), an effect
opposed by IL-4, IL-10, IL-13, and monocyte chemotactic protein-1.
Metabolic idiosyncratic reactions may result from genetic or acquired variations in
drug biotransformation pathways, with synthesis or abnormally slow detoxification of a
hepatotoxic metabolite. Metabolic idiosyncratic reactions may have a widely variable
latent period, but recur within days to weeks after re-exposure (An Official ATS Statement
: Hepatotoxicity of Antituberculosis Therapy, 2006).
2. Etiology
2.1

Isoniazid
Reactive metabolites of MAH are probably toxic to tissues through free radical
generation. In rats, the free radical scavenger glutathione-related thiols, and

antioxidant glutathione peroxidase and catalase activities, are diminished by

isoniazid, although glutathione reductase activity is increased. The antioxidant Nacetyl-cysteine, a sub-strate for glutathione synthesis, inhibits isoniazid-induced
liver injury in pretreated rats, with unknown relevance in humans (An Official ATS
Statement : Hepatotoxicity of Antituberculosis Therapy, 2006).
Additional metabolic idiosyncratic mechanisms appear to be operative. The
isoniazid metabolite acetyl-hydrazine covalently binds to liver macromolecules, a
process mediated by micro-somal enzymes. Patients with homozygous cytochrome
P450 2E1 c1/c1 host gene polymorphism, who have enhanced cytochrome P450
2E1 activity, in one study had a higher risk of hepatotoxicity, particularly in slow
acetylators.
2.2

(An Official ATS Statement : Hepatotoxicity of Antituberculosis

Therapy, 2006)
Rifampicin
Conjugated hyperbilirubinemia probably is caused by rifampin inhibiting the
major bile salt exporter pump. Asymptomatic elevated bilirubin may also result
from dose-dependent competition with bilirubin for clear-ance at the sinusoidal
membrane or from impeded secretion at the canalicular level
Rare hepatocellular injury appears to be a hypersensitivity reaction, and it may
be more common with large, intermittent doses. Hypersensitivity reactions have
been reported in combination with renal dysfunction, hemolytic anemia, or flulike syndrome (An Official ATS Statement : Hepatotoxicity of Antituberculosis

2.3

Therapy, 2006)
Pyrazinamide
Pyrazinamide may exhibit both dose-dependent and idiosyncratic
hepatotoxicity. Several decades ago, daily doses of pyrazinamide at 40 to 50 mg/kg
commonly caused hepatotoxicity, and a relationship to dose was noted. Pyrazinamide alters nicotinamide acetyl dehydrogenase levels in rat liver, which might
result in generation of free radical spe-cies. There may be shared mechanisms of
injury for isoniazid and pyrazinamide, because there is some similarity in
molecular structure. Patients who previously had hepatotoxic reactions with
isoniazid have had more severe reactions with rifampin and pyrazinamide given for
LTBI. Pyrazinamide may induce hypersensitivity reactions with eosinophilia and
liver injury or granulomatous hepatitis (An Official ATS Statement :
Hepatotoxicity of Antituberculosis Therapy, 2006).

2.4

Ethambutol
There has been one report of ethambutol-related liver chole-static jaundice,
with unclear circumstances (An Official ATS Statement : Hepatotoxicity of
Antituberculosis Therapy, 2006)

3. Treatment
Management of Tuberculosis in Drug Induced Liver Injury :
-

When Clinical (+) (jaundice, nausea, vomiting), the OAT was stopped
If symptoms (+) and SGOT, SGPT> 3 times, then stopped OAT
When clinical signs (-), there is a laboratory abnormalities (bilirubin> 2), then the

OAT was stopped

AST and ALT> 5 times the normal value, the OAT was stopped
AST and ALT> 3 times, then continue treatment with supervision

The recommended treatment regimen :

-

Stop OAT is hepatotoxic (RHZ)

After the clinical and laboratory monitoring, when clinical and laboratory back to
normal (bilirubin, AST and ALT), then add the Isoniazid (H) desensitization to the full
dose of 300 mg. Pay attention during clinical and laboratory check when the full dose
Isoniazid is given. When clinical and laboratory back to normal, add Rifampicin, do
the desensitization to the full dose (based on body weight). So that drugs become

RHES combination.
Pyrazinamide should not be given again

(Aditama, 2006)

REFERENCES
Aditama, Yoga Tjandra. 2006. Pedoman Diagnosis dan Penatalaksanaan di
Tuberkulosis di Indonesia. Jakarta : PDPI, 2006.
An Official ATS Statement : Hepatotoxicity of Antituberculosis Therapy.
Saukkonen, Jussi J, et al. 2006. s.l. : American Thoracic Society, 2006.
2012. Global Tuberculosis Report. s.l. : WHO, 2012.
Mehta, Nilesh. 2012. Medscape. [Online] 27 6 2012. [Dikutip: 17 7 2014.]
http://emedicine.medscape.com/article/169814-overview.
2008. Riset Kesehatan Dasar. Departemen Kesehatan Repubik Indonesia, Badan
Penelitian dan Pengembangan Kesehatan. Jakarta : Badan Penelitian dan
Pengembangan Kesehatan, 2008.