The role of low-density lipoprotein cholesterol (LDL-C) in the evolution of heart disease is fairly well established. In addition, the benefits of pharmacological treatment with agents that lower LDL-C in high-risk patients are well documented.
Structure of an LDL-particle. The core of the particle (yellow) contains cholesterol and triglycerides. The blue and white molecule is apolipoprotein B (ApoB). Every LDL particle contains one molecule of ApoB.
Lipoproteins are biochemical structures that enable the transport of lipids such as cholesterol in the circulation. LDL-C represents the amount or mass of cholesterol carried by low-density lipoprotein.
The interaction between circulating lipoproteins and the arterial wall is the first step in atherosclerosis and the development of heart disease. However, only some lipoproteins tend to interact with the arterial wall and trigger this bleak cascade of events (1). These lipoproteins are termed atherogenic. Low-density lipoprotein (LDL) is an atherogenic lipoprotein.
Today, there is ample evidence that the number of LDL particles (LDL-P) plays a much stronger role in the development of cardiovascular disease than the mass of cholesterol within these particles. This needs to be clarified because cholesterol mass does not always go hand in hand with the number of particles.
Furthermore, relying on LDL-C has several pitfalls (2). For example, LDL-C is a calculated variable that counts on measurements of total cholesterol, HDL-cholesterol, and triglycerides.
LDL-C does not accurately reflect the number of atherogenic LDL particles. This may explain why a large proportion of patients with cardiovascular disease do not have elevated levels of LDL-C.
Furthermore, clinical trials have shown that many patients who receive treatment with an LDL-C lowering drug and achieve a substantial reduction in LDL-C levels still develop clinical events (eg. heart attack or stroke)(3).
The LDL Particle
Lipoprotein particles are commonly classified according to their density, thus the terms high-density lipoprotein (HDL) and low-density lipoprotein (LDL).
There are six major types of lipoproteins; chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein(a) (4,5,6,6).
LDL is called low-density lipoprotein because LDL particles tend to be less dense than other lipoprotein particles. Its main function is to deliver cholesterol to cells of the body.
Apolipoprotein B (apoB) is the primary lipoprotein in LDL (7). apoB-containing lipoproteins play a hugely important role in atherosclerosis and heart disease. All atherogenic lipoproteins contain one molecule of apoB.
A key step in the atherosclerotic process is the entrapment of apoB-containing lipoproteins within the arterial wall (8).
The Difference Between LDL-C and LDL-P
There is strong scientific evidence that LDL and other apoB-containing lipoproteins, including VLDL and their remnants, IDL, and LP(a), are directly implicated in the development of atherosclerotic cardiovascular disease (9).
Accordingly, a biochemical marker reflecting the amount of all these atherogenic lipoproteins would be of great clinical value when predicting the risk of heart disease.
However, despite its flaws, the assessment of the amount of cholesterol within LDL particles (LDL-C) is the most commonly used indicator of risk in the clinical world. Furthermore, LDL-C is also used to target therapy in primary as well as secondary prevention of cardiovascular disease.
Here, it is important to underline that LDL and LDL-C are not synonymous. In fact, the cholesterol content of LDL particles varies greatly. Hence, measurements of LDL particle number (LDL-P) maybe of importance (10).
Let’s take an example. Two patients with the same LDL-P may have very different LDL-C, depending on the amount of cholesterol within each LDL particle. However, their risk of developing heart disease may be similar.
Hence, LDL-C is a surrogate measure that only provides a very rough estimate of LDL particle concentration (LDL-P). Studies clearly indicate that the risk for atherosclerosis is more related to the number of LDL particles than the total amount of cholesterol within these particles (11).
It is also important to remember that LDL particles carry other lipid molecules than cholesterol. For example, triglycerides (TG) are also carried within LDL particles. Similar to total cholesterol and LDL-C, there is an association between serum TG and the risk of cardiovascular disease (12).
If the number of TG molecules in an LDL particle is high, there will be less space for cholesterol molecules. Therefore, if TGs are high, it may take many more LDL particles to carry a given amount of cholesterol. Therefore high LDL particle count may be associated with small, cholesterol-depleted, triglyceride-rich particles. Research has shown that high levels of triglycerides are associated with small LDL particle sizes (13).
So, what does all this mean? It means that one person (person A) may have large cholesterol rich LDL particles, while another (person B) may have smaller cholesterol-depleted particles. These two persons may have the same LDL-C concentration. However, person B will have a LDLP. Despite similar levels of LDL-C, person B is at higher risk four future cardiovascular events.
Many studies have suggested that the size of LDL particles may be of importance (14). People whose LDL particles are predominantly small and dense, have a threefold greater risk of coronary heart disease. Furthermore, the large and fluffy type of LDL may actually be protective.
However, keep in mind that the association between small LDL and heart disease reflects an increased number of LDL particles in patients with small LDL. Therefore, the LDL particle count could be more important in terms of risk than particle size in itself.
ApoB and LDL-P both reflect the number of atherogenic lipoprotein particles. However, measurements of ApoB will reflect the number of all atherogenic particles, whereas LDL-P only reflects the number of LDL particles.
Research shows that ApoB and LDL-P are better predictors of cardiovascular disease risk than LDL-C (15).
Discordance
Discordance is when there is a difference between LDL-C and LDL-P. If LDL-C is high and LDL-P is low, there is discordance. If LDL-C is low and LDL-P is high, there is discordance. If both are low or both high, there is no discordance.
Studies have indicated that if there is discordance between LDL-C and LDL-P, cardiovascular disease risk tracks more closely with LDL-P than LDL-C (15). Specifically, when a patient with low LDL-C has a level of LDL-P that is not equally low, there is a higher “residual” risk. This may help explain the high number of cardiovascular events that occur in patients with normal or low levels of LDL-C.
The “Get With the Guidelines” study published in 2009 reported lipid levels in almost 137 thousand patients with an acute coronary event (16). Almost half of those had admission LDL levels <100 mg/dL (2.6 mmol/L) which may be considered fairly low. Hence, LDL-C did not seem to predict risk in these patients. However, low HDL-C and elevated TG was common among these patients. Low HDL-C and high TG levels are generally associated with higher LDL-P (16).
Among discordant patients in the Framingham Offspring Study the group with the highest risk for future cardiovascular events had high LDL-P and low LDL-C, while the group with the lowest risk had low LDL-P but higher LDL-C (17).
Many patients with metabolic syndrome or type-2 diabetes have discordance where LDL-P is elevated but LDL-C may be close to normal. In these individuals, measurements of LDL-C may underestimate cardiovascular risk. Measurements of ApoB or LDL-P are much more likely to predict risk in these individuals.
Discordance may be an important clinical phenomenon. Sometimes the question of medical therapy in primary prevention arises when there is an intermediate risk, based on LDL-C. In these cases, a low LDL-P level might help to confirm that the risk is indeed low, which might justify avoiding statin therapy.
Statins tend to lower LDL-C more than LDL-P. Many individuals who reach the target for LDL-C with statins, may still have raised LDL-P. This may indicate a higher residual risk despite what is generally defined as adequate treatment.
The article was initially published in 2012
It was revised, updated and republished on August 24, 2022.
An important question in clinical medicine is when to treat descending testosterone levels in men when there is no underlying cause other than advanced age.
Most men want to live to a ripe old age. But this could come at a price. We may have to depart with masculinity and vigor. Manliness may become a myth.
But, what if there was a simple way to retain the strength and hardiness of the 20s? Well, I guess most of us would at least give it a thought.
Could testosterone be the issue? We all know that testosterone is what makes men, men. The deep voice, the large muscles. It’s all about testosterone, isn’t it?
And, isn’t it true that testosterone levels start to fall in men by about 1% a year, beginning in the 40s?
And, isn’t low testosterone associated with weight gain, lack of energy, loss of muscle, and low sexual drive? Well, indeed it is.
So, could testosterone replacement therapy help us retain our hunkiness until old age?
Probably too good to be true.
Interestingly, there has been a dramatic increase in the use of testosterone therapy in healthy middle-aged and older men (1,2). The increased testosterone prescribing is primarily for age-related testosterone deficiency sometimes called andropause or age-related hypogonadism.
In other words, testosterone treatment is being used to correct a “normal” decline in testosterone levels that occurs with aging. Unfortunately, the evidence for the benefit of such therapy is somewhat limited (3).
Lately, the condition of “low T” among older men has been highlighted as an easily treated phenomenon. Direct-to-customer advertising (DTCA) has been guilty of encouraging the use of testosterone treatment for symptoms such as decreased energy and lack of sexual interest which have not always been proven to be caused by declining testosterone levels (4).
Furthermore, although the data are somewhat conflicting, some studies have suggested increased cardiovascular risk associated with testosterone replacement therapy (5).
However, although there is lack of general agreement among specialists, testosterone replacement therapy may be justified in selected cases. Hence, it is of utmost importance for clinicians and patients to understand when testosterone replacement therapy is appropriate and when it is not.
Testosterone Levels, Free Testosterone and Sex Hormone Binding Globulin (SHBG)
Testosterone is a hormone secreted by the testicles of males and in small amounts by the ovaries in females. It has several important biologic functions, particularly in men.
Testosterone is defined as an androgen. Andro means male in ancient Greek, and as an androgen, testosterone is responsible for the typical characteristics of the male human being such as the deep voice, the large muscle mass, and the facial and body hair.
Most of the testosterone in the blood is attached to two proteins: albumin and sex hormone binding globulin (SHBG).
Testosterone that is not attached to proteins is called free testosterone.
The normal range for serum total testosterone in males is about 270 – 1070 ng/dL or 9 – 38 nmol/L. The normal levels in adult men are approximately 300 – 800 ng/dl or 10 – 27 nmol/L
There is a diurnal variation in testosterone levels, particularly in young men (highest values are at approximately 8 in the morning and lowest at about 8 in the evening). It is recommended that serum total testosterone should be measured between 8-10 in the morning.
Hypogonadism
Hypogonadism is a term that refers to a decrease in either of two important functions of the testicles; sperm production and testosterone production.
Hypogonadism may be caused by an abnormality of the testicles themselves (primary hypogonadism) or by a disorder of the pituitary or hypothalamus (secondary hypogonadism).
Hypogonadism may be congenital or may begin before puberty or during adulthood. The symptoms of hypogonadism depend on the age it develops.
The development of hypogonadism in adult males may cause erectile dysfunction, loss of libido, infertility, decreased muscle mass, decreased facial and body hair growth, development of breast tissue (gynecomastia), loss of bone mass (osteoporosis), and emotional changes. These symptoms will be reflected by low blood levels of testosterone.
Testosterone replacement therapy is used for the treatment of hypogonadism caused by the failure of the testicles to produce testosterone. Such treatment may increase well-being, sex drive, and erectile function, restore muscle strength and reduce bone loss.
Laboratory Findings in Hypogonadism
Males with hypogonadism have low levels of serum testosterone and free testosterone.
The two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are produced by the pituitary. If testosterone production by the testicles drops, biofeedback mechanisms will respond by increasing the production of LH and FSH.
The serum levels of LH and FSH are above normal in primary hypogonadism. However, in secondary hypogonadism, serum concentrations of LH and FSH will be normal or low.
The term age-related hypogonadism has been used to describe the clinical condition associated with declining testosterone levels in middle-aged and older men.
Age-Related Hypogonadism (Andropause)
Several studies show a declining serum total testosterone concentration with increasing age (6,7). It is estimated that serum testosterone levels decline at a rate of one percent per year after the third decade of life (8).
SHBG concentrations increase gradually with age. As a result, there will be less free or biologically active testosterone available with increasing age.
The terms age-related hypogonadism and andropause have been used to describe the clinical condition associated with declining testosterone levels in middle-aged and older men.
The condition is also referred to as “late-onset hypogonadism.” It is typically diagnosed if, for no discernible reason other than older age, serum testosterone concentrations fall below the normal range and symptoms of low testosterone concentrations occur (9).
It has been suggested that the following symptoms may be associated with age-related hypogonadism:
a decline in muscle strength
reduced bone mineral density
a decline in sexual function
mood changes and depressive symptoms
anemia
central obesity
insulin resistance and metabolic syndrome
Nobody doubts that these symptoms may be present in men with hypogonadism due to pituitary or testicular disease. However, whether the same symptoms may occur with low testosterone levels associated with age has frequently been a matter of debate.
Another question is whether testosterone replacement therapy in men with age-related hypogonadism will improve these symptoms. If so, when and how should testosterone be administered?
Testosterone Replacement Therapy for Age-Related Hypogonadism
Clinical trials have reported some benefits of testosterone replacement therapy in older men. These include improved bone density, improved body composition, and improvement in physical function (8).
A relatively large randomized trial published 2016 suggests that testosterone replacement therapy for age-related hypogonadism in men aged 65 or older has beneficial effects on sexual function, depressive symptoms, mood, and possibly physical function (10).
However, in 2015 The US Food and Drug Administration (FDA) directed manufacturers of testosterone products to state in their labels that these products are approved only for men with low testosterone due to known causes (11).
Nonetheless, most experts today believe that testosterone replacement therapy may be recommended in the presence of clinical symptoms (decreased libido, low energy, depressive mood, osteoporosis or anemia) if low serum testosterone concentration has been documented on more than one occasion (12).
The cut-off value for low testosterone in middle aged or elderly men is usually considered to be less than 200 ng/dL (6.9 nmol/L).
The Potential Risks of Testosterone Replacement Therapy
Older men may be prone to testosterone dependent diseases. In other words, the presence of testosterone may promote disease.
Prostate cancer is an example of a prostate dependent disease. This is well illustrated by the fact that hormone analogs which lower testosterone levels are used for the treatment of prostate cancer.
Short-term trials have not shown that testosterone replacement therapy increases the risk of prostate cancer. However, more extensive trials of longer duration are needed to rule out an effect on prostate cancer risk.
Elevated red blood cell count is a common adverse effect of testosterone replacement therapy. The clinical implication of this phenomenon is uncertain. However, elevated red blood cell count has been associated with increased overall mortality and cardiovascular mortality in epidemiological studies (13).
Testosterone replacement therapy may reduce HDL-cholesterol which may be undesirable (14).
However, a recent meta-analysis did not support any causal role between testosterone treatment and adverse cardiovascular events. The authors concluded that this is especially true when hypogonadism is properly diagnosed, and replacement therapy is correctly performed (15).
Notwithstanding, testosterone replacement therapy should used with caution in patients with known clinically significant cardiovascular disease.
Testosterone Products
Several testosterone products are available for the treatment of hypogonadism, age-related or not.
Oral preparations, although available, are seldom used due to lack of efficacy and risk of liver-related adverse effects.
Long-acting injections (Delatestryl, Depo-Testosterone) are often used. These can be administered every one to two weeks in most men and every three weeks in a few.
Extra-long acting injections (Nebido, Aveed) may be administered every 10-14 weeks.
Transdermal patches (Androderm, Andropatch) and gel (Testogel, Testim, Androgel, Fortesta, Axiron, Tostran) are popular but have to be administered daily.
The Bottom-Line
Serum testosterone levels decline with increasing age. This may negatively affect energy, sexual function, mood, physical strength, muscle mass, and bone mineral density in some middle-aged and older men.
Testosterone replacement therapy in older men with low testosterone levels (less than 200 ng/dL (6.9 nmol/L)) may improve sexual function, mood, depressive symptoms and possibly physical function.
Other causes of hypogonadism such as testicular or pituitary disease should be excluded before treatment is initiated.
Testosterone replacement therapy may make prostate cancer worse. Hence it is important to screen for prostate cancer before testosterone treatment is initiated and patients should be monitored for signs of the disease during treatment.
Increased red blood cell count represents the most common adverse event related to testosterone replacement therapy.
Testosterone replacement therapy should be used with caution in patients with known clinically significant cardiovascular disease.
The article was initially published in 2017.
It was revised, updated and republished on March 22, 2022.
A recently published scientific paper shows that measuring cholesterol levels in the blood may not be an optimal tool to predict the risk of cardiovascular events (1). The study is especially important because our confidence in cholesterol, LDL-cholesterol (LDL-C) in particular, has been pretty consistent for a very long time.
Trapping of apoB-containing lipoprotein particles within the arterial wall is a primary cause of atheroscleoris.
The paper, published by Marston and coworkers, underlines the importance of lipoproteins containing apolipoprotein B (apoB) and their key role in the development of atherosclerotic heart disease. The study shows that the risk of myocardial infarction (heart attack) is best captured by the number of apoB-containing particles, independent of their cholesterol or triglyceride content.
Surely, we have known for decades that there is an association between circulating levels of cholesterol and cardiovascular risk. Numerous studies have shown a strong correlation between LDL-C and the risk of coronary heart disease (2,3,4,5). Moreover, cholesterol-lowering drugs have been shown to improve cardiovascular health (6).
So, we have come to believe that we should always aim at lowering LDL-C, whether it be by dietary measures or by drug treatment (7). Our progress, or lack thereof, could then be simply tested by checking the cholesterol numbers.
However, as I have pointed out in several blog posts over the years, relying on LDL-C to predict cardiovascular risk has many pitfalls (7,8,9).
Unfortunately, the deep-rooted and oversimplified cholesterol model of heart disease often leads us off-target and frequently promotes erroneous conclusions. Therefore, the study by Marston and coworkers is of huge importance.
Apolipoprotein B and Cholesterol – The Carrier and the Cargo
Cholesterol is an essential substance for the human body. Our liver constantly generates cholesterol. It is believed that only about 20 percent of the cholesterol in our bloodstream comes from the food we eat, the rest is produced by the liver. (10).
To be able to get to cells and organs, cholesterol has to be transported in the circulation. However, since cholesterol is a fat, it can’t travel in the bloodstream by itself,
The body solves the problem by packaging cholesterol together with proteins (apolipoproteins) that function as carriers, transporting important cholesterol molecules to the cells of the body. These combinations of fats and protein are termed lipoproteins.
The apolipoproteins are the carriers whereas the cholesterol is the cargo.
Different lipoproteins contain different types of apolipoproteins. The type of apolipoprotein present determines the structure and function of the lipoprotein.
There are several classes of apolipoproteins and many subclasses (11).
The amount (mass) of cholesterol in each lipoprotein particle is variable. For example, some LDL particles carry small amounts of cholesterol whereas other particles carry large amounts. Hence, the difference between small and large particles.
Evidence shows that lipoproteins play a fundamental role in atherosclerosis.
Some lipoproteins tend to interact with the arterial wall and initiate the cascade of events that leads to atherosclerosis which may progress to atherosclerotic cardiovascular disease (8). These lipoproteins are termed atherogenic.
The presence of apoB determines whether an apolipoprotein is atherogenic or not. Atherosclerosis is only promoted by aboB containing lipoprotein particles.
Trapping of apoB-containing lipoprotein particles within the arterial is a primary cause of atherosclerosis.
The mass of cholesterol within the lipoprotein particle does not influence whether it gets trapped within the arterial wall or not. Thus, the lipoprotein’s atherogenicity is determined by the surface protein, not the cholesterol.
Atherogenic lipoproteins such as LDL, VLDL, and Lp(a), all contain one ApoB100 molecule per particle.
Thus, all atherogenic lipoprotein particles contain one ApoB molecule each. Ergo, we can count the number of atherogenic particles by counting the number of ApoB molecules.
All atherogenic lipoprotein particles contain one ApoB100 molecule each. Ergo, we can count the number of atherogenic particles by counting the number of ApoB molecules.
LDL-C, Non-HDL-C or ApoB
A standard serum lipid profile measures the concentration of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. The LDL-C concentration is usually estimated from these numbers by using the Friedewald equation.
Over the years, LDL cholesterol (LDL-C) has been the most commonly used lipid variable to predict cardiovascular risk (12). However, recent evidence suggests that non-HDL cholesterol (non-HDL-C) may be a better tool for risk assessment (13,14).
Non-HDL-C is calculated by subtracting HDL-C from the total cholesterol. Hence it provides a measure of the amount of cholesterol carried by all lipoproteins except HDL.
Non-HDL-C will give us the amount of cholesterol carried within all atherogenic lipoproteins. In other words, a measure of cholesterol carried by all the “bad” lipoproteins but not the “good” ones (which is only HDL).
Importantly, LDL-C and non-HDL-C do not tell us anything about the number of atherogenic particles. They only provide information about the mass of cholesterol carried by the different types of lipoproteins.
Due to the fact that the mass of cholesterol per particle is variable, LDL-C and non-HDL-C can differ significantly from apoB.
In their recent study, Marston and coworkers provide evidence from a large prospective observational study (the UK biobank) and two large clinical trials (FOURIER and IMPROVE-IT) that cardiovascular risk is best predicted by measurements of apoB.
The study also shows that LDL-C and non-HDL-C are nonsignificant markers of risk when apoB is taken into account.
When cholesterol-depleted particles are present, LDL-C and non-HDL-C will underestimate risk. Conversely, when cholesterol-rich particles are present, LDL-C and non-HDL-C will overestimate risk.
So, it appears that LDL-C and non-HDL-C are unreliable surrogate markers of the number of atherogenic lipoprotein particles. ApoB on the other hand provides a reliable measure of particle number and is currently the best available lipid marker to predict cardiovascular risk.
Interestingly, apoB can be measured inexpensively, and more accurately than LDL-C or non-HDL-C by currently available methods (15).
Why not end the dispute? From now on, measurements of apoB should be used when deciding whom to target and how aggressively to treat people at risk and patients who already have established cardiovascular disease.
I assume headaches have always been a part of people’s daily lives.
But, somehow, headache has never been regarded as a symptom of immense public health importance. One of the reasons may be that most underlying causes of headache are benign.
However, there is now a large body of evidence highlighting the societal impact of headache disorders, their cost and the necessity to educate and provide more basic care for those who suffer.
According to the Global Burden of Disease survey 2010 (GBD 2010), tension-type headache and migraine are the second and third most prevalent disorders in the world (1).
It is estimated that two-thirds of people will suffer from headache at some time during their lifespan: 14% to 16% are caused by migraine and 46% to 78% are due to a tension-type headache (2).
Patients with headache constitute up to 4.5 percent of emergency department (ED) visits (3).
Headache is one of the most common reasons why people use over-the-counter analgesics such as paracetamol (acetaminophen), aspirin, and other non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, naproxen, and diclofenac.
While these drugs are generally safe and effective when used as directed, their use has been associated with certain risks.
Paracetamol (acetaminophen) may harm the liver and aspirin has been associated with increased risk of bleeding from the gastrointestinal tract. Furthermore, NSAIDs should be used with caution in patients with cardiovascular disease or liver or kidney impairment (4).
Headache may be defined as primary or secondary. A secondary headache is a symptom of an underlying condition whereas a primary headache is not.
Primary Headache
1. Tension-Type Headache (TTH)
Tension headache, also known as a tension-type headache (TTH), is the most common type of primary headache. It is also the most common headache in the general population, and the second-most prevalent disorder in the world (1).
The mean global prevalence of TTH in adults is 42% (5). Due to its high prevalence in the population, TTH causes a high degree of disability.
Before 1988, no precise definition of TTH was available, and several terms such as muscle contraction headache, tension headache, psychogenic headache, or stress headache were used (6).
The headache in TTH is rarely severe. It is often band-like and aching and usually not throbbing. It usually affects both sides of the head and is not associated with light and sound sensitivity or nausea and vomiting (7). Muscle tenderness in the head, neck, or shoulders is often present.
Stress and mental tension are known to promote TTH (8).
Infrequent episodic TTH, with headache episodes less than one day a month
Frequent episodic TTH, with headache episodes 1 to 14 days a month
Chronic TTH, with headaches 15 or more days a month
Simple over-the-counter analgesics (aspirin, ibuprofen (Advil, Motrin IB, others) and naproxen (Aleve)) are the mainstays of treatment of episodic TTH. Aspirin or acetaminophen are sometimes combined with caffeine or a sedative drug in a single medication.
However, it is crucial to avoid excessive use of simple analgesics to prevent the development of medication-overuse headache (10).
Tricyclic antidepressants, including amitriptyline and protriptyline, are the most commonly used medications to prevent TTH.
Acupuncture, massage, and relaxation therapies are sometimes used.
2. Migraine
Migraine is a disorder of recurrent attacks of headache. It is often described as severe throbbing pain or a pulsing sensation, usually on one side of the head. It is commonly accompanied by nausea, vomiting, and sensitivity to light and sound.
Prodromal symptoms may occur one or two days before the attack (11). These include constipation or diarrhea, mood changes, appetite changes including food cravings, concentration difficulties, cold extremities, increased thirst, frequent urination and constant yawning.
Warning symptoms known as aura may occur before or together with the headache. These include visual disturbances and sensory abnormalities such as a tingling or touching sensation on one side of the face or in an arm or a leg (12). However, most patients (75-80%) with a migraine don’t experience an aura.
There are some known trigger factors for migraine attacks such as emotional stress, menstruation, visual stimuli such as bright lights, fasting, wine, physical exertion, sleep disturbances, intake of highly caffeinated beverages and aspartame, among others (13).
The exact cause of migraines is unknown. They may result from abnormal brain activity, partly caused by imbalances in brain chemicals including serotonin. These abnormalities may temporarily affect nerve signals and blood vessels in the brain.
3. Cluster Headache
Cluster headache, also known as histamine headache, is a rare disorder that affects about 1-2 people in every 1.000.
It is characterized by a severe pain in one side of the head, often the eye, temple or forehead. The pain may begin quickly and without warning. It may be very intense but does usually not last for more than 1-2 hours.
At least one of the following associated symptoms is usually present (14):
a red and watering eye
drooping and swelling of one eyelid
a smaller pupil in one eye
a sweaty face
a blocked or runny nostril
People who smoke seem to have a higher risk of getting cluster headaches. Some cases also appear to run in families. Cluster headache attacks can sometimes be triggered by drinking alcohol or by strong smells, such as perfume, paint or petrol.
Secondary Headache
4. Upper Respiratory Tract Infections
Upper respiratory tract infections are a common cause of headache.
In children and adolescents presenting to the ED, upper respiratory tract infections are the most frequent underlying cause of acute headache (57%). There is often associated fever and a sore throat.
Headache is a common symptom of infections with the SARS-CoV-2 coronavirus (COVID-19)(15).
Sinusitis is may cause headache. It is an inflammation, or swelling, of the tissue lining the sinuses. It is commonly associated with nasal mucus and plugged nose.
5. Encephalitis and Meningitis
Encephalitis is an infection of the brain most often caused by a viral infection. It is characterized by fever, seizures, change in behavior, confusion, and disorientation
Meningitis is an inflammatory process of the membranes that surround the brain. When caused by bacteria it is called bacterial meningitis. The bacteria usually infect the mucosa of the upper airways from where they may enter the bloodstream and ultimately cross the blood-brain barrier and enter the brain.
The most common types of bacterial meningitis include pneumococcal meningitis and meningococcal meningitis. Some 6,000 cases of pneumococcal meningitis are reported in the United States each year (16).
Bacterial meningitis is a rare but potentially fatal disease. Haemophilus meningitis used to be the most common form of bacterial meningitis. The Haemophilus influenza b vaccine has significantly reduced the number of cases in the United States.
Given the success of routine childhood vaccination programs, over the past 25 years, the median age of a patient diagnosed with meningitis has risen from 15 months to 42 years old (17).
Meningitis is classified as aseptic meningitis if it is due to other causes such as drugs or non-bacterial infections.
The diagnosis of encephalitis and meningitis is usually made by performing a lumbar puncture (spinal tap).
The hallmark signs of bacterial meningitis are sudden fever and severe headache. Patients with bacterial meningitis often have nausea/vomiting, double vision, drowsiness, sensitivity to bright light, and a stiff neck.
Early diagnosis is crucial because acute bacterial meningitis must be treated immediately with intravenous antibiotics and, and sometimes, corticosteroids.
6. Subarachnoid Hemorrhage (SAH)
The subarachnoid space is the area between the brain and the skull. It is typically filled with cerebrospinal fluid. Subarachnoid hemorrhage (SAH) is a life-threatening condition caused by bleeding into the subarachnoid space
SAH can be caused by a ruptured aneurysm, vessel malformations (arte
riovenous malformations), or head injury.
SAH typically presents with a severe headache, nausea and vomiting, stiff neck, sensitivity to light (photophobia), and sometimes blurred or double vision, loss of consciousness, and seizures (18).
Treatment for SAH varies, depending on the underlying cause of the bleeding, the condition of the patient, and the extent of damage to the brain.
7. Stroke
A stroke occurs when the blood flow to the brain is interrupted. If blood doesn’t reach the brain, brain cells will die, and permanent brain damage can occur.
In ischemic stroke, a blood clot blocks the flow of blood to areas of the brain. In hemorrhagic stroke, there is bleeding into brain tissue, most commonly because of a burst vessel.
A patient in the early phases of a stroke may experience a headache. The headache may be accompanied by dizziness or vomiting. However, most patients will have neurologic deficits as well, such as an inability to move a limb, sensory deficits, slurred speech or an inability to speak.
8. Head Trauma
A headache immediately following a head injury usually disappears after minutes or days. However, sometimes headaches may persist for months or years after the injury. These long-term headaches are called post-traumatic or post-concussion headaches.
Post-traumatic headaches typically affect both sides of the head and often occur daily. They are of slight to moderate intensity. However, bouts of more severe headache may occur and these may be similar to migraine with one sided throbbing pain associated with nausea and sensitivity to light and noise (19).
Today, many cases of post-traumatic headache will be classified as chronic TTH.
9. Chronic Subdural Hematoma (SDH)
A chronic subdural hematoma (SDH) is an old clot of blood on the surface of the brain beneath its outer covering (20). The most common complaint is headache, seen in up to 80 percent of patients.
SDH is most common in patients age 60 and older. Many patients have an underlying brain atrophy, a shrinking of brain tissue, usually due to age or disease.
SDH is usually precipitated by a minor head trauma which cause tearing of blood vessels over the brain surface, resulting in a slow accumulation of blood over several days to weeks. The traum
a may be trivial and is often not remembered by the patient himself.
Risk factors include alcohol abuse and blood thinning medications.
10. Brain Tumor
Headache is one of the most common symptoms experienced by patients with brain tumors. The headache is usually steady but often worse in the morning. It is generally much more persistent than migraine headache. It is sometimes associated with nausea or vomiting. It may worsen with coughing, exercise, or a change in body position and does not usually respond to the usual headache remedies.
The signs and symptoms of a brain tumor vary greatly and depend on the brain tumor’s size, location, and rate of growth.
Tumors in the back part of the brain (posterior fossa) may be accompanied by dizziness or unsteady gait.
Tumors in the principal part of the brain (cerebrum) may cause speech difficulties or gradual loss of sensation or movement in an arm or a leg.
Tumors around the pituitary gland may have accompanying vision problems, such as blurred vision, double vision or loss of peripheral vision.
Sometimes there may be confusion in everyday matters, personality or behavior changes, seizures, and hearing problems (21).
11. Temporal Arteritis
Giant cell arteritis is a condition in which medium and large arteries become inflamed. It’s sometimes called temporal arteritis because the arteries around the temples are often affected. There is often aching and soreness in and around the temples and pain in the jaw muscles while eating. Vision loss may occur. The headache is localized to one side and usually throbbing.
Temporal arteritis is usually a disease of the elderly and should be suspected in anyone over the age of 50 years with a new onset of a headache in one side of the head (unilateral headache).
A blood sample will usually reveal an elevated erythrocyte sedimentation rate. The diagnosis is made by taking a tissue sample from the temporal artery (temporal artery biopsy). Temporal arteritis usually responds well to steroid treatment. A two-year course of corticosteroids may be required.
12. Dissection of Carotid or Vertebral Arteries
The carotid and vertebral arteries are important vessels that transport oxygen-rich blood through the neck to the brain.
The word dissection describes a sudden tear in the artery wall that allows blood flow to separate the wall layers. Blood flow into this “false” channel can grow to compress the true artery channel, resulting in a total artery blockage, or occlusion (22).
Dissection may develop without an apparent cause (spontaneous carotid artery dissection) or secondary to trauma (e.g., motor vehicle accident, sports injury, surgery, chiropractic neck manipulation).
The headache associated with a dissection of the carotid or vertebral arteries often radiates to the neck and face. The pain may be constant, instantaneous, gradual, throbbing, or sharp.
Pieces of the clotted blood can break off and block smaller arteries in the brain resulting in a stroke. Consequently, the patient may experience weakness on one-side of the body, visual disturbance, facial droop, and difficulty with speech.
13. Medication-Overuse Headache
Medication-overuse headache (MOH) is a chronic daily headache caused by frequent use of pain-relief medication (23)
As soon as the effect of the drug wears off, the pain comes back, leading the patient to take more. Ultimately, the medicine stops working and may contribute to maintaining the disorder. MOH can occur with both over-the-counter and prescription pain-relief medications.
Codeine and opioids are not recommended for the treatment of a tension-type headache or migraine. Regardless of this, many MOH patients use these agents.
Codeine and caffeine-containing analgesics are available as over-the-counter medication in many countries.
Codeine, opioids, and caffeine are known to be psychotropic drugs; thus abuse and dependence on headache drugs may be a problem (24).
Patients with MOH can usually be effectively treated. Weaning them off the medication is the first step.
Most patients experience withdrawal symptoms lasting 2–10 days after detoxification. The most common symptom is an initial worsening of the headache, accompanied nausea, vomiting, heart palpitations, restlessness, anxiety, and nervousness.
14. Acute Herpes Zoster
Herpes zoster (shingles) is an infection caused by the varicella-zoster virus, the same virus that causes chickenpox. The virus may remain dormant in the nervous system for years before reactivating as herpes zoster.
Herpes zoster is characterized by a red skin rash that can cause pain and burning. Typically it occurs as a stripe of blisters on one side of the body, often on the torso, neck, or face.
Most cases of herpes zoster clear up within two to three weeks. The disorder rarely occurs more than once in the same person, but approximately 1 in 3 people in the United States will have herpes zoster at some point in their life (25).
Herpes zoster involving the trigeminal and cervical nerves may cause headache. The headache commonly occurs before the typical rash appears.
In some cases, postherpetic neuralgia may occur. The diagnosis is made when pain persists beyond four months in the same distribution as a preceding episode of acute herpes zoster.
15. Idiopathic Intracranial Hypertension (IIH)
Idiopathic intracranial hypertension (IIH), sometimes called benign intracranial hypertension (BIH) or pseudotumor cerebri, is a rare disorder characterized by increased intracranial pressure (pressure around the brain) in the absence of an other underlying causes (26).
Idiopathic means that the underlying cause of the raised pressure is unknown. The main symptoms are headache and visual loss.
IIH mostly affects women of childbearing age who are overweight or obese. Treatment is aimed at preventing permanent visual loss and includes treatment with medicines, and sometimes brain surgery may also be used.
16. Hypertension
Hypertension is considered to exist when systolic blood pressure is above 140 mm Hg and/or diastolic blood pressure is above 90 mm Hg (27).
Hypertension affects approximately 86 million adults in the United States; and is a major risk factor for stroke, coronary artery disease, and chronic kidney disease.
The relationship between headache and hypertension has been debated for many years.
Obviously, hypertension is very common and so is headache. Hence, many people with hypertension will complain of headache. Nevertheless, some, but not all, studies have shown that headache is somewhat more common in those who are hypertensive than among those who are not (28).
Although many experts still believe there is an association between moderate hypertension and headache, definitive evidence is lacking (29).
17. Trigeminal Neuralgia
The term neuralgia describes pain caused by injury or damage to a nerve.
The trigeminal nerve is the fifth (V) cranial nerve, which arises from the brainstem inside the skull. It exits the skull in three branches and provides feeling and movement to the face.
Trigeminal neuralgia is characterized by a sudden, severe facial pain.
Trigeminal neuralgia is also called tic douloureux because of an uncontrollable facial twitching sometimes associated with the pain.
18. Hangover
Hangover headaches or alcohol-induced headaches are headaches that come the day after consuming alcohol. These may be caused by a direct toxic effect of alcohol and its byproducts.
Alcoholic drinks have also been reported as a relatively common migraine trigger (30).
Alcohol may also trigger TTH and cluster headache. Hence, it has been argued that alcohol is merely a trigger of primary headache and that hangover headaches should therefore not be regarded as a type of a secondary headache.
Hangover headache is usually experienced on both sides of the head, mainly in the front of the forehead. The headache is often pulsating or throbbing and usually worsens with physical activity.
19. Caffeine Withdrawal
Caffeine is the most widely used behaviorally active drug in the world. In North America, 80–90% of adults report regular use of caffeine (31).
In the United States, coffee and soft drinks are the most common sources of caffeine, with almost half of caffeine consumers ingesting caffeine from multiple sources, including tea (32).
Studies on caffeine consumption demonstrate that when people don’t get their usual dose they can suffer a range of withdrawal symptoms, including headache, muscle pain, fatigue, drowsiness, dysphoric mood, difficulty concentrating and flu-like symptoms.
Caffeine withdrawal refers to a time-limited syndrome that develops after cessation of chronic caffeine intake (33).
Headache is the most common symptom of caffeine withdrawal. It usually begins within 12 to 24 hours after discontinuing caffeine, peaking during the first two days, and may last for 7-9 days.
Re-introducing caffeine during the withdrawal period can stop the headache within just 30 to 60 minutes but the ultimate cure is total abstinence from caffeine.
A recent google search provided me with the following top results:
11 Foods that Lower Cholesterol – Harvard Health Publishing…
How to Lower Cholesterol with Diet: MedlinePlus
Top 5 lifestyle changes to improve your cholesterol – Mayo Clinic
Cholesterol: Top foods to improve your numbers – Mayo Clinic
10 Tips to Lower Cholesterol With Your Diet – Healthline
13 Cholesterol-Lowering Foods to Add to Your Diet Today
…. and the list is much longer
Clearly, none of these articles was able to answer my question.
However, there is no doubt that we can lower LDL cholesterol by changing our diet. The most effective way to do so is probably by reducing the intake of saturated fats.
Indeed, this is the reason why reducing the amount of saturated fat in our diet has been a central theme of public health recommendations since the late 1970s (1).
But, lowering a number is one thing. The big question is whether lowering LDL cholesterol by diet improves health and reduces the risk of heart disease.
LDL Cholesterol and Heart Disease
Scientific evidence certainly shows a positive association between serum cholesterol and the risk of dying from cardiovascular disease (2,3,4).
It is also evident that LDL particles play a causal role in developing of atherosclerotic cardiovascular disease (ASCVD) (5).
Furthermore, a consensus panel of respected scientists recently concluded that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL cholesterol (6).
But the same panel also concluded that this is true “provided that the achieved reduction in LDL cholesterol is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects.”
I want to emphasize these two key issues:
provided that the achieved reduction in LDL cholesterol is concordant with the reduction in LDL particle number
and that there are no competing deleterious off-target effects
Saturated Fats, LDL Particle Size and Number
Low-density lipoprotein occurs as large buoyant LDL particles, and as small dense LDL particles (7).
Large LDL particles are more cholesterol-enriched, whereas small dense LDLs carry less cholesterol per particle.
Large LDL particles have a much weaker association with ASCVD than do smaller LDL particles (8,9).
Lowering LDL cholesterol by reducing the intake of saturated fats primarily reflects reduced levels of large LDL particles, whereas, in most individuals, the number of small LDL-particles is not reduced by reducing saturated fats (10).
Many recent studies have concluded that the number of LDL-particle present is a strong predictor of cardiovascular risk.
It is possible indeed, that the association between the number of small LDLs and heart disease reflects an increased number of LDL particles in patients with predominantly small particles. Therefore, the number of LDL particles could be more significant in terms of risk than the particle size itself (11).
Lowering LDL cholesterol by reducing the intake of saturated fats primarily reflects reduced levels of large LDL particles, whereas, in most individuals, the number of small LDL-particles is not reduced by reducing saturated fats
Moreover, decreasing saturated fat intake also lowers the levels of high-density lipoprotein (HDL) cholesterol which may have a negative impact on the risk of ASCVD (12).
Also, as recently pointed out in a blog article here, a low-fat, high-carbohydrate diet may increase lipoprotein (a) levels compared to a high-fat, low-carbohydrate diet(13). Lipoprotein(a) is strongly associated with the risk of ASCVD.
The PURE study reported that the association between saturated fat and ASCVD events does not fit a relation with plasma LDL cholesterol but is related to the ratio of apolipoprotein B (apo B) to apo A1(14).
Interestingly, ApoB correlates with LDL particle number (15).
In fact, several randomized trials have shown that changes in LDL cholesterol achieved by modulating the intake of saturated fat do not correlate with the risk of ASCVD (16,17,18)
This is brilliantly discussed by Arne Astrup and colleagues in a state-of-the-art-review published last year in the Journal of the American College of Cardiology (10).
As the review article points out, “the potential benefit of dietary restriction of saturated fat could be substantially overestimated by reliance on the change in LDL cholesterol levels alone.”
Is There A Downside of Diets that Lower LDL Cholesterol?
Dietary guidelines usually recommend replacing saturated fatty acids with cis-unsaturated fatty acids.
The recently published guidelines for Americans 2020-2025 discuss the importance of limiting intakes of saturated fat to support healthy dietary patterns (19).
The major purpose of these measures appears to be to lower blood cholesterol and reduce the risk of cardiovascular disease.
Among other things the guidelines suggest using lean meats and low-fat cheese or substituting beans in place of meats as the protein source.”
It is also pointed out that “saturated fat can also be reduced by substituting certain ingredients with sources of unsaturated fat (e.g., using avocado, nuts, or seeds in a dish instead of cheese). Cooking with oils higher in polyunsaturated and monounsaturated fat (e.g., canola, corn, olive, peanut, safflower, soybean, and sunflower) instead of butter also can reduce intakes of saturated fat.”
However, it is often forgotten that saturated fats are a heterogenous group of fatty acids that differ on the basis of their carbon chain length.
Furthermore, saturated fats are obtained from foods that have other ingredients that may modify their health effects.
In my opinion, judging the health effects of foods based on their amount of saturated fat is unwise and may promote bad food choices.
Also, remember that a Mediterranean-style diet appears to reduce the risk of ASCVD without reducing LDL cholesterol (20).
So, if we are to recommend food choices that lower LDL cholesterol, we have to be sure that the same recommendations do not include any competing deleterious off-target effects.
Is Lowering LDL Cholesterol Helpful?
So, let’s go back to the initial question.
Is Lowering LDL Cholesterol by Diet Helpful?
As my google search showed, there are tons of articles explaining how we can lower our cholesterol by changing our diet.
But, is it helpful?
Does it lower our risk of developing heart disease?
Frankly, I’m far from convinced. And, due to the fact that I have been studying the scientific data for more than thirty years, I believe I’m entitled an opinion.
I think that LDL cholesterol is a lousy surrogate marker and I fear that letting it control our dietary choices may lead to more harm than good.
