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“Ye baal nahi hai, ye main hu” the line says it all!

Our hair speaks volumes about our health and well-being. So, if you are suddenly noticing lots of hair on your hair brush or bathroom floor, it could be a sign of underlying health conditions. There are several ways to fix hair fall, but before finding the right fix, it is essential to understand the cause of your hair fall.

Genetics at play

One key factor for hair fall is genetics. Genetics determine how your hair will grow (or worsen) with age. Hereditary hair fall is called androgenic alopecia (male pattern baldness or female pattern baldness). We all have 23 chromosome pairs containing genes packed with genetic information. These genes decide all your traits, right from your eye colour to blood type. A pair of sex chromosomes determines your biological sex (women contain XX, whereas men contain XY chromosomes).

The X chromosome contains an AR gene that helps synthesize androgen receptor protein. Changes in this gene increase the activity of androgen receptors in hair follicles, causing shortened hair growth cycle, delayed growth of new hair and shorter weaker hair. Men inherit the X chromosome from their mother, hence the common myth that male pattern baldness comes from maternal family. Now before you get all upset over your mother for your hair fall, know that the latest research suggests that >80% of people with alopecia have a father suffering from the same. Also, hereditary hair fall involves >63 genes, and only six of them are found on the X chromosome.

Lifestyle matters too

Before blaming your parents for anything, consider that problem might also be you. Your lifestyle choices are the second biggest contributing factor to hair fall. Let’s take a look at your enemies that are masquerading as allies in this battle against hair fall.

1. You are what you eat, and so are your hair

Anything in excess is bad for your health, mainly excess sugar. If you are eating foods high in glycemic index (GI), it is not going to affect only your body but your hair too. Common examples include white bread, white rice, potatoes, refined flour and sweets. High-GI foods disturb the hormonal balance. This further spikes up your insulin and androgens, which bind to hair follicles and cause hair fall. Moreover, if your body is running low on proteins, it will find ways to conserve them, and this includes halting hair growth. After 2–3 months, your hair will start falling out. So, include more proteins and iron in your diet. Also, be sure to eat enough beans, pulses, meat, eggs, fish, nuts, seeds and mineral-rich foods.

2. Worth the weight?

If you spend almost 9 hours/day sitting and are overall physically inactive, the resulting obesity is going to play havoc with your hormones. When you are overweight, your body goes under extreme stress to produce thyroxine and insulin, causing hormonal imbalance. The link between insulin resistance and hyper/hypothyroidism creates a chain of reactions throughout the body, which affects your hair too. Obesity also hampers your heart functions. With problems like abnormal blood pressure and high cholesterol, you might have to live on medications for life, and prolonged use of some drugs has a tendency to impact hair structure and growth.

It’s not just about weight gain. If you have undergone weight-loss surgery, your hair is at risk of falling too. Post surgery, your zinc levels will likely be low, making your hair dry and prone to breakage. Check with your doctor whether you need zinc and copper supplements.

3. Skin conditions

Not only our emotions, but our scalp is sensitive too. Various scalp conditions can lead to hair fall. Seborrheic dermatitis is a common culprit. It often occurs near the oil-secreting sebaceous glands on your scalp and skin and causes scaly patches, inflamed skin, itching and dandruff.

4. Steroids: Gaining muscles or losing hair?

If you are fitness fanatic, you might have taken steroids to bulk up. Steroids increase muscle mass, strength and athletic performance, but they can also strip off your scalp. Steroids can do both: 1) accelerate male pattern baldness and 2) induce hair fall in those who are not genetically predisposed to it. In men, testosterone is the most common steroid hormone. Taking steroids increases the production of testosterone and its byproduct dihydrotestosterone. Both strongly bind to hair follicles, causing them to shrink and shortening the hair growth cycle. This makes your hair thinner, more brittle and fall out fast. So, higher the levels of steroids, higher the damage to hair.

5. Smoking kills

And it doesn’t get said enough. Be it your heart, lungs, kidneys, brain, teeth, gums or hair, cigarettes induce a slow death that no part of your body can escape. Cigarette components are vasoconstrictors. Meaning? They narrow down your blood vessels and block/reduce blood flow throughout the body. Your hair follicles always require a fresh supply of blood to stay healthy. Reduced blood flow slows down hair growth and damages hair structure. There is simply no good reason to spark up that next cigarette. Just quit!

6. Relax, don’t stress it

Stress: No one wants it, but sometimes some situations present it in front of us. Cortisol is a primary stress hormone released by your body. The resulting hormonal imbalance causes either of the following:

1. Telogen effluvium: Stress pushes your hair follicles into resting phase, so that they don’t produce new hair strands and are prone to falling out.
2. Trichotillomania: Some people under stress have an irresistible urge to pull out hair. This is often a psychological way of handling stress, which leads to hair fall.
3. Alopecia areata: The body’s immune system can start attacking hair follicles, causing hair fall.

In today’s world, it is an absolute must to prioritize your mental health. You can deal with stress in many ways. Learn some relaxation techniques (meditation, yoga, breathing exercises, etc.), get regular exercise, follow a healthy diet or seek positive-minded company. Remember, be it hair fall or mental health, if there is a problem, there is always a solution.

7. Medical conditions & medications

A wide spectrum of health conditions can cause hair fall, like pregnancy, childbirth, menopause, polycystic ovary syndrome, nutrient deficiencies, thyroid problems, eating disorders, cancer, etc. Certain medications can also exert effects that lead to hair fall. Some common examples include:

1. Blood thinners
2. Acne medicines
3. Antidepressants
4. Beta-blockers
5. Cholesterol-lowering drugs
6. Medications high in vitamin A
7. Anabolic steroids
8. Birth control pills

If you are already on medications and experiencing hair fall, consult your doctors for proper guidance.

8. Treat your hair with care

If none of the above are applicable or make sense as to why you are having hair fall, then maybe it’s time to step back and reconsider your hair care routine. Several mistakes in our routine can damage hair and scalp:

1. Using too much shampoo
2. Using chemical products (sulfate-based shampoos, bleach, hair sprays, dyes, etc.)
3. Brushing hair vigorously
4. Combing wet hair
5. Drying wet hair with a towel
6. Using excess heat on hair (blow dryers, curling/flat iron, etc.)
7. Tying your hair tight
8. The list might be too long to continue…

Testing at Thyrocare

Our body is always giving signs and symptoms of potential health problems. So, instead of visiting your doctor tomorrow (which never arises), get regular health check ups for prevention and early diagnosis. Thyrocare has launched Hair Fall Screening Advanced Profiles for men and women. The profiles evaluate over 40 health parameters and help you get to the root cause of your hair fall. Don’t delay and get tested today!

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PCA is one of the most common cancers in men, accounting for about 15% of all cancer incidences worldwide and the fifth leading cause of cancer death in men. Most PCAs grow slowly and are relatively low-grade with low risk and limited aggressiveness. When suspected of PCA, what comes next is identifying the culprit, followed by assessing disease progression.¹

The Culprits

Through efforts to understand the aetiology of PCA, it was found that they are multi-factorial and remain baffling with numerous modifiable/unmodifiable risk factors.^1,2

• Age

Age is an established unmodifiable risk factor for PCA. It is found to be rare below the age of 40. The chances of developing PCA go up from 0.005% in <39-year-oldmen to 2.2% in 40-59-year-old men, and 13.7% in 60-70-year-old men. The probability of histological diagnosis of PCA is 50% higher in 70-80-year-old men, showing evidence of malignancy. Fortunately, low-grade histological diagnosis of PCA often follows a course without any significant risk of death.³

• Family History & Genetic Predisposition

PCA has an increased heritability. Men with brothers or fathers diagnosed with PCA have a four-fold risk of developing PCA, with a higher risk if a brother is diagnosed. The genetic risk factor increases with more relatives being affected. The risk of PCA is also high when families have breast cancer and PCA traits.³

• Smoking & Alcohol

Among the modifiable risk factors for PCA, smoking is associated with increased cancer incidence and mortality. In one meta-analytical study, the risk of PCA increased with increased smoking frequency. Ex-smokers had an increased risk of PCA, and heavy smokers had a 30% increased risk of PCA-related deaths. The association between alcohol consumption and PCA risk remains to be fully elucidated. However, a significant dose-response relationship between the two has been reported, where the risk increases with increasing alcohol intake compared to non-drinkers.³

• Obesity & Metabolic Syndrome

Obesity and increased body mass index are associated with PCA. Increased adiposity increases PCA-related mortality risk. Possible reasons relating to PCA risk and obesity are insulin-like growth factor 1 (IGF-1), adipokines and sex hormones. Plasma adiponectin concentrations fall with increasing obesity, especially in men. Therefore, adiponectin can be used as a potential biomarker in PCA diagnosis.

A cluster of conditions including excess body fat with increased waist circumference, hyperglycemia, hypertension, hypercholesterolemia/ high triglycerides, is associated with metabolic syndrome, which increases the risk of colorectal and breast cancers. Metabolic syndrome is slightly associated with the incidence of PCA and greatly associated with aggressive disease spread and biochemical recurrence.³

• Physical Activity

Inverse relationship exists between the risk of progression and mortality from PCA and physical activity. A study of 2705 men with PCA revealed a 61% reduction in risk of PCA-specific mortality in men who did minimum 3 hours/week of vigorous exercise. However, there is no concrete evidence to prove that regular physical activity reduces the risk of developing PCA.³

• Diet & Nutrition

Numerous studies have investigated the association between PCA and our diet. Consumption of high-processed foods exhibit increased PCA risk, and conversely, intake of unprocessed/limited processed foods exhibit lower risk of PCA.³

• Medication

Metformin, an antidiabetic agent, is the cornerstone of type 2 diabetes mellitus treatment, but recent research has shed light on its anti-neoplastic properties, particularly in PCA patients. Metformin usage is reportedly associated with reduced PCA risk and progression. Various antineoplastic mechanisms of metformin involve pathways like adenosine monophosphate-activated protein kinase activation and inhibition of the mammalian target of rapamycin activity and induction of apoptosis.³

• Hormones

Decades ago, studies described a close relationship between testosterone/androgens to prostate growth, which led to anti-androgen treatment as a cornerstone of metastatic PCA treatment. However, recently, there has been a paradigm shift in this understanding and application of testosterone to PCA risk, progression and survival. Considering intraprostatic androgen receptor sites are completely saturated/bound, anything above the baseline serum testosterone concentration plays no further role in stimulating prostate growth.^1,3

• Infection, Inflammation and Chemokines

Chronic inflammation often results from exogenous stimuli like infections, chemicals, radiation, hormones and other noxious stimuli. Cancers/tumours can often be a subsequent chain of events related to chronic inflammation. The key feature of cancer-related inflammation is crowding leukocytes, production of cytokines and chemokines, subsequent disease progression, angiogenesis, epithelial-mesenchymal transition, migration and metastasis. PCA is no different and numerous studies have investigated the role of cancer cell-produced chemokines and PCA-related chronic inflammation pathways.³

Figure 1: Prevention and Early Detection of Prostate Cancer

Paving way for Diagnosis

Early detection and treatment improves disease management and survival. Unfortunately, there aren’t any early warning signs for small bulk-localised PCA. The growing tumour does not push against anything to cause pain, so for many years, the disease may be silent. Hence, regular screening for PCA is important for all men, mainly >50-year olds.⁴

• Knowing the Genes

PCA seems to run in some families, suggesting that in some cases there is an inherited or genetic factor. Therefore, it is essential to determine the family history of PCA.

• Physical Examination

Physical examinations often include digital rectal exam (DRE). DRE test helps determine if the cancer is on only one or both sides of the prostate or if it has spread beyond the prostate to nearby tissues. Other areas of the body may also be examined.

• PSA blood test

PSA is a protein found in the prostate gland and produced by both normal and cancer cells. Although present majorly in semen, PSA is found in the blood in small amounts. This test is used mainly to screen for PCA in men without symptoms. It’s also one of the first tests performed in men with symptoms of PCA.

• Prostate biopsy

If PSA blood test, DRE or other test results suggest the presence of PCA, a biopsy is demanded to confirm the diagnosis.  Small samples of the prostate are removed and looked at under a microscope. Core needle biopsy is the main method used to diagnose PCA.

• Staging and Grading

Once PCA is confirmed by biopsy, it’s important to learn the location (stage) and aggressiveness (grade) of the tumour.

Figure 2: Histological Descriptions of New Grading Categories

• Prostatic intraepithelial neoplasia

Premalignant changes in the epithelium are referred to as prostatic intraepithelial neoplasia (PIN). It is observed in over 70% of invasive PCA cases. It is seen much less frequently in normal prostates removed at necropsy. Around 40% non-cancerous prostates harbour PIN.³

• Genetic Testing

Some men with PCA are recommended to get tested for certain inherited gene changes. This includes men with suspected family cancer syndrome, such as BRCA gene mutation or Lynch syndrome, and men with PCA with high-risk features or metastatic growth.

• Transrectal ultrasound

Transrectal ultrasound is a procedure in which a small finger-wide probe is inserted in the rectum. This probe gives off sound waves that enter the prostate and create echoes. The probe then picks up the echoes, and the computer converts them into black-and-white image of the prostate.²

• Magnetic resonance imaging

Magnetic resonance imaging scans create detailed images of soft tissues in the body using radio waves and strong magnets. These scans can give doctors a very clear picture of the prostate and nearby areas. A contrast material called gadolinium may be injected into a vein before the scan to see details better.

• Computed Tomography scan

Computed tomography is less often required for newly diagnosed PCA, if the cancer is confined to the prostate. Still, it can help in analysing if PCA has spread into nearby lymph nodes. These scans can often tell if the cancer is growing into other organs or structures in the pelvis.⁴

• Lymph node biopsy

In a lymph node biopsy, also known as lymph node dissection or lymphadenectomy, one or more lymph nodes are removed to see if they have cancer cells. This is not done very often for PCA, but it is used to check if the cancer has spread to nearby lymph nodes.²

Beating PCA

Though it has one of the highest survival rates of any type of cancer, early accurate diagnosis, better therapies, understanding disease aggressiveness and progression, highlighting and addressing the key challenges and bridging the gap between unresolved questions in PCA can help improve the outcomes in successfully beating cancer.

References

1. Currier, J. M., Holland, J. M., Drescher, K., & Foy, D. (2015). Initial psychometric evaluation of the Moral Injury Questionnaire—Military version.Clinical psychology & psychotherapy, 22(1), 54-63. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911573/
2. Cuzick, J., Thorat, M. A., Andriole, G., Brawley, O. W., Brown, P. H., Culig, Z., … & Wolk, A. (2014). Prevention and early detection of prostate cancer.The lancet oncology, 15(11), e484-e492. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203149/
3. Gann, P. H. (2002). Risk factors for prostate cancer.Reviews in urology, 4(Suppl 5), S3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1476014/
4. Ng KL. The Etiology of Prostate Cancer. In: Bott SRJ, Ng KL, editors. Prostate Cancer [Internet]. Brisbane (AU): Exon Publications; 2021 May 27. Chapter 2.Available from: https://www.ncbi.nlm.nih.gov/books/NBK571322/ doi: 10.36255/exonpublications.prostatecancer.etiology.2021 https://www.ncbi.nlm.nih.gov/books/NBK571322/#:~:text=The%20etiology%20of%20prostate%20cancer%20is%20multifactorial%20and%20remain%20quite,family%20history%2C%20and%20African%20ancestry.

Writer & Reviewer: Namitha Prabhu & Dr Sachin Patil

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It was hard to imagine that a new infection would wreak a global havoc, causing loss of lives and economic devastation. The recent pandemic has once again highlighted the vulnerability of our species to disease-causing pathogens. Despite advanced healthcare systems, we struggled to effectively limit this outbreak in time, resulting in grave consequences. Medical personnel worldwide risked their lives during the pandemic to provide round-the-clock treatment and care to inflicted. It is imperative to have stringent protocols towards controlling spread and effective healthcare strategies to combat such threats. Among the most contagious diseases capable of reaching a pandemic scale was Influenza or ‘flu’, which still poses a potential threat if not addressed appropriately.

Influenza as a global epidemic

The ‘Spanish Flu’ or 1918 Influenza Pandemic was one of the deadliest disease outbreaks of the 20th century. It recorded nearly 50 crore global infections and 10 crore deaths. When it struck India in 1918, it wiped out nearly 5% of the population, i.e., 1.2 crore deaths. Three subsequent Influenza pandemics encountered in 1957, 1968 and 2009, collectively claiming around 26 lakh lives albeit with successively declining mortality rates.^[1]

Origin of the Influenza virus

Although it is impossible to trace back when the first human-infecting Influenza strain evolved, historical writings from as early as 6,000 BC mention afflictions with similar symptoms. The term Influenza originated nearly in the 15th century from the Latin word Influentia translating to ‘Influence’ and was later commonly used to describe illness similar to severe cold. The microbial cause of the disease was unknown until the virus was discovered in 1892 and Influenza A was isolated in 1933.^[2]

Figure 1: Timeline of pandemics in the world

Influenza and its strains

Influenza is a group of helix-shaped single-stranded RNA viruses from the orthomyxovirus family classified into A, B, C and D genera. Influenza A, B and C result in respiratory illness in humans with majority of the cases resulting from type A and B and rarely from type C. Type D is reportedly affects cattle and swine populations.^[3]

Figure 2: Naming of flu viruses

Monitoring of Influenza A or alphainfluenza virus (AIV) is considerably crucial with virulent strains capable of affecting humans pandemically. AIV is further classified into subtypes determined by surface antigens hemagglutinin and neuraminidase. Reportedly, eight H and six N subtypes infect humans. AIV was the cause of the 2009 H1N1 (swine flu) pandemic and recurring H5N1 (bird flu) outbreaks.^[3]

Prevention and Treatment

Measures limiting the spread of the Influenza in 1918 were similar to those applied for COVID-19, e.g. social distancing and using masks in public. Curfews were implemented for non-essential services and personnel. Affected individuals were quarantined. The treatment involved supportive healthcare with antibiotics to prevent secondary viral infection. Although the first wave was mild, second one was remarkably more virulent. Notably, individuals who had contracted the disease in the first wave were relatively immune to the virus in the second and third waves. This provided strong evidence that the 1918 pandemic was a series of a mutated variant of the same Influenza virus. Young adults were the worst affected, and the concept of cytokine storm was then poorly understood. Older adults had acquired protective immunity from earlier influenza outbreak, exhibiting milder infections. The only treatment then effective was blood transfusions from recovered patients; however, this could not be carried out on a large scale.

Figure 3: Newspaper articles for prevention of Influenza spread

In 2001, the frozen tissue and lung samples of victims from the 1918 pandemic were analysed to understand the cause and epidemiology of the virus. Molecular techniques used to analyze the strains revealed their ancestry to H1N1 virus. Different strains were documented with an increased virulence in the successively encountered strains due to pantropism (affecting multiple organs).^[6]

Public Health Lessons

Highly contagious and often asymptomatic, Influenza spreads rapidly, especially in highly populated areas. In 1918 when the flu struck Bombay, it soon came to be known as the ‘Bombay fever’ among the local populace. By the time its lethality was ascertained, it had invaded countless households and communities. Within a few months, it reached every state with an alarming number of casualties.

An interesting article published in the Times of India on 25th June 1918 highlighted the effect on businesses and implied hope for future medical sciences to better understand and contain such diseases.

Figure 4: Newspaper article, TOI, June 25 1918

Statistical data was analysed to understand the diffusion of the virus through the population. However, this was difficult to accomplish on a large scale as various factors, including public health response, social interactions and travel patterns, are location-specific. Such analyses pinpoint vulnerabilities of specific communities to pathogenic threats, leading to better management during crisis.^[4][5]

One of the factors limiting the spread of infection in the past was the lack of transport facilities. A small proportion of individuals were involved in long distance travel, which took longer by trains or ships. Today, travel is frequent with commercial airlines. As with COVID-19, it is crucial to restrict symptomatic individuals at airports. Despite such measures, asymptomatic individuals may still be overlooked, raising the requirement of rapid assays. Although rapid test kits for several diseases are developed based on the lateral flow immuno-chromatographic technique, these are not usually available for a new pathogen when it emerges. Although preventive measures limit the contagion till effective treatment or vaccines are available, it takes considerable time with clinical trials and stringent protocols for their implementation.^[4][5]

For COVID-19, a global R&D initiative was undertaken by private healthcare and government sectors for vaccine development. Multiple effective vaccines were produced and disseminated by many countries among the population in a short time-frame. Vulnerable sections of society, including senior citizens and those with pre-existing conditions, were prioritized, which was followed by administering the vaccines to the entire population.^[5]

Advancement in laboratory sciences and medical fields has resulted in molecular techniques that better identify and characterize the genotypic structure of pathogens, thereby accelerating vaccine development. Clearer understanding of the mechanisms involved in the transmission and manifestation of symptoms has led to effective drug therapies and supportive care. With each encountered pandemic, we have gained experience on how to mitigate and cure rapidly spreading diseases.

What should India do next?

To reduce the risk of a future endemic, we should increase the awareness about influenza as well as citizen’s responsibilities in controlling the spread of the disease. Indian healthcare system is now well-developed with a large number of competent medical personnel and advanced healthcare facilities available in nearly all parts of the country with stable access to pharmaceutical remedies. In the event of an unexpected contagion, supply of critical drugs may be hampered for a short time-frame. Controlling spread during this period could alleviate the consequences of supply concerns and buy us more time.

In India, Influenza as a threat has often been taken lightly despite our past experience. Spreading general awareness and guidelines of prevention, care and treatment could help decrease the risk and consequences in an outbreak. The initial and quick response to a new contagion is critical to completely eliminate the spread of disease. If such an event should arise, government-mandated regulations must be swiftly put together and enforced.

Healthcare facilities must have action plans ready for quarantining affected individuals. A team of medical personnel must be ready to handle such situations so as to ensure safety of themselves and patients.

Is India prepared for the next pandemic?

India has taken a strong stand with the COVID-19 pandemic. Despite our high population, effective treatment and vaccination were availed to a large proportion of masses. Research and development facilities for vaccines and drugs have successfully delivered results within a short time-frame. The robust healthcare system is capable of supportive care therapies and advanced treatment, and we now possess the knowledge and tools to fight such diseases.

Although anticipating what kind of pathogen/disease will emerge next is difficult, our citizens, government, and healthcare system must be aware and vigilant to protect themselves, their families and communities. We might face many different threats of diseases but would stand a strong chance as long as united efforts are ensured.

References: 

1. Influenza Pandemic of 1918 Lessons in Tackling a Public Health Catastrophe; Economic and Political Weekly; 2021; T V Sekhar.

Reviewing the History of Pandemic Influenza: Understanding Patterns of Emergence and Transmission; McLaughlin Centre for Population Health Risk Assessment; 2016; P R. Saunders-Hastings and D Krewski.

3. Influenza Virus; Transfusion Medical Hemotherapy 2009; S. Karger

4. The evolution of pandemic influenza: evidence from India, 1918–19; BMC Infectious Diseases Volume 14 Article number: 510 (2014); Siddharth Chandra, Eva Kassens-Noor

5. Pandemic influenza – Indian experience; Lung India. 2011; J. C. Suri; M. K. Sen.

6. The Threat of Pandemic Influenza: Are We Ready?; Institute of Medicine (US) Forum on Microbial Threats 2005; Knobler SL, Mack A, Mahmoud A.

Writer & Reviewer: Kauser Jumkhawala & Dr Prachi Sinkar
 

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What is Hepatitis?

Hippocrates was the first to describe benign epidemic jaundice in book ‘De Morbis Internis’ which resembled hepatitis A. The definition is accurate even today. Hepatitis is commonly defined as the inflammation of the liver. It might be due to a wide variety of causes, such as heavy alcohol consumption, autoimmunity, drugs or toxins; however, viral infection is the most frequent cause. Virally mediated liver inflammation, called viral hepatitis, is a significant burden. On the basis of severity, the condition can range between mild and self-limiting to a severe illness that requires liver transplantation. Based on the duration of the inflammation to the liver, hepatitis is categorised as acute inflammation (lasting for <6 months) or chronic inflammation (lasting for >6 months). Acute hepatitis is usually self-resolving but can cause fulminant liver failure. Contrastingly, chronic hepatitis can induce liver damage, fibrosis, cirrhosis, hepatocellular carcinoma and characteristics of portal hypertension that lead to significant morbidity and mortality.²

Table 1: Viral Hepatitis At a Glance

Aetiology & Epidemiology of Viral Hepatitis

Viral hepatitis is considered a major public health issue. Chronic infection with HBV and HCV can cause liver damage.^2,3

• Hepatitis A Virus

HAV, a spherical 27-nanometer particle, was first discovered by Feinstone in 1973. It is a non-enveloped single-stranded RNA virus and the only species from the Hepatovirus genus that infects humans.⁴ The global infection rate of HAV is considerably high, but only 1.5 million cases are reported annually. Generally, people with access to safe drinking water and stronger socioeconomic regions have very low cases of HAV infection with <50% of the population being endemic, whereas people without access to safe drinking water and low-income regions have high levels of HAV infection with >90% of the population being endemic. In highly endemic countries, HAV infection at an early age with asymptomatic exposure acquires lifelong immunity in children.

• Hepatitis B Virus

HBV is a double-stranded DNA virus belonging to the Hepadnaviridae family and has ten genotype variants (A-J). The intact HBV virion is called the ‘Dane particle’. The viral core of HBV consists of nucleocapsid, hepatitis B core antigen that surrounds the viral DNA and DNA polymerase. The nucleocapsid is coated with hepatitis B surface antigen (HBsAg), a viral surface polypeptide. The gene coding for core antigen also codes for hepatitis B envelope antigen. Nearly one-third of the global population has had an HBV infection and around 5% of them remain carriers, whereas about 25% of these carriers develop chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Variations in the genotype distribution and risk factors rely on common factors in high-risk populations like vertical transmission which is associated with an increased risk of chronic disease and hepatocellular carcinoma. History of blood transfusion, intravenous drug or paraphernalia use, contaminated piercing instruments, sexual intercourse with an infected person and organ transplantation from HBV-positive donors are all risk factors for HBV transmission.

• Hepatitis C Virus

HCV, an RNA virus, was first discovered in 1989. It belongs to the Flaviviridae family with one serotype, minimum six major genotypes and 80+ subtypes. The extensive genetic variability poses a major challenge in developing a vaccine for the prevention of HCV infection. Globally, the most prevalent cause of parenteral hepatitis is HCV. High-risk groups for HCV infection include people who need frequent blood transfusions and people who receive organs from infected donors. With the development of safer screening and viral elimination techniques for blood transfusion, transfusion-associated HCV incidence is decreasing.

• Hepatitis D Virus

HDV, a single-stranded RNA virus, was first described in 1977 by Rizzetto et al in Italy by direct immunofluorescence. It contains the hepatitis D antigen and has HBsAg as its envelope protein. There are 8 different HDV genotypes; however, HDV-1 is responsible for most cases in North America, Europe and the Middle East. It is assumed as a defective virus as HDV requires the existence of HBsAg for full expression and replication. HDV infection occurs in HBsAg-positive patients as a coinfection with HBV or as a superinfection in chronic HBV carriers. About 10.58% of HBV carriers were coinfected with HDV, which is two-fold higher than the previously estimated. Western and middle Africa, the Amazon Basin, eastern and Mediterranean Europe, the Middle East and parts of Asia are the areas with the highest HDV infection carriage.

• Hepatitis E Virus

HEV, a small single-stranded RNA virus, is considered one of the most common yet underdiagnosed aetiologies. As per the World Health Organization, approximately 20 million HEV infections are detected annually, of which 3.3 million lead to symptomatic cases of acute hepatitis.² HEV has been associated with outbreaks of food and waterborne diseases and is common in developing countries with limited access to sanitation, clean water and hygiene.

Pathophysiology

A virus enters the host system either through the enteric system or blood. Irrespective of the entry, the virus eventually travels to the liver where it infects hepatocytes, replicates either by direct translation of RNA or via reverse transcription of DNA and sheds the virions. HAV transmits via faecal-oral route. The virus disseminates into the liver via the portal vein, after it traverses the mucosa of the small intestinal wall. In HBV-infected cases, after the virus uncoats, its DNA integrates into the host nucleus as a covalently closed circular DNA (cccDNA) that can persist indefinitely in the hepatocytes, explaining the reactivation possibility in chronic inactive disease. Reverse transcriptase aids in the assembly of new viral molecules from cccDNA that are released by exocytosis. HCV is transmitted percutaneously (needlestick injuries containing contaminated blood) or non-percutaneously (perinatal transmission, sexual intercourse, blood transfusions, organ transplantation, religious scarification, body piercings or tattoos). The host-derived factors facilitating HCV entry are:

1. Scavenger receptor class B type I
2. Occludin
3. Claudin-I
4. CD81

Hepatocyte injury can either be self-limited and acute or insidious and chronic. The mechanism of hepatocyte injury is mediated by the host immune response against viral antigens which are expressed by infected hepatocytes and not as much by the cytopathic effects of the virus itself. The progression to chronic infection, as observed with HBV and HCV, is associated with the attenuation of T-cells that are virus-specific. Research shows that exhaustion of these virus-specific T-cells leads to an inability to clear the viruses, thereby allowing them to dwell chronically in host hepatocytes.^3,4

Evaluating & Monitoring Hepatitis

Baseline evaluation of patients suspected with viral hepatitis begins with a hepatic function panel. Severely affected patients might have elevated aminotransferases and bilirubin levels. Acute hepatitis patients typically show aminotransferase levels in thousands. Chronic hepatitis varies in presentation with aminotransferase levels. Often, the levels are elevated to 2-10 times of the upper normal. In most cases, alkaline phosphatase levels remain within the reference range; however, significantly elevated levels should be considered as biliary obstruction or liver abscess. The values of prothrombin time and international normalized ratio may appear prolonged in advanced liver disease. Leukopenia and thrombocytopenia might also be observed. Advanced liver disease patients suffering from easy bruising, variceal bleed or hemorrhoidal bleed may have anaemia with low haemoglobin and hematocrit levels. For patients suspected to have advanced liver disease, blood urea nitrogen and serum creatinine tests might be necessitated to check for renal impairment. For patients with altered mental status, serum ammonia levels must be checked as these are usually elevated in hepatic encephalopathy.²

Enzyme-linked immunosorbent assay and polymerase chain reaction are the technologies that aid in the diagnosis of acute and chronic viral hepatitis. Other specific tests for evaluating the viral hepatitis type include:

• Hepatitis A

Immunoglobulin M (IgM) antibody against HAV is the standard test for diagnosing acute HAV infection as it disappears after a few months. The presence of immunoglobulin G (IgG) antibodies against HAV signifies past infection and most patients with IgG antibodies have lifelong immunity against HAV.^2,3

• Hepatitis B

The first serum marker to appear in HBV-infected patients is HBsAg, whereas the first antibody is IgM antibodies against hepatitis B core antigen. However, the presence of HBsAg does not signify acute or chronic infection in the absence of symptoms. In symptomatic patients, the presence of HBsAg strongly suggests acute infection but does not rule out chronic infection with an acute superinfection by another hepatitis virus.^2,3

The presence of HBsAg, IgM core antibody, envelope antigen and viral load indicate acute HBV infection. A ‘window period’ is the duration during which HBsAg disappears before IgG antibodies appear against HBsAg. The presence of HBV DNA, HBsAg for >6 months, IgG core antibody and absence of surface antibody are indicators of chronic HBV infection.^2,3

• Hepatitis C

The presence of HCV RNA with/without IgM antibody signifies acute HCV infection, whereas chronic infection is suggested by the presence of HCV RNA and IgG antibodies. HCV RNA would become undetectable once the patient has cleared the infection.^2,3

• Hepatitis D

The presence of antibodies signifies HDV infection, whereas viral load is used for detecting current infection.^2,3

• Hepatitis E

The presence of HEV antigen, RNA viral load and IgM antibodies indicate acute HEV infection. The patient’s response to antiviral therapy is evaluated using RNA viral load. IgG antibodies against HEV confirm vaccine efficacy or natural protection.^2,3

Figure 1: Action Plans for Controlling Viral Hepatitis

Join the Fight

The early detection of viral hepatitis depends on understanding the peculiar features of the five hepatitis viruses. Advances in the healthcare and diagnostics field have enabled timely and effective diagnosis as well as helped in establishing the multisystemic impact on the population. The advent of newer and improved therapies coupled with advanced diagnosis would promisingly aid in achieving control over this affliction a reality!

References

1. World Health Organization. (2022, June 10). World Hepatitis Summit 2022 statement.https://www.who.int/news/item/10-06-2022-world-hepatitis-summit-2022-statement
2. Mehta, P., & Reddivari, A. K. R. (2021). Hepatitis. In StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK554549/
3. Castaneda, D., Gonzalez, A. J., Alomari, M., Tandon, K., & Zervos, X. B. (2021). From hepatitis A to E: A critical review of viral hepatitis. World journal of gastroenterology, 27(16), 1691. https://doi.org/10.3748/wjg.v27.i16.1691
4. Zarrin A, Akhondi H. (2022). Viral Hepatitis. In: StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK556029

Writer & Reviewer: Kayshu Grover & Dr Prachi Sinkar

The post Hepatitis A to E: A Critical Review of Viral Hepatitis appeared first on HealthScreen Magazine.

With this expressive description in 1721, Italian scientist Antonio Vallisneri described for the first time the clinical and anatomopathological features of polycystic ovary syndrome (PCOS).¹ In 1935, PCOS was for the first time identified and investigated by Stein and Leventhal in a group of seven hirsute amenorrheic women based on typical ovarian morphology—fibrotic thickening of the tunica albuginea and outer cortex and multiple follicular cysts with distinct thecae.¹ PCOS has since been one of the most controversial and explored areas of endocrinological gynaecology.

PCOS affects 4–20% of women of reproductive age worldwide. In India, nearly one in five (20%) women suffer from PCOS. As estimated by the World Health Organization, PCOS affected 116+ million women (3.4%) globally in 2021 alone.² In 2003, the European Society of Human Reproduction and Embryology along with the American Society for Reproductive Medicine conducted the first international consensus on the clinical criteria for PCOS at Rotterdam, Netherlands.² As per the Rotterdam consensus, PCOS is defined by the presence of two of the three predetermined criteria, highlighting the range of clinical expressions within PCOS (Figure 1).

Figure 1: The Rotterdam criteria for PCOS

The clinical presentation of PCOS includes the following:

1. Ovulatory dysfunction (oligomenorrhea, irregular periods and/or anovulatory cycles)
2. Male-pattern baldness
3. Hirsutism
4. Acne
5. Fatigue
6. Polycystic ovaries
7. Weight gain
8. Mood changes
9. Low sex drive
10. Trouble conceiving

Women with PCOS are at increased risk of type II diabetes mellitus, high cholesterol, high blood pressure and obesity, thus exhibiting insulin resistance and metabolic syndrome. They are also at increased risk of certain cancers due to metabolic–endocrine abnormalities. An association between PCOS and cancer was first suggested 14 years after its original description. In 1949, Harold Speert, one of the world’s foremost historians of obstetrics and gynaecology, noted a recurrent presence of cystic ovaries in <40-year-old women with endometrial cancer (EC).³ Since then, several studies have supported this association.

Figure 2: Development of PCOS

Endometrial cancer

Women with PCOS are associated with three times greater risk of EC than healthy women. This is due to the prolonged exposure of the endometrium to the continuous unrestricted secretion of oestrogen caused by anovulation. The prolonged exposure induces endometrial hyperplasia, wherein the lining of the uterus becomes unusually thick. Endometrial hyperplasia is the potential precursor to adenocarcinoma. The risk factors of PCOS-associated EC include obesity, long-term exposure of unopposed oestrogen, nulliparity, infertility, hypertension and diabetes. Nearly 18% cases of adenomatous hyperplasia progress to cancer in the subsequent 2–10 years. Women with PCOS with a ≥3-month menstruation interval are at increased risk of endometrial hyperplasia and EC.⁴

Possible biologic mechanisms of action

Long-term anovulation with continuous exposure to oestrogen unopposed by progesterone explains the increased risk of EC (an oestrogen-sensitive disease) in PCOS.⁵ Accordingly, intermenstrual cycle length correlates with the risk of endometrial hyperplasia. Endometrial responsiveness to progesterone is inherently different in PCOS. Secretory endometrium of some women with PCOS receiving ovulation induction or exogenous progesterone exhibits down-regulation of progesterone-regulated genes and up-regulation of cell proliferation genes. Hence, dysregulation of endometrial gene expression in PCOS accompanies progesterone resistance.^5,6

Hyperandrogenism is one main component of all three clinical diagnostic criteria for PCOS. In 1998, Risch proposed that ovarian cancer (OC) is associated with factors related to androgen stimulation of ovarian cells.⁵ As demonstrated by animal studies, testosterone stimulates the growth of epithelial cells in the ovary.⁶ Androgens are crucial in OC development based on the following two hypotheses: 1) There is an increased risk of the borderline serous subtype of OC among women with PCOS. 2) Androgen receptors are relatively higher in serous borderline tumours compared to serous invasive.⁵ Moreover, androgen receptors and 5a-reductases are found in the human endometrium. Some women with PCOS exhibit the overexpression of endometrial androgen receptors, indicating disordered androgen action within the endometrium.⁶

Another common feature of PCOS is the hypersecretion of luteinizing hormone (LH), which acts as a regulator of endometrial growth, considering the ability of LH to promote the growth of EC cells in vitro. This is crucial as endometrial LH receptors are overexpressed in women with anovulatory PCOS with endometrial hyperplasia or carcinoma, as they are in EC relative to tumour invasiveness.⁶

Nearly 70% women with PCOS develop disordered glucose-insulin homeostasis and insulin resistance. Hyperinsulinemia occurs due to distorted post-receptor signal transduction and decreases insulin-mediated glucose uptake without impacting steroidogenesis. Resultantly, excess insulin stimulates the activity of theca cell androgen and increases serum-free testosterone levels through reduced production of hepatic sex hormone-binding globulin, LH- and insulin-like growth factor (IGF)-I-stimulated androgen production and serum IGF-I bioactivity through suppressed IGF-binding protein production.⁶

PCOS is also associated with the dysregulation of glucose metabolic pathways in the endometrium. Treating cultured EC cells with IGF-I accelerates their growth, whereas exposing them to sera from metformin-treated women with PCOS diminishes cell growth and curbs inflammation and tumour invasion in signalling pathways. Hence, PCOS-related insulin resistance and EC share common mechanisms of metabolic dysfunction. The shared mechanisms likely include macrophage-secreted cytokine action on adipokines, which is concurrent with the ability of concomitant metformin treatment to reverse atypical endometrial hyperplasia in overweight women resistant to progestin therapy alone.⁶

PCOS affects body size through dietary intake and cravings as well as through its impact on metabolic factors linked to weight gain. Thus, BMI is a mediator and confounder of PCOS–cancer association, making it challenging to characterise a BMI-independent PCOS association.⁶

Figure 3: Development of Endometrial Cancer

Diagnosis of EC in PCOS

Along with medical history and general physical tests, EC is diagnosed as follows:

1. Internal pelvic exam: It is performed to confirm the presence of lumps or modifications in the shape of the uterus.
2. Pap test/ Pap smear: Cells are collected from the cervix and observed under microscope to check for abnormalities, which can be a potential cancer or increase the risk of it, and non-cancerous conditions, e.g., inflammation and infection.
3. Endometrial biopsy: A small flexible tube inserted into the uterus collects a sample from endometrial tissue, which is viewed under a microscope to check for cancer or abnormal cell growth.
4. Transvaginal ultrasound or ultrasonography: A transducer inserted inside the vagina produces sound waves that ricochet off the pelvic cavity organs. The echoes from the sound waves are captured by a computer to generate a sonogram.
5. Dilation and curettage: This is a minor operation wherein the cervix is opened and the cervical canal and uterine lining are scraped using a spoon-shaped curette. The tissue is then subjected to microscopic examination.

In anovulatory women with PCOS and infertility, >7-mm endometrial thickness or >3-month intermenstrual interval is associated with endometrial hyperplasia.⁶

Ovarian Cancer

The risk of OC in women with anovulation has been a topic of debate and concerns in gynecologic oncology due to the extended use of ovulation-inducing drugs. Research suggests an association between OC and PCOS. The risk is particularly high in nulliparous women with early menarche and late menopause undergoing multiple ovulations. Women with PCOS fall in the low-risk group for developing OC due to their life-time reduced ovulation rate. However, certain ovulation-inducing treatments and multifollicular ovulation-inducing treatments theoretically create a technical imbalance to the risk of OC. Infertility alone increases the risk of borderline and invasive ovarian tumours. Another study linking clomiphene and OC suggests that the relative risk for OC for women with PCOS is 4.1 as compared to controls.⁴

Breast cancer

The link between PCOS and breast cancer (BC) remains debatable. Increased androgen and oestrogen levels increase the risk of oestrogen receptor-positive BC. The risk factors include genetic mutations, age, chemo and radiation therapies and family history. Hormonal contraceptives, a preferred treatment for PCOS symptoms, also increase the risk of BC.⁴ Circulating androgens participate in BC. In one pooled analysis, the risk of BC had increased with increasing testosterone levels in postmenopausal and premenopausal women.⁵

Majority of the clinical trials and research studies have investigated the correlation between PCOs and EC, whereas that between PCOS and OC/BC remains less explored.

Fighting PCOS!

1. Diagnostics and treatment

Women with PCOS should undergo routine tests in a timely manner. These tests cover a broad range of profiles, including cholesterol, diabetic markers and hormone levels. In case of any PCOS-related symptoms, consult with a doctor so as not to delay the treatment. If untreated, disrupted hormone levels affect the whole body and increase the risk of life-threatening diseases, such as cancer.⁷ Regular testing assists in recognizing early signs of EC and initiating appropriate therapeutic measures as needed.

2. Watch what you eat

Women with PCOS often have insulin resistance, for which a low-sugar low-fat diet is recommended, comprising vegetables, fruits, lean meats and high-fibre grains. Doctors also recommend foods with a low glycemic index, which allows slow and steady release of insulin, making energy utilisation easier than storing the food as fat.⁷

3. Weight management

Nearly 50% women with PCOS exhibit overweightness/ obesity—risk factors of EC. Regular exercise helps reduce weight and testosterone concentration in the blood.‌ Short-term weight loss restores fertility and ovulation and improves insulin resistance.⁷

4. Mind–body exercises

Exercise also improves your mental health. PCOS is associated with an increased risk of mental and psychological disorders. Exercises that engage and elevate your mind and body are beneficial, e.g., meditation, yoga, Pilates and tai chi.⁷

References:

1. Battaglia, C. (2003). The role of ultrasound and Doppler analysis in the diagnosis of polycystic ovary syndrome. Ultrasound Obstet Gynecol, 22(3), 225-232. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1002/uog.228
2. Bulsara, J., Patel, P., Soni, A., & Acharya, S. (2021). A review: Brief insight into Polycystic Ovarian syndrome. Endocrine and Metabolic Science, 3, 100085.. https://www.sciencedirect.com/science/article/pii/S266639612100008X
3. Speert H. Carcinoma of the endometrium in young women. Surg Gynecol Obstet (1949) 88:332–6.https://pubmed.ncbi.nlm.nih.gov/18111780/
4. Daniilidis, A., & Dinas, K. (2009). Long term health consequences of polycystic ovarian syndrome: a review analysis. Hippokratia, 13(2), 90.. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683463/
5. Harris, H. R., & Terry, K. L. (2016). Polycystic ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review. Fertil Res Pract, 2(1), 1-9. https://fertilityresearchandpractice.biomedcentral.com/articles/10.1186/s40738-016-0029-2
6. Dumesic, D. A., & Lobo, R. A. (2013). Cancer risk and PCOS. Steroids, 78(8), 782-785. https://doi.org/10.1016/j.steroids.2013.04.004.
7. What to Know About Lifestyle Changes for PCOS. WebMD. June 08, 2021. Reviewed by Dan Brennan, MD. https://www.webmd.com/women/what-to-know-about-lifestyle-changes-for-pcos

Writer & Reviewer: Sharvari Indulkar and Dr Prachi Sinkar

The post PCOS and The Risk of Cancer appeared first on HealthScreen Magazine.

On October 12, 1492, three ships docked on the lands of North America. Aboard the ship was Christopher Columbus and his crew. Upon arrival, he came across Native Americans. To show that his exploration didn’t mean any harm, he offered them gifts, clothes and food. In return, the tribesmen handed over dried up tobacco leaves. Confused Columbus soon realised that the leaves were a prized possession and loaded bagfuls of them overboard. Smoking was thereby introduced to Europeans, and before long, cigarette smoking became an entrenched habit worldwide.¹

While loading his ship, Columbus didn’t know that tobacco smoke contains over 7000 chemicals, of which 250 are harmful and over 69 carcinogenic. He also didn’t know that tobacco would one day be responsible for 8 millions deaths/year and smoking would be the number one risk factor of lung cancer.^2.3

In the 1900s, technological advancement allowed large-scale cigarette production. By the end of the 19th century, mass marketing glamorised smoking, leading to the global lung cancer epidemic in the 1940s and 1950s. Before the 1900s, lung cancer was a very rare disease. Today, it has become one of the leading causes of cancer death, and tobacco has become the main cause of 90% of male and 79% of female lung cancers.^1,3

What’s in a cigarette?

The devastating link between tobacco smoke and lung cancer is due to toxic chemicals in cigarettes. As a tobacco plant grows, it absorbs chemicals, like cadmium (used in battery acid) and lead (used in batteries and house paint), from soil, both toxic and carcinogenic. During the curing process, more harmful compounds form, e.g. tobacco-specific nitrosamines.² While manufacturing, other chemicals are added as follows:

1. Nicotine – used in insecticides; it increases the release of neurotransmitters in the brain and elevates mood
2. Ammonia – common household cleaner
3. Acetone – used in nail polish remover
4. Acetic acid – used in hair dyes
5. Arsenic – used in rat poison
6. Benzene – used in gasoline
7. Butane – used in lighter fluid
8. Carbon monoxide – released in car exhaust fumes
9. Naphthalene – used in mothballs
10. Methanol – used in rocket fuel
11. Tar – used for paving roads

Once a cigarette is lit, more harmful chemicals are produced in the burning process that were not present initially in the curing and manufacturing processes.²

Tobacco and Lung Cancer Pathogenesis

These carcinogenic compounds activate/inactivate several signalling pathways in malignant cells. They allow cancer cells to proliferate and multiply by inducing epigenetic alterations, which help the development and pathogenesis of lung cancer.⁴

1. Tobacco and genetic changes

TP53

TP53 is the most important tumour suppressor gene. In nearly 50% of lung cancers, DNA repairment and apoptosis induction are deregulated and mutated in p53-harbouring cells. Polycyclic aromatic hydrocarbons in cigarettes increase thymine and guanine replacement frequency in p53. Nicotine-derived nitrosamine ketone (NNK) in cigarette smoke increases substitution of guanine to adenine in exon 5 of p53. Tobacco smoke also downregulates p16 expression. It methylates the promoter region of p16. This allows cancer cells to proliferate and escape from apoptosis. Nicotine and NNK increase the expression of neurotransmitters adrenaline and noradrenaline and inhibit the expression of GABA in lung cancer cells.

Free radicals and reactive oxygen species

Every cigarette pack produces nearly 5 × 10⁴ free radicals that induce oxidative stress and DNA damage, causing replication/transcription errors and genomic instability. In healthy cells, chemical-induced damages to single-stranded DNA are repaired by nucleotide excision repair and base excision repair (BER) systems. Xrcc1 protein in the BER system detects single-stranded breaks in DNA and acts as a scaffold for binding other repair enzymes. In smokers, polymorphisms in XRCC1 gene reduce this protein activity and disturb the DNA repair system.

β-gelatinase

β-gelatinase enzyme decomposes collagen, elastin, fibronectin, and non-matrix molecules, including pro-TNF-α, IL-8 and TGF-β. Considering its carcinogenicity, β-gelatinase releases pro-angiogenic factors and enhances tumour cell angiogenesis. It inhibits T cell proliferation and hinders immune system response by incising alpha interleukin-2 receptor, activating TGF-β and separating ICAM-1.⁴

Figure 1: Lung cancer progression and staging

2. Tobacco and epigenetic changes

Epigenetics modulations, including DNA methylation, histone modifications, nucleosome changes and microRNAs (miR)-associated gene regulation, refer to heritable alterations in gene expression that are not due to changes in DNA sequence. These mechanisms regulate gene expression by altering the chromatin structure.

In healthy cells, DNA methylation occurs mainly in regions with a high frequency of CG sites and at 5′ end of the genes. Being repressive to transcription, the modification is catalysed by DNA methyltransferases. Different methylation patterns are reported in infants whose mothers smoked during pregnancy. Nicotine changes the expression of DNA methyltransferases, causing demethylation of synuclein-gamma oncogene. Smoking can also cause the formation of methylated tumour suppressor gene p16.

The human genome contains nearly 1600 miR—non-coding small RNAs regulating expression of several genes. Chemicals in cigarette smoke alter the miR expression pattern. MiRs regulate the expression of oncogenes and tumour suppressor genes and act as oncogenes themselves. Cigarette smoke enhances miR-504 expression, an important miR for dopamine receptor gene DRD1 expression, ultimately inducing tobacco addiction.⁴

Figure 2: Healthy Lungs vs Smokers Lungs

3. Tobacco and Growth Signalling pathways

Nicotine binds to nicotinic acetylcholine receptors (nAchR), epidermal growth factor receptor (EGFR) and β-adrenergic receptor (AR-β). Owing to its ability to pass through the cell membrane, in non-neuronal settings, nAchR regulates growth, differentiation and migration of cancer cells. Several signal transduction pathways, such as MAPK, AKT and PKC, become activated, which further inhibit apoptosis, stimulate tumour cell proliferation and induce angiogenesis. However, the activation and secretion of neurotransmitters through nAchR is mediated by smoking. Nicotine binds to EGFR and AR-β and acts as a growth factor. EGFR is a tyrosine kinase receptor and crucial in cell growth, development and tumorigenesis. NNK contributes to cancer cell proliferation by synthesising thromboxane A2 (TXA2) and activating the TXA2 receptor. TXA2 activates the transcription factor cAMP response element-binding protein, enhances Bcl-2 expression and increases cell proliferation.⁴

4. Impact of Tobacco on Cell Survival, Growth and Apoptosis

Nicotine acts as a mitogen through cyclin D1 overexpression and cell cycle transition from G1 to S phase. It elevates the proliferative potential of cells by activating PI3K/AKT signalling pathway as a fundamental axis in tumorigenesis, tumour growth and drug resistance. Nicotine and NNK activate ERK and STAT pathways and disrupt anti-growth signals to increase cell growth. Cigarette chemicals suppress NK cell activity and proliferation. Defects in the apoptosis lead to cell survival and unlimited tumour cell growth. NNK and its metabolites inhibit apoptosis through upregulating hemeoxygenase (HO-1) and activating NF-κB and ERK pathway in lung tissue.⁴

5. Impact of Tobacco on Angiogenesis and Cancer Metastasis

Angiogenesis or blood vessel formation from endothelial cells is important for nutrition and oxygen delivery to tumour cells. In one mechanism, nicotine increases the expression and secretion of nitric oxide, a vasoconstrictor and angiogenesis mediator, as well as of endothelial growth factors.

Tumour metastasis, the major cause of lung cancer mortality, is the spread of tumour cells from one organ to others. The progression and metastasis of cancer in smokers is faster than non-smokers. Prolonged nicotine use decreases the expression of adhesion molecules, such as E-cadherin and β-catenin, in lung cancer cells. Additionally, breaking the extracellular matrix using matrix metalloprotease enzymes is important for tumour cell metastasis and invasion. Also, cyclooxygenase-2 (COX-2) elevates both angiogenesis and aggressive potential of tumour cells by increasing the production of prostaglandins and converting the pre-cancerous agents to carcinogens. Nicotine enhances the metastasis of esophageal carcinoma in that it upregulates and increases the activity of MMP-2 and COX-2.⁴

Beyond lung cancer…

Smoking is associated with over 15 types of cancer, including breast, bladder, colorectal, larynx, liver, pancreas, kidney, ovary, mouth, pharynx, and nose and sinuses cancer. It induces cardiac and lung diseases, stroke, diabetes, and chronic obstructive pulmonary disease, including emphysema and chronic bronchitis. Smoking increases the risk of tuberculosis, eye ailments, and immune system-related illnesses, e.g., rheumatoid arthritis.

Lipid Profile Modifications

Smokers demonstrate high serum cholesterol, triglyceride, and low-density lipoprotein levels, but low high-density lipoprotein. Nicotine increases blood sugar levels, thus increasing the risk of diabetes. Diabetic smokers require high insulin doses to maintain blood sugar levels.⁵

Blood Cell Parameter Changes

Carbon monoxide in cigarette smoke leads to high Hb levels, increased capillary permeability, increased erythrocytes and hematocrit values and decreased plasma volume. The irritating effect of the tobacco smoke on the respiratory tree as well as nicotine-induced release of catecholamine and steroid hormones increase the leukocyte count. Smoking-induced oxidative stress causes increased platelet activation and aggregation, atherothrombotic cardiovascular events and endothelium injury caused by nicotine.

Figure 3: Smoking, lung cancer and associated comorbidities

Is there a safe level of smoking?

‘One cigarette a day is not harmful’.

‘Passive smoking won’t kill you’.

‘Cutting back is just as good’.

‘Mild cigarettes are less risky’.

‘I only smoke occasionally’.

No matter the excuses, there is no denying that ‘smoking is injurious to health’. There is no safe level of smoking. Smoking 1-5 cigarettes daily is as harmful as smoking 20+ cigarettes daily. For daily heavy smokers, the risk of lung cancer mortality is 23 times in men and 13 times in women than non-smokers.

Ways to Quit:

Tobacco urges and cigarette cravings can be strong, but if you are determined, you can stand up against these.

• Cold turkey and gradual withdrawal
• Nicotine-replacement therapy
• Avoid triggers like alcohol
• Eat fruits and vegetables
• Exercise, meditate and relax
• Delay ‘the next cigarette’
• Lean on your loved ones

Quit for Good

Cigarettes come at a great cost: your life. Irrespective of the amount and times you smoke, it’s never too late to quit.⁵ As soon as you stop smoking, your body starts healing itself:

• In 20 minutes, heart rate and blood pressure drop.
• In 12 hours, carbon monoxide in blood drops to normal.
• In 1-3 months, blood circulation and lung function improve.
• In 1 year, the risk of heart disease is half that of smokers.
• In 5-10 years, the risk of mouth, throat and larynx cancer is halved.
• In 10 years, the risk of lung cancer is nearly half that of smokers.

Don’t wait, quit today!

References:

1. Tobacco-Free Life. History of Tobacco. https://tobaccofreelife.org/tobacco/tobacco-history/. 2016.
2. American Lung Association. What’s in a cigarette? https://www.lung.org/quit-smoking/smoking-facts/whats-in-a-cigarette. July 13, 2020.
3. World Health Organization. Tobacco. https://www.who.int/news-room/fact-sheets/detail/tobacco. 24 May 2022.
4. Nooshinfar, E., Bashash, D., Abbasalizadeh, M., Safaroghli-Azar, A., Sadreazami, P., & Akbari, M. E. (2017). The molecular mechanisms of tobacco in cancer pathogenesis.Int J Cancer Manag. 2017;10(1):e7902. https://brieflands.com/articles/ijcm-7902.html. doi: 10.17795/ijcp-7902.
5. Centers for Disease Control and Prevention.  Smoking and Diabetes. https://www.cdc.gov/diabetes/library/features/smoking-and-diabetes.html. August 10, 2021.

Writer & Reviewer: Sharvari Indulkar & Dr Prachi Sinkar

The post Smoking-induced Lung Cancer appeared first on HealthScreen Magazine.