What’s in the web for family physicians − Quaternary prevention for primary care practice – Part 2

Sio-pan Chan 陳少斌，Wilbert WB Wong 王維斌，Alfred KY Tang 鄧權恩

In our previous issue, we explored various aspects of quaternary prevention, including:

• Statin overuse
• Percutaneous Coronary Intervention (PCIs)
• Screening for Cancer with PET and PET/CT
• Probiotics

In this issue, we will explore additional topics related to quaternary prevention, as outlined below:

Attention deficit hyperactivity disorder (ADHD) in children and adolescents

1. Centers for Disease Control and Prevention (CDC). Data and Statistics About ADHD. [Internet]. 2022 [cited 2023 Oct 10]. Available from: https://www.cdc.gov/ncbddd/adhd/data.html
2. Kazda L, Bell K, Thomas R, et al. Overdiagnosis of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Systematic ─ lScoping Review. JAMA Netw Open.
   2021;4(4):e215335. doi:10.1001/jamanetworkopen.2021.5335.

According to the Centers for Disease Control and Prevention (CDC), an estimated 11.0% of U.S. children aged 3-17 years have been diagnosed with ADHD based on recent data. This translates to approximately 6 million children. ADHD diagnosis rates vary by gender, with boys being diagnosed more frequently (13%) compared to girls (6%). The prevalence is more common in White and Black children and less common in Asian children. The above review article suggests that ADHD may be overdiagnosed in children and adolescents, particularly in cases with milder symptoms. For these individuals, the potential harms associated with an ADHD diagnosis include stigmatisation and adverse effects of medication. ADHD medications, particularly stimulants like methylphenidate (e.g. Ritalin) and amphetamines (e.g. Adderall), can have serious side effects. These include cardiovascular issues, psychiatric side effects, growth suppression, seizures, and the potential for substance abuse. It is crucial to ensure that the benefits of treatment outweigh the potential harmful effects, which can persist into adulthood.

Biomarkers for Alzheimer's disease (AD)

1. Boenink M, van der Molen L. The biomarkerization of Alzheimer’s disease: From (early) diagnosis to anticipation? In: Schermer M, Binney N, editors. A pragmatic approach to conceptualization of health and disease. Cham: Springer; 2024. p. 151. Available from: https://doi.org/10.1007/978-3-031-62241-0_11
2. National Institute on Aging. How Is Alzheimer's Disease Treated? [Internet]. 2023 [cited 2023 Oct 10]. Available from: https://www.nia.nih.gov/health/how-alzheimers-disease-treated

AD is primarily a clinical diagnosis. However, the advent of technologies such as PET scanning and CSF analysis has enabled the observation of plaques and neurofibrillary tangles (now known to consist of amyloid (A) and tau (T) proteins, respectively). The criteria for diagnosing AD, issued by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA), have undergone significant changes. Over the past 15 years, these criteria have been adjusted to incorporate new findings and to introduce the concept of ‘preclinical Alzheimer’s disease.’ Biomarker research has gradually shifted the approach to AD from an ‘ontological’ (focused on the nature of the disease) to a ‘physiological’ (focused on biological processes) perspective. The National Institute on Aging (NIA) and the Alzheimer's Association (AA) proposed a draft for new diagnostic criteria and staging of AD in 2023 as follows:

• Preclinical Stage: This stage involves the presence of biomarkers (A and T) without clinical symptoms. It is divided into two phases: early preclinical (A+/T-) and late preclinical (A+/T+).
• Mild Cognitive Impairment (MCI): Individuals may experience mild cognitive changes that do not interfere significantly with daily life. Biomarkers are used to distinguish between MCI due to AD and other causes.
• Mild AD: This stage is characterised by noticeable cognitive decline that affects daily activities. Biomarkers confirm the presence of AD pathology.
• Moderate to Severe AD: Cognitive decline becomes more pronounced, and individuals require substantial assistance with daily activities. Biomarkers continue to be used to monitor disease progression.

According to the new diagnostic criteria, there is a large number of preclinical AD and MCI patients. Overdiagnosis and overtreatment with very expensive treatments targeting the biomarkers may pose a real financial burden and significant adverse effects. Biologics such as lecanemab and donanemab can have significant side effects, including brain swelling and microhaemorrhages. These risks may outweigh the potential benefits, especially in patients with MCI who may not progress to AD.

Tumour markers

1. National Cancer Institute. Tumor Markers Fact Sheet. [Internet]. [cited 2023 Oct 10]. https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet
2. Moyer VA. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120-134. doi:10.7326/0003-4819-157-2-201207170-00459.
3. Ilic D, Neuberger MM, Djulbegovic M, et al. Screening for prostate cancer. Cochrane Database Syst Rev. 2013;(1):CD004720. doi:10.1002/14651858. CD004720.pub3.

Tumour markers are substances often found in higher concentrations in the blood, urine, or tissues of patients with cancer. A notable example is the prostate-specific antigen (PSA), which is widely used for the early detection of prostate cancer. However, reliance on such markers requires careful evaluation to avoid the risks of overdiagnosis. Elevated tumour marker levels do not always indicate the presence of clinically significant malignancies, which can lead to unnecessary anxiety among patients and result in invasive procedures that may not be warranted. Research on PSA testing, multi-parametric MRI (mp-MRI), and ultrasound-guided biopsies reveals that while advancements in imaging technology have improved diagnostic capabilities, they also raise concerns about the potential for overdiagnosis. Many men with elevated PSA levels may never develop life-threatening prostate cancer. In the United Kingdom, there is no national prostate cancer screening program because the PSA test is considered not reliable enough. A large study from 2013 looked at the results of different trials comparing men who underwent prostate screening with those who did not. The study showed that screening did not save any lives, and the men who took part in screening were more likely to be overdiagnosed.

More examples of tumour markers associated with overdiagnosis

CA-125: CA-125 is a marker used mainly for ovarian cancer. It can help monitor treatment response or recurrence. Many benign conditions, such as endometriosis or pelvic inflammatory disease, can elevate CA-125 levels. This can lead to overdiagnosis and unnecessary surgeries in patients who might not have ovarian cancer, highlighting the importance of careful interpretation of CA-125. It is also important to note that CA125 level may vary with the menstrual cycle, with higher readings often observed during menstruation, as a result of endometrial shedding. CA 125 should ideally be tested after menstruation for more reliable results.

CEA is a glycoprotein that plays a role in cell adhesion and is primarily associated with colorectal cancer, though it can also be elevated in other cancers. While often used to track disease progression and treatment response, its lack of specificity can complicate cancer diagnosis and may lead to overdiagnosis, especially when used for screening asymptomatic individuals. Elevated CEA levels can result from benign conditions like inflammation, infection, or smoking. High CEA levels have often led to additional tests, such as imaging and invasive procedures, imposing significant psychological and physical stress on patients. It is crucial to adopt a cautious approach to CEA testing, ensuring its use is warranted and that patients are protected from unnecessary harm.

Depression

1. Aragonès E, Piñol JL, Labad A. Overdiagnosis of depression in non-depressed patients in primary care. Fam Pract. 2006;23(3):363-368. doi:10.1093/fampra/cmi115.

This article investigates the prevalence and determinants of overdiagnosis in primary care settings. The research involved a cohort of 906 patients from Spain, utilising Zung's Self-Rating Depression Scale and the Structured Clinical Interview for DSM-IV Disorders for assessment. The study revealed that 26.5% of non-depressed patients were mistakenly diagnosed with depression. Contributing factors to this overdiagnosis included elevated scores on the depression scale, reduced functioning scores, a previous history of depression, and the presence of generalised anxiety. The article concludes that family physicians frequently misclassify patients as depressed despite the absence of formal diagnostic criteria, potentially due to psychological distress or historical depressive episodes. The study underscores the necessity for enhanced diagnostic tools and training for primary care physicians to prevent overdiagnosis and ensure accurate treatment.

Chronic kidney disease (CKD)

1. Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin C-based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737- 1749. doi:10.1056/NEJMoa2102953.
2. O'Hare AM, Hotchkiss JR, Kurella Tamura M, et al. Rethinking the use of race in estimating kidney function. JAMA Intern Med. 2021;181(5):743- 745. doi:10.1001/jamainternmed.2021.4823.
3. O'Hare AM, Rodriguez RA, Bowling CB. Rethinking chronic kidney disease in older adults: a perspective. JAMA Intern Med. 2021;181(5):745- 6. doi:10.1001/jamainternmed.2021.4823.

The estimated Glomerular Filtration Rate (eGFR) is a key measure of kidney function. It is calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula and factoring in blood creatinine levels, age, sex, and sometimes race. While eGFR is useful for detecting and monitoring kidney disease, it has limitations. These include reduced accuracy among certain populations (e.g., very young or old individuals, pregnant women), dietary creatine intake, body muscle mass, medication, and hydration. Additionally, it may not detect early kidney damage and assumes stable kidney function. A more accurate method of measuring eGFR is the combined measurement of blood levels of both creatinine and cystatin C (CKD-EPI Creatinine-Cystatin C). A 24-hour urine creatinine clearance test is another reliable way to calculate GFR.

The articles listed both address the issue of overdiagnosing CKD in older adults due to the lack of age-adjusted diagnostic criteria. They highlight that such overdiagnosis can lead to unnecessary treatments, increased healthcare costs, and reduced quality of life. Both reviews emphasised the need for prevention, early detection, and appropriate management of CKD, including the use of nephroprotective drugs and patient-centered care. Furthermore, they advocate for personalised renal replacement therapies and revised diagnostic criteria to more effectively identify individuals who are genuinely at risk and to mitigate the adverse consequences of overdiagnosis.

Conclusion

In family medicine, quaternary prevention is essential for addressing the challenges of overdiagnosis and overtreatment. Family physicians, often the first point of contact in healthcare, play a pivotal role in ensuring that patients receive appropriate care without unnecessary interventions. As diagnostic technologies advance, the risk of identifying conditions that may never cause harm increases, leading to treatments that can expose patients to unwarranted side effects and stress. This not only affects individual patients but also places a significant financial burden on the healthcare system. By focusing on quaternary prevention, family medicine practitioners can prioritise patient-centered care, ensuring that interventions are necessary and beneficial. This approach helps to allocate healthcare resources more effectively, reducing waste and enhancing the overall sustainability of the healthcare system. By fostering a careful and considered approach to diagnosis and treatment, family medicine can lead the way in promoting a more balanced and equitable healthcare environment.