1.

REFERENCE ID: 2019-04601

2.TITLE:

Evaluation of hepatotoxicity of anti-tubercular regimens in patients suffering

from tuberculosis in a district hospital in tribal region of central India –
A prospective study

3.INTRODUCTION:

Tuberculosis is a world-wide health problem and is one of the top 10 causes of death. In 2016,
the WHO estimated that there were 10.4 million cases of TB and 1.7 million deaths due to TB all
over the world. [1].India accounts one fourth of world's TB burden. Annual incidence rate of TB
in India is around 2 million and around 3,00,000 death occurs due to TB every year in the
country. [2]TB leads loss of productivity causing loss of 20-30% of annual household income.
Directly observed treatment short course (DOTS) is the main pillar employed for control of TB
under RNTCP (Revised National TB control Program) in India. Isoniazid (INH),
pyrazinamide (PZA) and rifampicin (RMP) are used in DOTS as the main drugs. They have the
potential to cause hepatotoxicity, the incidence of which is reported to be 2-28%. [3]The spectrum
of hepatotoxicity ranges from asymptomatic rise in transaminase (upto five-fold) in 2.3-28% to
acute liver failure in approximately <0.01% of the individuals. [4] This might result in treatment
withdrawal, substitution, dosage regimen adjustment, non-adherence, and drug resistance. [5]
Ethambutol and streptomycin in the DOTS regimen have different adverse effects profile than
hepatotoxicity.[6] A higher risk of hepatotoxicity has been reported in Indian patients than in their
western counterparts. [7]

There are many factors that contribute to the development of the anti TB drug induced
hepatotoxicity. In a study reported by Wondwossen Abera et al it has been shown that history of
chronic alcohol intake is a pre disposing factor for anti TB drug induce hepatotoxicity. [8]A study
in Taiwan showed that slow acetylators are at a higher risk of developing hepatotoxicity as
compared to the rapid acetylators. [9] A study conducted by Rajani Shakya et al revealed that
the incidence of anti TB drug induced hepatotoxicity was higher in younger patients .[10] Similar
studies noted nutrition, low albumin, high dose acetaminophen intake, female gender , older age

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and low serum cholesterol as the risk factors. [11] Body mass index [BMI] found to be
significantly lower in ATT (Anti-tubercular treatment) induced hepatitis patients. [12]However
some studies reported that there was no significant association between hepatotoxicity and
various factors. [13, 14]

The risk factors that contribute to the development of anti-TB drug hepatotoxicity are still
unclear and controversial. Understanding anti - TB drug hepatotoxicity is restricted to the
difference in study populations, definition of hepatotoxicity and monitoring practices.

4. REVIEW OF LITERATURE

Studies were identified from an electronic search of MEDLINE, and Science Citation Index
Expanded. Variants of key words such as “tuberculosis,” “first-line drugs,” “anti-tubercular
agents”, “hepatotoxicity,” and “adverse effects” were used. References from articles we
identified were also searched for relevant publications. Only manuscripts in English were
considered.

Anti-tubercular drugs and toxicity:

Anti-tuberculosis treatment regimens are considered the leading cause of drug induced liver
injury (DILI) and drug-induced acute liver failure (ALF) in much of the developing world. The
clinical spectrum includes asymptomatic elevation in liver tests to acute hepatitis and acute liver
failure. Anti TB therapy - DILI can occur across all age groups including children with
significant morbidity and mortality. Although anti-TB therapy DILI develops more commonly in
males, ALF is noted to be commoner in females with a worse prognosis. . S. N. Gellis and R.
V.Murphy in their studies in the year 1955 found the presence of jaundice, hypoalbuminemia,
ascites, encephalopathy and high prothrombin time are poor prognostic markers. [15]

INH and Hepatotoxicity:

After the introduction of INH in 1952, several cases of INH induced hepatotoxicity were
reported. [16-24].

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INH and Polymorphism:

According to drug-induced liver injury guidelines the hepatotoxicity caused by INH appears to
be due to metabolic idiosyncratic reactions. INH is metabolized mostly by the liver, primarily by
acetylation by N-acetyl transferase -2 (NAT-2) to acetyl-isoniazid. Acetyl-isoniazid is
metabolized mainly to monoacetyl hydrazine (MAH) and to the nontoxic diacetyl hydrazine, as
well as other minor metabolites The influence of acetylation rate on INH hepatotoxicity is
controversial; however, the involvement of INH’s metabolites has been proposed: first by free
radical generation from reactive metabolites of MAH and second by the covalent bond of acetyl
hydrazine to liver macromolecules. Patients with enhanced cytochrome P450 2E1 activity
carrying the homozygous cytochrome P450 2E1 c1/c1 host gene polymorphism showed an
increased risk of developing hepatotoxicity particularly if known to be slow acetylators. This has
[25]
been supported by J J. Saukkonen, D. L. Cohn, R. M. Jasmer et al in the year 2006

Preventive treatment of tuberculosis:

In the five years follow-up of a large Eastern European clinical trial (International Union
Against Tuberculosis –IUAT, Committee on prophylaxis), showing efficacy of various durations
of isoniazid preventive therapy for TB, a total of 28 000 persons with fibrotic pulmonary lesions
compatible with tuberculosis received 12, 24, or 52 weeks of preventive treatment with isoniazid
or placebo. Compared with placebo, 12 weeks of isoniazid eliminated less than one-third, and 24
weeks eliminated two-thirds of the tuberculosis risk. Where preventive treatment is not currently
practised, adopting a 24-week regimen could decrease the incidence of tuberculosis in such
populations by 65%.Hepatitis, the only serious side-effect encountered, occurred infrequently but
was more common among isoniazid recipients (0.5%) than among placebo recipients (0.1%).
Fifty-two weeks of isoniazid prevented the most tuberculosis, but 24 weeks prevented more
tuberculosis cases per case of hepatitis caused. Where preventive treatment is currently practised
for 52 weeks, adopting a 24-week regimen would decrease hepatitis by one-third and increase
tuberculosis by 40%. The rate of fatal INH hepatitis was estimated as 14 per 100,000 person-
years. The above theory is supported by the joint statement of the American Thoracic Society
(1971) and IUAT (1982) trial [26] [27]

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INH and fatal hepatitis:

Salpeter et al evaluated articles published from 1966 to 1992 on INH use (with or without other
anti-tuberculosis drugs) in chemoprophylaxis. All patients were appropriately monitored
according to the guidelines. Results showed 2 hepatotoxic deaths in 202,497 patients (an
adjusted fatality rate of 0.003%). Both patients were taking INH monotherapy but had additional
risk factors for hepatotoxicity [28]

In 1996, Millard et al. estimated rates of fatal INH hepatitis to be around 4.2 per 100,000
persons newly starting therapy and around 7 per 100,000 while completing therapy .[29]

Pyrazinamide and hepatotoxicity:

The toxic mechanism of pyrazinamide (PZA) remains unknown and hepatotoxicity due to it
remains unpreventable. Shih et al. conducted the first cell line, animal, and clinical study to
confirm that metabolite5-hydroxypyrazinoic acid (5-OH-PA)causes PZA-induced
hepatotoxicity.Potential PZA and pyrazinoic acid (PA) hepatotoxicity was then tested in rats.
Urine specimens were collected from 153 TB patients, and the results were evaluated to confirm
whether a correlation existed between PZA metabolite concentrations and hepatotoxicity. This
led to the hypothesis that co-administration of amidase inhibitor (bis-p-nitrophenyl phosphate
[BNPP]) decreases or prevents PZA- and PZA metabolite.The study by Tung-Yuan Shih et al
in April 2013 presents a novel and feasible strategy for preventing PZA-induced hepatotoxicity
by inhibiting amidase. Because certain PZA metabolites contribute differently to PZA toxicity,
the activity or expression level of metabolic enzymes, such as amidase and xanthine oxidase,
may be correlated with PZA-related side effects, such as hepatitis and hyperuricemia[30]

Rifampicin and hepatotoxicity:

Rifampicin is one of the most common anti-tuberculosis therapies and has well-known
hepatotoxicity. To understand the mechanism of rifampicin-induced liver injury, Ju-Hyun Kim
et al in the year 2017 performed a global proteomic analysis of liver proteins by Liquid
chromatography-mass spectrometry (LC-MS/MS) in a mouse model after the oral administration
of 177 and 442.5 mg/kg rifampicin ,lethal dose (LD10 and LD25) for 14 days. Based on the
biochemical parameters in the plasma after rifampicin treatment, the hepatotoxic effect of

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rifampicin in the mouse liver was defined as a mixed liver injury. They identified 1101 proteins
and quantified 1038 proteins. A total of 29 and 40 proteins were up-regulated and 27 and 118
proteins were down-regulated in response to 177 and 442.5 mg/kg rifampicin, respectively.
Enrichment analyses to characterize the mechanism of rifampicin-induced hepatotoxicity. In the
molecular function category, glutathione transferase activity was up-regulated and proteins
related to arachidonic acid metabolism were down-regulated. In the KEGG pathway enrichment-
based clustering analysis, the peroxisome proliferator-activated receptor-γ (PPARγ) signaling
pathway, cytochrome P450, glutathione metabolism, chemical carcinogenesis, and related
proteins increased dose-dependently in rifampicin-treated livers. Taken together, this study
showed in-depth molecular mechanism of rifampicin-induced liver injury by comparative toxic
proteomics approach [31]

Thus the authors concluded in their studies that hepatotoxicity due to anti-tubercular therapy is
matter of concern and should be taken into consideration to maximize the benefit and minimize
the harm.

The recent diagnostic algorithm is according to guidelines of Chaudhuri: RNTCP 2016 [32]

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5. AIM AND OBJECTIVES:

 To evaluate incidence of hepatotoxicity after ATT regimen.

 To evaluate association between risk factor, anti-tubercular regimen and hepatotoxicity.

6. MATERIAL AND METHODS:

Study design:
This was a prospective open label study carried out for a period of 8 months and 10 days, from
21st Jan to 30th September 2019 in District TB Centre [DTC] and attached Peripheral Health
Centres (PHCs) of a tertiary care institute in tribal region of central India.

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Study population:
Men and women who were newly diagnosed pulmonary TB [P], extra-pulmonary TB [EP] or
multi-drug resistant [MDR] falling in the age group of 18-80 years constituted the study
population. A total of 65 patients were included.

Ethical considerations:

The study was started after getting approval from the Institutional Ethics Committee (Reg.
no.ECR/1033/Inst/MH/2018) .The patients were explained the entire procedure of the study in
the local language, then patients were asked to sign the informed consent form. Their
participation and identity was not revealed.

Inclusion Criteria:

The newly diagnosed TB patients who had

 serum aspartate aminotransferase (AST) less than 45 IU/L,
 alanine aminotransferase (ALT) less than 45 IU/L
 total bilirubin <1mg/dl.

Exclusion Criteria:

Patients who had

 ALT and AST values greater than two times the upper limit of normal (ULN > 42U/L
and 37U/L, respectively)
 patients positive for hepatitis B surface antigen
 patients positive for anti-HCV antibodies
 HIV positive cases
 Patients not willing to participate
 Patients receiving any other hepatotoxic drugs
 Pregnant women
 Children

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Data collection Procedure:

Initial history of patients diagnosed at DTC was obtained. The participants information was
gathered on a case record form (CRF).The demographic details ,diagnosis, anti-tubercular kit
and regimen details, history of co-morbid illnesses, history of other drug intake , addiction to
alcohol was elicited. Alcohol addiction was defined as a daily consumption of more than 40gm
of alcohol for at least five years. After taking the history, complete physical examination was
done.

The patient’s TB status was classified according to the standard guidelines. [33] The Gene Xpert
(CB-NAAT), a PCR test was used for diagnosis of TB and check for rifampicin resistant TB in
each patient. The clinically diagnosed patients of TB were subjected to sputum examination .
Before the start of treatment in the smear positive cases following lab test were done in the
Central Clinical Laboratory of the study site-Estimation of blood sugar, Hb, CBC, HIV,HBs
Ag, anti-HCV Ab, ALT,AST, Bilirubin [direct and indirect].

Treatment was given according to RNTCP 2016 –guidelines [32]

The newly diagnosed patients

Pulmonary TB [P] were started on Category I regimen - Isoniazid, Rifampicin, Pyrazinamide,
Ethambutol. The treatment was for 6 months
Initial phase (IP): Isoniazid, Rifampicin, Pyrazinamide & Ethambutol- for 2 months
Continuous phase (CP): Isoniazid, Rifampicin, Ethambutol- for 4 months.
Extra-pulmonary TB [EP] were started on the same regimen as stated above but the treatment
was of 12 months.
Initial phase (IP): for 2 months
Continuous phase (CP): for next 10 months

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Dose of each patient was decided on the basis of RNTCP weight band
Drug Dosage for Adult TB
Weight category Number of tablets (FDCs)
Intensive phase HRZE* Continuous phase HRE*
75/150/400/275 75/150/275
25-39 kg 2 2
40-54 kg 3 3
55-69 kg 4 4
>=70 kg 5 5
*H=isoniazid; R=rifampicin; Z= pyrazinamide; E= ethambutol

MDR/RR-TB CASES

Type of TB case Treatment regimen in IP Treatment regimen in CP

Rifampicin resistant + 6-9 months 18 months
isoniazid sensitive or Km Lfx Eto Cs Z E H Lfx Eto Cs E H
unknown
Rifampicin sensitive 3-6 months 6 months
Isoniazid resistant TB Km Lfx R E Z Lfx R E Z
Km = Kanamycin; Lfx = Levofloxacin; E = Ethambutol, Z = Pyrazinamide; Etio = Ethionamide,
Cs = Cycloserine, H= Isoniazid; R= Rifampicin

1. Clinical evaluation: patients were observed for signs and symptoms of hepatotoxicity like
nausea, anorexia, vomiting, malaise, organomegaly or jaundice. Patients were kept under close
observation during the study period and were asked to report any unusual signs and symptoms

2 Lab investigations: The liver function tests were repeated at the end of 1, 3 and 6 months

Diagnosis of hepatotoxicity [6]

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In the present study anti-TB drug induced hepatotoxicity was defined by the presence of any one
of the following criteria:
1) A rise to ≥5 times the normal serum level of transaminases (normal serum glutamate-
pyruvate transaminase or SGPT: 7-41 U/L, normal serum glutamic-oxaloacetate
transaminase or SGOT: 12-38 U/L).

2) A rise in the level of serum total bilirubin > 1.47 mg/dL.

3) Any increase in serum transaminase above pretreatment levels together with symptoms
of anorexia, nausea, vomiting, and jaundice.

A causal relationship between the anti-TB drugs and hepatotoxicity was made by using the
WHO-UMC causality analysis scale. [34] These reactions were reported to the NCC, PvPI.

At the end of 1, 3 and 6 month the empty strips were checked to ensure that the patient has taken
his/her proper dose

Statistical analysis:
Analyses were carried out using MS Excel 2010. Data was pooled as count and percentages. The
main outcome variable was hepatotoxicity (symptomatic hepatitis ± ALT >3 _ ULN). Baseline
characteristics of the 65 patients were described and the characteristics of patients with
hepatotoxicity were compared with those without. Continuous variables were presented as mean
(standard deviation [SD]) while the categorical variables were presented as proportions.
Comparisons between two means or between two medians were done using paired t test.
A p-value <0.05 was considered significant for all tests.
For proportions the test of significance applied was a Fisher Exact Probability test.

7. OBSERVATIONS AND RESULTS:

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Demographic and anthropometric data
A total of 65 TB patients taking anti-TB drugs participated in this study, 70.76 % of the
respondents were males and 29.23% were females. The mean age of respondents was 39.64 ±
15.19 years but the highest number of participants was found in the age group of 18-30 years
(38.46%). The weight of the participants ranged from 25kg -70 kg with the mean value being
50 ± 9.6 kg. The total duration of the study was for 8 months and 10 days. Each patient was
followed up for a period of 6 months. Till the completion of study, 54 patients were followed up,
4 died and 7 didn’t turned up.
[Table1] {fig. 1 a, b, c}.
Diagnosis of study participants and history of alcohol addiction
Among the total 65 participants, 25(38.46%) were newly diagnosed smear-positive pulmonary
(P) TB cases, 27(41.53%) were extra-pulmonary (EP) TB cases and 13(20%) were MDR TB
cases. Only one patient was diabetic amongst all participants and 26.15% of patients were
addicted to alcohol. The life and follow up status of participants till completion of study is
presented in [Table 2] {fig. 2 a, b, c}.

In the present study 6 out of 65 patients developed hepatotoxicity with certainty, which account
for 9.23%. For causality analysis WHO –UMC scale was used. The cases developing
hepatotoxicity were reported to NCC, PvPI. All the 6(100%) patients were males. The time
period for development of hepatotoxicity is as follows. Four patients (66.66%) developed in first
month, one (16.66%) at the end of 3 months, and another one (16.66%) at the end of 6 months.
Out of 65 patients, 4 died. The various factors affecting development of hepatotoxicity is shown
in [Table 3] {fig. 3 a, b, c, d, e}

The base line and peak level values of SGOT, SGPT, direct and indirect bilirubin of
respondents participating in the study is presented in [Table 4].

Clinical signs and symptoms in patients of anti-TB drug induced hepatotoxicity is presented in
[Table 5] {fig. 4}

Table 1: Demographic and anthropometric data of study participants (n=65)

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Characteristics n (%)
Gender Male 46(70.76)
Female 19(29.23 )
Age (years) 18-30 25(38.46 )
31-40 12( 18.46)
41-50 10( 15.38)
>50 18( 27.69)

Weight (kg) 25-39 23( 35.38)

40-54 30(46.15 )
55-69 11(16.92 )
>=70 1(1.53)

Male (46=70.76%)
70.76%
Female (19=29.23%)

Fig. 1 a: Gender distribution in study participants [n=65]

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 27.69%
38.46%

15.38%

18.46% 18-30 years (25=38.46%)

31-40 years (12=18.46%)
41-50 years (10=15.38%)
> 50 years (18=27.69%)

Fig. 1 b: Age distribution of the study participants [n=65]

30

23
Number of respondents

11

25-39 kg 40-54 kg 55-69 kg >70 kg

Weight (in kg)

Fig. 1 c: Weight distribution in study participants (n=65)

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Table 2: Type of TB and other characteristics of study participants (n=65)

Characteristics n (%)
Type of TB
Pulmonary 25(38.46)
Extra-Pulmonary 27(41.53)
MDR* 13(20)
Diabetic status
Diabetic 1(1.53)
Non-diabetic 64 (98.46)
Alcohol addiction
Addicted 17(26.15)
Non-addicted 48(73.84)
Out-come of patients in TB units
Did not turned for follow up 7(10.76)
Followed till the last date of study (6months) 54(83.07)
Dead 4(6.15)
*MDR-Multidrug resistance

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 20%

Pulmonary TB
(25=38.46%)
Extra pulmonary TB
(27=41.53%)
MDR TB (13=20%)

Fig.2 a: Diagnosis of the study participants [n=65]

26.15%
Addicted (17=26.15%)

Not-addicted
73.84% (48=73.84%)

Fig.2 b: Addiction of alcohol among the study participants [n=65]

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 Fig.2 c : Outcome at the end of 6 months [n=65]
10.76%

6.15% Not developing hepatotoxicity

(48=73.84%)

9.23% Developing hepatotoxicity (6=9.23%)

Died (4=6.15%)
76.92%

Lost to follow up (7=10.76%)

Note: The incidence of hepatotoxicity in the study population came out to be 9.23%.

Table 3: Comparison of type of TB and other characteristics of participants in hepatotoxic

and non-hepatotoxic patients (n=65)
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Variable Groups Patients without Patient p values
hepatotoxicity with hepatotoxicity
(n=59) (n=6)

Age (years) 18-39 32 1 0.104

40-80 27 5
Gender Males 40 6 0.168
Females 19 0
Type of TB Pulmonary 24 1 0.203
Extra 25 2
pulmonary 10 3
MDR

Weight (kg) 25-54 48 5 1

55 and above 11 1

Alcohol Present 12 5
Addiction Absent 47 1 0.003*

Fisher Exact Probability Test

*p value <0.05 statistically significant

Note:

 The relative risk of developing hepatotoxicity in alcoholic addicted males is 14.11.

 Hence we can say that withdrawl of alcohol from the population will cause a drop in
developing hepatotoxicity by 93%.

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 Fig 3 a:Gender distribution in the hepatotoxic patients [n=6]
NUMBER

Male Female

Fig 3 b: Age distribution of hepatotoxic patients [n=6]

18-39 years
(1=16.67%)

40-80 years
(5=83.33%)

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 Fig 3 c: Diagnosis of the hepatotoxic patients [n=6]

Pulmonary TB
(1=16.67%)
Extra pulmonary TB
(33.33%)
MDR (3=50%)

Fig 3 d: Alcohol Addiction in hepatotoxic patients [n=6]

Present (5 =
83.33%)

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Fig 3 e: Weight distribution in hepatotoxic patients [n=6]

25-54 kg (5 = 83.33%)

>54 kg (1 =16.67%)

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 Laboratory test Patients with anti –TB p value Patients without anti TB p-value
drug drug
hepatotoxicity(n=6) hepatotoxicity(n=48**)
mean ± SEM mean ± SEM

SGPT (U/L)
Baseline 26.74 ± 12.23 0.000774* 28.66 ± 9.51 3.221
Peak value 99.50 ± 42.50 42.23 ± 13.12

SGOT(U/L)
Baseline 31.33± 11.29 0.006694* 32.16± 9.60 7.102
Peak value 99.50 ± 43.23 43.61± 13.47

Total bilirubin 0.69 ± 0.16 0.90 ± 0.15

Baseline 1.16 ± 0.24 0.003701* 1.08 ± 0.12 6.100
Peak value

Table 4: Base line and peak level values of liver function test during study in respondents
(n=54)

** 48= number of patients not developing hepatotoxicity which are followed till end

Student’s paired t test

*p-value < 0.05(Statistically significant)

Table 5: Clinical signs and symptoms in patients of anti-TB drug induced hepatotoxicity
(n=6)

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 Signs and Symptoms n (%)
Nausea 4(66.67%)
Vomiting 2(33.33%)
Anorexia 5(83.33%)
Malaise 3(50%)
Number of respondents

Nausea Vomiting Anorexia Malaise

Fig.4: Presenting symptoms of the 6 hepatotoxic patients

8. DISCUSSION:

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 Hepatotoxicity can cause permanent injury and death. Early recognition with immediate
withdrawal of offending agent is very important to arrest its development and allow liver to heal.
Anti-tubercular drugs are known to cause hepatotoxicity. Identification of patients with high risk
factors is important because hepatotoxicity causes significant morbidity and mortality and may
require modification of drug regimen.
In the present study sixty-five patients were recruited and started on a particular anti-TB
regimen depending on their respective diagnosis pulmonary /extra pulmonary /MDR-TB cases.
They were followed in both intensive and continuous phase of therapy for a period of 6 months.
Cases were followed up at the end of 1, 3 and 6 months of treatment.
In our study 38.46% participants were of pulmonary TB, 41.53% were of extra-pulmonary and
20% were of MDR TB cases. 6 patients out of 65 developed hepatotoxicity. Out of six, three
cases were of MDR TB, two of extra-pulmonary and one of pulmonary TB. There was no
statistically significant difference found between type of TB and development of hepatotoxicity.
The incidence of anti-TB treatment induced hepatotoxicity in the present study is found to be to
be 9.23%. This finding coincides with the findings from other studies. [1,9,10 ] However, it is lower
than that of a study from Egypt[35] and higher than that of the western world .[1] This variation in
the incidence could be due to the differences in patient’s characteristics, genetic predisposition,
environmental factors, and the difference in criteria of hepatotoxicity.
According to this study, the time interval for the onset of hepatotoxicity after the initiation of
treatment was 25–180 days (median- 65 days). Similar findings have been reported in other
studies in literature. [36,37] But in some studies the time interval reported is 15-60 days (median -
28 or 30 days)[38] This difference could be due to difference in the follow up time of patients.
Advancing age was associated with anti-TB drugs induced hepatitis in many studies. In the
present study, participants below the age of 40yrs were 57% and above age of 40yrs were 43%
with mean age of 39.64 ± 15.19 years .The six patients with hepatotoxicity were 28, 40, 42, 52,
54, 63 years old. There was no statistically significant difference between incidence of anti –TB
drug induced hepatotoxicity with age distribution of the study group. The probable reason is that
the patients who participated in our study were young with the median age <40 years. Our
findings are consistent with some studies reported in literature [39, 40]. Pande et al showed that
increasing age is associated with more hepatotoxicity. [41] One study reported 4-fold increased

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risk in patients older than 35 years. M.A. Steele et al observed in their meta-analysis that all age
groups are at risk for anti-TB drugs induced hepatitis. [1, 42]

In the present study 70.76 % of the participants were males and 29.23% were females. Out of the
six participants developing hepatotoxicity all were men. There was no statistically significant
difference between incidence of anti –TB drug induced hepatotoxicity with gender distribution of
the study group. This could be because nearly 2/3rd of participants were males. Sharma SK,
Balamurugan A in their study found that 51.7% of patients developing hepatotoxicity were
females but statistically non-significant.[39] In some studies reported in literature it is found that
women showed four times higher risks of developing hepatotoxicity post anti TB drug treatment.
[41,43]

This study showed that the history of alcohol intake was a potential risk factor for anti-TB-drug
induced hepatotoxicity and there was statistical significant difference seen (P<0.05) between
alcoholics and non-alcoholics. The relative risk of developing hepatotoxicity in alcoholic
addicted males is 14.11. Hence we can say that withdrawl of alcohol from the population will
cause a drop in developing hepatotoxicity by 93% (Population attributable Risk). This
discrepancy is perhaps due to the maximum number of men participants 46(70.76%) in our
study. In India consumption of alcohol is a trend in men as compared to women. The number of
alcoholics were 17 (26.15%) in our study population. Pande JN, Singh SPN, C. Gronhagen-
Riska in their study reported that the history of alcohol intake was common among the cases.
[41,44]
On the contrary, some studies showed that alcohol intake had no correlation with
development of hepatotoxicity.[43] Alcohol consumption is a risk factor ascribed to malnutrition
and glutathione store depletion [41]

Nutritional status which is considered as one of the risk factor for the anti-TB drug induced
hepatotoxicity is assessed by body mass-index and serum albumin. [ 9 ,43 , 45]. In the present study
serum albumin levels of patients could not be measured. In our TB units the anti TB drugs are
given according to per kg body weight, hence weights of all patients were recorded but not the
heights. So the BMI of all patients could not be calculated. The paramedical staff working in
TB units should be taught the importance of anthropometric measurements in TB patients and
the record keeping on every visit of patients should be made mandatory by applying
regulations. 81.53% patients had weight below 54 kg. Out of the 6 patients who developed
hepatotoxicity, 4 had BMI in range of 14.15-17.57kg/m2. There was no statistically significant
difference between incidence of anti –TB drug induced hepatotoxicity with weight distribution of

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the study group. In malnutrition, glutathion stores are depleted which makes one vulnerable to
oxidative injury. In a malnourished person liver metabolizes drug at a slower pace. In a study
done in India, incidence of hepatotoxicity was found to be three times higher in malnourished
patients [41]
In the present study elevations of liver enzymes was found in all the cases. In the patients who
developed hepatotoxicity there was statistical significant difference seen in pre and post
treatment values of SGOT, SGPT, total bilirubin. All the six patients developing hepatotoxicity
had shown gastrointestinal manifestations like nausea, vomiting, abdominal discomfort, anorexia
and jaundice.
In present study with regards to outcome 56 (86.15 %) participants followed up till completion
of study, 5 (7.69%) did not turned for follow up and 4 (6.15%) died, but we could not co- relate
the reason of their death to the disease itself or drug regimen related side-effects. The patients
who died were all male with ages 22, 60, 60, 78 years. The history given by patient’s relative
was as follows, one died on third day of treatment, one was a MDR case who died after taking 22
weeks of treatment, two cases with the history of excess alcohol intake at night and didn’t wake
up in the morning. Some studies in literature reported similar findings. [46] Considering the death
cases as Serious Adverse Events (SAE), they were reported to NCC after doing the causality
assessment scale using WHO-UMC causality assessment scale. [34]

Continued Medical Education of the medical and paramedical staff working in TB units is of
utmost importance. Their education regarding proper counseling of patients can help in effective
and safe therapy of TB patients avoiding harm to the patients.

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Limitations:

 Patients enrolled in the study were taking combination of anti-TB drugs. Due to this
reason, it is difficult to conclude which drug was the main culprit for causing hepatitis.
 Nutritional status of patients could not be assessed as serum albumin levels were not
done.
 Serum cholesterol levels were not estimated because of lack of kits in the institutional set
up. Hence we could not correlate serum cholesterol and development of hepatotoxicity.
 The height records of all patients were not maintained hence BMI of all patients was not
available, hence we could not correlate BMI and development of hepatotoxicity.
 Acetylator status of patients determine the development of hepatotoxicity but in
present study we could evaluate the relation between the two due to unavailability of
acetylator status of participants
 Some patients did not turned for follow up the reason, could not be cited.

Conflict of interest: Nil

Funding source: Nil

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9. CONCLUSIONS:

In the present study

1. A total of 65 patients recruited, 38.46% participants were of pulmonary TB, 41.53% were
extra-pulmonary and 20% were MDR TB cases.
2. The incidence of anti-TB drug regimen induced hepatotoxicity is found to be 9.23%
3. Out of six patients who develop hepatotoxicity, three cases were of MDR TB, two of
extrapulmonary and one of pulmonary TB.
4. There was no statistically significant difference found between type of TB and
development of hepatotoxicity.
5. All the six patients developing hepatotoxicity were men.
6. The patients developing hepatotoxicity fall in the age group of 40 -60 yrs.
7. The time interval for the onset of hepatotoxicity after the initiation of treatment was 25–
180 days (median, 65 days), so it is essential to monitor the liver function throughout the
therapy.
8. This study showed that the history of alcohol intake was a potential risk factor for anti-
TB-drug induced hepatotoxicity.
9. There was no statistically significant difference between incidence of anti –TB drug
induced hepatotoxicity with weight distribution of the participants in study.
10. In the patients who developed hepatotoxicity there was statistical significant difference
seen in pre and post treatment values of SGOT, SGPT, total bilirubin.
11. Patients developing hepatotoxicity had shown gastrointestinal manifestations like nausea,
vomiting, abdominal discomfort in addition to anorexia and jaundice.
12. Out of 65 participating patients, four patients died.
13. The cause of deaths could not be ascertained.

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10. SUMMARY:

Rationale for study:

Anti TB drugs contribute to the development of hepatotoxicity, incidence of which is reported to
be 2-28%. This may result in treatment withdrawal, substitution, dosage regimen adjustment,
non-adherence, drug resistance. Understanding of risk factors is restricted to the difference in
study populations, definition of hepatotoxicity and monitoring practices.

Objectives:
 To evaluate incidence of hepatotoxicity after ATT regimen.
 To evaluate association between risk factor, anti-tubercular regimen and hepatotoxicity.
Study design, setting and Methods:
Longitudinal study carried out in 65 men & women participants on anti-tubercular regimen
according to respective diagnosis of pulmonary, extra pulmonary and MDR TB. The study was
started after getting approval from the Institutional Ethics Committee. Patients who were positive
for hepatitis B surface antigen, positive for anti-HCV antibodies, HIV positive cases, receiving
hepatotoxic drugs were excluded from the study. The patient participation was voluntary and
their written informed consent was taken. The patients were followed up in both intensive and
continous phase of therapy. The patients were monitored both clinically and biochemically for
hepatotoxicity. The liver function tests were repeated at the end of 1, 3 and 6 months. A specific
criteria was set for diagnosing hepatotoxicity. The WHO-UMC scale was used for causality
assessment. The participant’s complete information was gathered on a case record form (CRF).
Statistical evaluation of the data was done.
Results & Conclusions:
Six out of sixty-five participants developed hepatotoxicity giving incidence of 9.23%. All were
men in age group of 40-60 years. No statistical significance was found among the weight,
gender, age group of participants with the development of hepatotoxicity. Only the history of
alcohol intake and development of hepatotoxicity in patients, could be correlated which was
statistically significant. 7 patients did not come for follow up till completion of study. 4 patients
died, but we were unable to correlate death to hepatotoxicity or disease itself .All cases of
hepatotoxicity were reported to NCC and deaths were reported as SAE. Amongst anti TB drugs
we could not make out which particular drug caused hepatotoxicity as the drugs were given in
combination.

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12. Justification:

 We earlier mentioned to assess serum albumin and serum cholesterol levels in the
protocol but it was not done because of unavailability of kits in the hospital.
 Since the dosing of all patients was done according to their weight, their weight records
were properly maintained. The heights were not properly maintained for all the
participants so to avoid any error we didn’t consider them, hence BMI was not calculated
and correlated.

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Reference ID: 2019-04601

13. Case record form

Demographic profile:

Registration number: _________ Date: __________

Age: Gender: Occupation:

Residence:

Diagnosis: pulmonary/extra-pulmonary tuberculosis

History:

History of disease: (DM/ HTN/ malnutrition/ anemia) –

if yes then hereditary/ non-hereditary

History of any other drugs: yes/no

if yes then on which drug
dose
time

History of addiction: smoking/ alcohol/ any other addiction

if yes then quantity time

History of increased fatigue

fever
skin itching

Physical examination:

Weight: height: BMI:

Systemic examination:

CVS

RS

CNS

GIT

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X-ray examination :

ATT Regimen and the kit details:

Drugs Dose
Duration

Outcome:

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Lab investigations:

Variables Baseline 15 days 30 days 90 days 180 days

Sputum for AFB
Pill count
Alanine transaminase
(ALT)
5-40 IU/l

Aspartate transaminase
(AST)
5-45 IU/l

Albumin
3.5-5g/dl
Bilirubin
0.2-1mb/dl
Serum Cholesterol
150-200mg/dl

Clinical investigations:

Acetaminophen intake

Stomach pain and upset

Nausea
Dark coloured urine
Stool dark colour
Loss of appetite
Yellowish skin and eyes

Itchy skin

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 14. INFORMED WRITTEN CONSENT FORM

I, the undersigned, am voluntarily willing to participate as a study subject in this research study. I
have been informed in detail regarding the investigative procedures and techniques involved in
the study in the language understood by me. I will allow them to withdraw my blood samples on
the coming follow up dates. I have no objection what so ever to the results of the study being
published for the advancement of medical knowledge as long as confidentiality is maintained
and my identity is not revealed anywhere.

I have fully understood the aforesaid and willingly give my consent for the same.

Date: Signature of subject

Place: Name of subject

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