HZ, Metabolic Disorders, and TB

Mendelian Randomization and Tuberculosis

Mendelian Randomization (MR) is a scientific approach that assesses causal relationships between modifiable risk factors and clinically relevant outcomes by utilizing genetic variants as instrumental variables. Unlike traditional observational studies, MR is less susceptible to confounding factors and reverse causality, focusing on genetic components derived from genome-wide association studies (GWAS). When clinical research through randomized controlled trials (RCTs) is too costly, impractical, or unethical, MR provides a robust alternative for understanding disease mechanisms and informing preventive or therapeutic interventions.

In this study, two-sample MR analysis was employed to investigate the causal relationships between metabolic factors and pulmonary tuberculosis (PTB). Key findings include:

• Causal Links: HDL-C, HbA1c, TP, and diabetes mellitus (DM) were found to be causally linked to PTB incidence.
• Lipid Metabolism and TB: HDL-C, LDL, and triglycerides (TG) were positively correlated with PTB, while total cholesterol (TC) was negatively correlated.
• Metabolic Disorders: Hyperglycemia and dyslipidemia were associated with active PTB, highlighting abnormalities in lipid metabolism as direct contributors to TB risk.

See also: https://lintblab.weebly.com/source-code-package-for-download.html

Tuberculosis Pathogenesis and Continuum

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and transmitted via airborne droplet nuclei (1–5 µm). Following exposure:

• 20–25% of individuals become infected.
• 5–10% of these may develop active TB within five years, while the remaining cases are typically controlled by innate and adaptive immune responses.
• Risk of progression to active TB is significantly higher for individuals with HIV co-infection.

Evolving Understanding of TB Pathogenesis: Historically, TB was classified as either latent TB infection (LTBI) or active TB disease. Recent evidence indicates a continuum from LTBI to active TB, influenced by:

• The metabolic state of Mtb, transitioning from dormancy to active replication.
• Host immune responses that control infection.

To capture this spectrum, the World Health Organization (WHO) has proposed replacing "latent TB infection" with "TB infection" and recognizing additional stages: incipient TB, subclinical TB without symptoms, subclinical TB with unrecognized symptoms, and symptomatic TB disease.

Stages of TB Infection and Disease

1. Incipient TB: A transitional stage with minimal bacterial replication. Diagnostic tools like TST and IGRAs remain positive, but specific markers for this stage are lacking.
2. Subclinical TB: Classified as disease due to viable, replicating Mtb. Despite the absence of clinical symptoms, radiological and microbiological tests reveal abnormalities. Subclinical TB may contribute significantly to Mtb transmission, with an estimated 7 million cases globally.

Public Health and TB Care

To monitor and improve TB management, the "cascade of care" framework is used to track progress through stages like screening, diagnosis, treatment initiation, and completion. Maintaining registries for TB infection and active TB cases is essential.

WHO Research Priorities:

1. Assessing progression risks from TB infection to active disease.
2. Developing algorithms to exclude active TB.
3. Improving TB infection diagnostic tools and preventive therapy for at-risk populations.

Metabolic Comorbidities and TB

Metabolic disorders, particularly diabetes mellitus (DM), significantly affect TB outcomes. Key findings include:

• Impact on TB Outcomes: DM increases the risk of extended TB treatment duration and recurrence, with a hazard ratio (HR) of 0.72 for non-DM patients compared to TB-DM patients.
• Prevalence: In Korea, DM prevalence among TB patients ranges from 17.4% to 38.9%, with older men and lower-income groups at higher risk.
• New-Onset Diabetes: Approximately 12.5% of TB patients develop diabetes post-TB diagnosis, often presenting with advanced TB stages.

TB and Comorbid Risks

• Herpes Zoster (HZ): TB patients have an increased risk of developing HZ, with adjusted hazard ratios (aHR) of 1.23. The risk is exacerbated by comorbidities like DM, CKD, CAD, and cancer. Even without comorbidities, TB independently raises HZ risk by 1.28 times.
• Lipid Abnormalities and TB: Dyslipidemia and hyperglycemia were linked to active PTB, with HDL-C, LDL, and TG positively correlated, while TC showed a negative correlation.

Future Directions

• Research Gaps: Current data lack insights into behavioral factors (e.g., smoking, drinking) and glycemic control among TB-DM patients.
• Recommendations: Future studies should integrate hospital-based cohort data with national registry systems to better understand and address TB and its comorbidities.

References:

1. Du, Z.X., Ren, Y.Y., Wang, J.L., Li, S.X., Hu, Y.F., Wang, L., Chen, M.Y., Li, Y., Hu, C.M. and Yang, Y.F., 2024. The potential association between metabolic disorders and pulmonary tuberculosis: a Mendelian randomization study. European Journal of Medical Research, 29(1), p.277.
2. Migliori GB, Ong CWM, Petrone L, et al. The definition of tuberculosis infection based on the spectrum of tuberculosis disease. Breathe 2021; 17: 210079. https://tuberculosis101.blogspot.com/2024/11/the-definition-of-tuberculosis.html
3. Wang C-A, Chen C-H, Hsieh W-C, Hsu T-J, Hsu C-Y, Cheng Y-C, Hsu C-Y. Risk of Herpes Zoster in Patients with Pulmonary Tuberculosis—A Population-Based Cohort Study. International Journal of Environmental Research and Public Health. 2023; 20(3):2656.
4. Khattak M, et al. (2024). Tuberculosis (TB) treatment challenges in TB-diabetes comorbid patients: a systematic review and meta-analysis, Annals of Medicine, 56:1, 2313683.
5. Jeong D, et al. Prevalence and associated factors of diabetes mellitus among patients with tuberculosis in South Korea from 2011 to 2018: a nationwide cohort study. BMJ Open 2023;13:e069642. https://tbreadingnotes.blogspot.com/2024/11/dm-among-patients-with-tb-in-south.html

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