Effects Of Anti–Tubercular Drugs on Liver Function Tests – An Observational Study

Abstract

Background: Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the major reasons that can lead to treatment interruptions in tuberculosis patients. In the current research, we intend to investigate and evaluate the association between anti-tubercular medications and changes in serum liver enzyme patterns. Methods: An observational study was conducted to assess the impacts of anti-tubercular drugs on liver function tests in different individuals. Study was conducted among 75 subjects, 3 (4%) subjects were lost to follow-up during study. After gaining informed consent form from the patients or their legal representatives, any individuals who fit the study's eligibility requirements were included to the study. The required data from each patient was obtained and analysed using descriptive statistics. Results: SGPT is found to be elevated after 2 months of ATT moderately in 55.55% of patients and is >80 IU/L in 16.66% of patients. SGOT is observed to be elevated after 2 months of ATT moderately in 68.05% of patients and is >100 IU/L in 8.33% of patients. The Complete Blood Count values before and after 6 months of treatment were also assessed. CONCLUSION: The anti-tubercular therapy has a statistically significant effect on the liver function tests especially after intensive phase of therapy. DILI is the most frequent type of anomaly to which most of the patients were found to be well tolerant while few required intrusions in the therapy. The impact of anti-tubercular therapy on blood picture was found to be relatively mild.

Keywords

Introduction

3.1.1. Distribution based on Co morbidity: Among 72 subjects, 2 subjects (2.8%) have AIDS, 2 subjects (2.8%) have Pneumonia, 1subject (1.4%) have Asthma, 9 subjects (12.5%) have COPD, 19 subjects (26.4%) have Type 2 Diabetes mellitus, and 14 subjects (19.5%) have Hypertension.

Fig 1 – Distribution based on Co morbidity

3.2. Liver function tests (LFT) changes: Pre and Post anti – tubercular therapy.

3.2.1. Changes in Serum Glutamic Pyruvic Transaminase (SGPT) Patterns: SGPT is elevated after 2 months of ATT moderately in 55.55% of patients and is >80 IU/L in 16.66% of patients. These values return to normal in maximum number of patients (i.e., 83.33%) after 6 months of treatment.

3.2.2. Changes in Serum Glutamic Oxaloacetic Transaminase (SGOT) Patterns: SGOT is elevated after 2 months of ATT moderately in 68.05% of patients and is >100 IU/L in 8.33% of patients. These values return to normal in maximum number of patients (i.e., 76.38%) after 6 months of treatment.

3.2.3. Changes in Alkaline Phosphatase (ALP) Patterns: ALP is elevated after 2 months of ATT moderately in 72.22% of patients and is >200 IU/L in 15.27% of patients. These values return to normal in maximum number of patients (i.e., 75%) after 6 months of treatment.

DISCUSSION

One of the most typical side effects of anti-TB treatment is drug-induced hepatitis. Thus, it is essential to regularly monitor liver function test results to avoid negative outcomes ⁽¹⁹⁾.

In the present study, the evaluation of demographics among the study subjects was performed. Most of the patients were between the age group 26-40 years, then 41-60 years. Male subjects had a higher frequency of tuberculosis than female subjects. The body mass index assessment was performed and it was found that over 50% of the individuals enrolled in the study had normal BMI whereas 34.7% of patients were underweight. The alcohol consumption and tobacco smoking status of the patients was also evaluated. Type-2-diabetes mellitus was found to be the most prevalent comorbidity followed by hypertension and COPD. Very few patients presented with asthma, pneumonia, and AIDS.

76% of patients in research by Rupam Kumar T A et al. had impaired concentrations of liver enzymes (that is, SGPT and SGOT). Just 16.7% and 28.9%, respectively, had no increment in SGPT and SGOT. Thus, the research population exhibited a common adaptive response to ATT ⁽¹⁾. In the current study, the enzymes SGPT and SGOT showed elevations after an initial intensive phase of therapy which were normal before the start of therapy. These elevations tend to normalize as the therapy is continued.

The process of developing DILI is complex and involves both sequential and concurrent processes. Drug-specific pathways that are initiated by specific medications or their metabolites are among the important upstream events. An initiating event is most likely to be increased reactive metabolite production or detoxification failure. These reactive metabolites cause an overabundance of reactive oxygen species (ROS), which causes cell death and lipid per oxidation. Events that follow initial drug metabolism may have an impact on the occurrence and severity of liver damage. In recent times, studies have demonstrated that DILI might be mediated by inhibiting a histone change. Histone acetyltransferases are enzymes that facilitate histone acetylation, which opens the chromatin structure and allows genes to be read in that region ⁽¹²⁾.

The occurrence and natural history of this phenomena has been documented, which is sometimes referred to as "adaptation," using precise case definitions; the underlying processes of this phenomenon remain to be discovered ⁽¹³⁾.

In a study conducted by Kassa et al, medication-naïve TB patients had somewhat greater haemoglobin concentration and PCV than those receiving anti-TB medication. When anti-TB medication was started, the total number of white blood cells in TB patients was comparatively like the total white blood cell count at the conclusion of the intensive treatment phase. The MCV measurements before and after treatment did not significantly differ from one another. However, the differences in the MCH and MCHC values were statistically significant when the data were examined before and after the intensive stage of TB treatment ended ⁽¹⁸⁾.

In our current study, there is slight decrease in the haemoglobin and RBC levels after therapy compared to before initiation of treatment. A chronic infection, such as tuberculosis, can result in anaemia. Many Patho physiologies have been proposed for TB-associated anaemia, but most studies have demonstrated that inflammatory mediators decrease erythropoiesis, which is the root cause of anaemia ⁽¹⁸⁾.

It was observed that platelet counts slightly decrease after completion of therapy, but is not considered as an area of concern as it remains within the normal range. The MCV and MCH values remain normal and there were no obvious statistically significant changes in these levels before and after ATT. MCHC was slightly reduced below the normal range after completion of therapy.

5.6% (4 out of 72) of patients reported drug-induced hepatitis which was confirmed by evaluation of signs and symptoms and liver function tests. Five patients out of 114 treated cases in research by Rupam Kumar T A et al. developed hepatitis and had their therapy interrupted; the remaining patients were able to continue their treatment without experiencing any symptoms ⁽¹⁾.

Drug-induced hepatotoxicity primarily results from hypersensitivity reactions, which might present clinically as fever, rash, or eosinophilia ⁽¹⁴⁾. The most common symptoms reported in our study include nausea, vomiting, loss of appetite, generalized weakness and urticaria. The treatment was interrupted due to incidence of drug-induced hepatitis for a period of 1-2 weeks during which the patients were closely monitored and retreatment was started after the liver enzymes returned to normal.

Since N-acetylcysteine shortens hospital stays, it may be a therapy option for liver damage caused by antituberculosis. In contrast, hepatoprotector medications are used in the treatment of antituberculosis liver damage patients in India ⁽⁹⁾. In our study, all the patients were prescribed with Pyridoxine Hydrochloride for prevention of peripheral neuritis as a neuroprotectant.

In this study, a female patient reported ATT induced GI intolerance and ethambutol induced ocular toxicity after 1 month of ATT with symptoms such as dyspepsia, haemoptysis, vomiting and blurring vision. The therapy was interrupted till the retrieval of symptoms and ethambutol was replaced with levofloxacin to prevent the progression of ocular degeneration.

Also, a male patient reported generalized xerosis with complaints of itching and scaling noted over the body after intensive treatment phase. This condition was treated with a suitable moisturizer to soothe dryness after which the continuation treatment phase was started.

4 out of 72 (5.6%) patients had to continue ATT for 3 more months after completion of continuation phase and the rest of the study subjects were treated successfully without any treatment interruption or complications. It is equally important to continue monitoring of LFT’s in these patients until completion of therapy.

LIMITATIONS

The study sample size was relatively small therefore; inference of the study has limited value and lower statistical power. Only individuals who were accessible and willing to participate at the time of study had their data collected. We were unable to evaluate how concurrent medication use and comorbidities affected the course of treatment.

CONCLUSION

The antitubercular therapy has a statistically significant effect on the liver function tests especially after intensive phase of therapy. DILI is the most frequent type of anomaly to which most of the patients were found to be well tolerant while few required intrusions in the therapy. Other rare events that were observed include skin complaints such as urticaria and generalized xerosis and ocular toxicity.

The impact of antitubercular therapy on blood picture was found to be relatively mild and does not lead to any significant changes on health outcomes.

The incidence of adverse effects may prolong hospital stay and has impact on both clinical as well as economic outcomes of the treatment. The treatment interruption may lead to development of drug resistance that is unintended. It also encounters economic impact such as increasing the cost of treatment.

Ethical Approval: Ethics Review Board of MVJ Medical College and Research Hospital, Bangalore has granted the approval with IEC No – MVJMC&RH/IEC-117/2024

Declaration of Competing Interest: None declared

Acknowledgements: No acknowledgements

Data Linking: The authors prefer not to provide the data collected in the study as it is unethical to reveal any patient specific information according to Institutional Ethics Committee.

REFERENCES

1. T.A RK, Khan S, Sen P, Banerjee S. A Study to Detect Liver Enzyme Dysfunction among Patients on First Line Anti-Tubercular Drugs from RNTCP during the Course of Anti-TB Treatment. J Evol Med Dent Sci. 2020 Mar 2;9(9):645–50.
2. Knechel NA. Tuberculosis: Pathophysiology, clinical features, and diagnosis. Crit Care Nurse. 2009 Apr;29(2):34–43.
3. Brodie D, Schluger NW. The diagnosis of tuberculosis. Vol. 26, Clinics in Chest Medicine. W.B. Saunders; 2005. p. 247–71.
4. Leading The Way, India TB Report, 2023.
5. Mejbel FAH, Aljanaby IAJ, Al Hadrawi KK, Aljanaby AAJ. Pulmonary tuberculosis risks and challenges. In: E3S Web of Conferences. EDP Sciences; 2023.
6. Global Tuberculosis Report, 2023.
7. Standard Treatment Guidelines.
8. Vijayalakshmi A, Thanmayi G, Jayakumari S. A prospective study on abnormal liver function test patterns in patients receiving anti-tuberculosis therapy. Asian Journal of Pharmaceutical and Clinical Research. 2016 Sep 1;9(5):136–9.
9. Perwitasari D, Setiawan D, Safaria T, Dania H, Faridah I, Irham L. LIVER FUNCTIONS PROFILE OF TUBERCULOSIS PATIENTS IN INDONESIA DURING ANTITUBERCULOSIS TREATMENT. International Journal of Applied Pharmaceutics. 2024 Feb 1;16(Special Issue 1):89–92.
10. Zhong T, Fan Y, Dong XL, Guo X, Wong KH, Wong WT, et al. An Investigation of the Risk Factors Associated With Anti-Tuberculosis Drug-Induced Liver Injury or Abnormal Liver Functioning in 757 Patients With Pulmonary Tuberculosis. Front Pharmacol. 2021 Nov 8;12.
11. Ali N, Gupta N, Saravu K. Malnutrition as an important risk factor for drug-induced liver injury in patients on anti-tubercular therapy: an experience from a tertiary care center in South India. Drug Discov Ther. 2020 Jun 30;14(3):135–8.
12. Ramappa V, Aithal GP. Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management. Vol. 3, Journal of Clinical and Experimental Hepatology. 2013. p. 37–49.
13. Jiang F, Yan H, Liang L, Du J, Jin S, Yang S, et al. Incidence and risk factors of anti-tuberculosis drug induced liver injury (DILI): Large cohort study involving 4652 Chinese adult tuberculosis patients. Liver International. 2021 Jul 1;41(7):1565–75.
14. Zhao H, Wang Y, Zhang T, Wang Q, Xie W. Drug-induced liver injury from anti-tuberculosis treatment: A retrospective cohort study. Medical Science Monitor. 2020 Mar 7;26.
15. Xing Z, Sun T, Janssens JP, Chai D, Liu W, Tong Y, et al. Airflow obstruction and small airway dysfunction following pulmonary tuberculosis: a cross-sectional survey. Thorax. 2023 Mar 1;78(3):274–80.
16. Hadida M, Abo-Smhadana A, Draid M. Effects of Anti-Tuberculous Drugs on Liver Function Profile in Libyan Patients with Tuberculosis. Egypt J Hosp Med. 2013 Jul;(52):740–51.
17. Wai YEW W, Chiu LEUNG C. Antituberculosis drugs and hepatotoxicity. Respirology [Internet]. 2006;11:699–707. Available from: https://onlinelibrary.wiley.com/doi/10.1111/j.1440-1843.2006.00941.x,
18. Dijkman K, Aguilo N, Boot C, Hofman SO, Sombroek CC, Vervenne RAW, et al. Pulmonary MTBVAC vaccination induces immune signatures previously correlated with prevention of tuberculosis infection. Cell Rep Med. 2021 Jan 19;2(1).
19. Chang TE, Huang YS, Su WJ, Perng CL, Huang YH, Hou MC. The role of regular liver function monitoring in antituberculosis drug-induced liver injury. Journal of the Chinese Medical Association. 2019;82(7):535–40.