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22 Key Causes of Abdominal Pain – Stomach Pain Explained

Estimated reading time: 13 minutes

Stomach pain, also known as abdominal pain, is caused by a variety of conditions most of whom are innocent or benign.

However, sometimes, abdominal pain may be due to a severe disorder needing immediate intervention.

The abdomen is the part of the body between the chest and the pelvis. Other common names used to describe the abdomen are belly, stomach, and tummy.

The location of the pain is a of key importance. Hence, pain may be classified as upper abdominal pain and lower abdominal pain.

Upper abdominal pain is further divided into upper right abdominal pain, epigastric pain, and upper left abdominal pain.

Lower abdominal pain may also be divided into right and left lower quadrant pain.

Abdominal pain can also be diffuse and not distinctly positioned in a particular part of the abdomen.

Acute vs. Chronic Abdominal Pain

Determining whether the pain is acute or chronic is crucial.

The term ‘acute abdomen’ was defined to describe a rapid onset of severe abdominal pain that may represent a serious condition. It needs an urgent and specific diagnosis and sometimes immediate surgical intervention.

Examples of underlying causes of ‘acute abdomen’ are acute appendicitis, acute cholecystitis, acute pancreatitis, acute diverticulitis, gallstones, and kidney stones.

Upper Right Abdominal Pain

Upper right abdominal pain is typically caused by disorders of the liver, gallbladder, and biliary tree.

1. Gallstones

Pain caused by gallstones is called biliary colic.

Biliary colic is a steady or intermittent ache usually located in the upper right abdomen. Sometimes the pain spreads backward to the right shoulder blade.

The pain usually lasts for 30 minutes to an hour but may continue at a lower intensity for several more hours.

Ultrasound is commonly used to detect gallstones.

Surgical removal of the gallbladder is a standard treatment for patients with gallstones and biliary colic. It is often performed by keyhole (laparoscopic) surgery.

Biliary colic is a steady or intermittent ache usually located in the right upper quadrant of the abdomen. It is generally caused by gallstones blocking the normal flow of bile from the gallbladder.

2. Acute Cholecystitis

Acute cholecystitis is an inflammation of the gallbladder.

Gallstones blocking the transport of bile from the gallbladder are the most common underlying cause.

Most often, patients experience steady, severe upper right abdominal pain. Nausea and vomiting are common and fever is usually present as well.

Hospital admission is usually necessary.

Treatment is based on fasting, pain medication, and antibiotics if an infection is present.

Sometimes, removal of the gallbladder is necessary.

3. Acute Cholangitis

Acute cholangitis is caused by a bacterial infection of the bile ducts. It occurs when gallstones become impacted in the biliary ducts (1).

Sometimes, a tumor blocking the bile ducts is the underlying cause.

Acute cholangitis is characterized by fever, jaundice, and abdominal pain (2).

Jaundice is a term used to describe yellowing of the skin and the whites of the eyes. It is caused by the build-up of a substance called bilirubin in the blood and tissues of the body.

Cholangitis is a serious medical condition.

Treatment includes fasting and intravenous fluids.

Antibiotics are administered to treat the underlying infection.

It is essential to restore normal flow in the bile ducts by removing the blockage.

4. Hepatitis

Hepatitis is an inflammation of the liver, usually caused by a viral infection.

Typical symptoms include right upper right abdominal pain, fatigue, nausea, vomiting, and clay-colored stools. Furthermore, some patients have dark urine and jaundice as well.

There are several types of viral hepatitis.

Hepatitis A is caused by the hepatitis A virus. The virus is primarily spread when a person ingests food or water that is contaminated with the feces of an infected person. The disease is closely associated with unsafe water or food, inadequate sanitation, and poor personal hygiene (3).

Hepatitis B is also caused by a viral infection. The virus is transmitted through contact with the blood or other body fluids of an infected person.

The disease may lead to scarring of the liver. Moreover, there is  an increased risk of liver cancer and liver failure.

Most patients with hepatitis B have no symptoms.

A vaccine is available for both hepatitis A and B.

Hepatitis C is caused by the hepatitis C virus. It is a blood-borne virus and usually spreads through exposure to small quantities of blood. This commonly happens through injection drug use.

Approximately 80% of people with hepatitis C have no symptoms.

Some patients have mild symptoms but others suffer from a serious, lifelong illness (4).

A significant number of those who are chronically infected will develop scarring of the liver or liver cancer (5).

Medical treatment for hepatitis C is available but remains limited.

Epigastric pain

Epigastric pain is located in the central portion of the upper abdomen, below the sternum, and above the navel. It is often caused by disorders of the stomach and pancreas.

Dyspepsia is a common term used to describe epigastrial pain, sometimes combined with other complaints (6).

5. Peptic Ulcer Disease (PUD)

Ulcers in the lower esophagus, the stomach, and the first part of the small intestine (duodenum) are common causes of epigastrial pain. Together these disorders are known as peptic ulcer disease (PUD).

PUD is characterized by a gnawing or burning sensation in the epigastrium (7).

Infection of the lining of the stomach from a bacteria called H pylori is a common underlying cause of peptic ulcer disease (8).

A gastroscopy usually reveals the diagnosis. It is an examination of the upper digestive tract (the esophagus, stomach, and duodenum) using a long, thin, flexible tube to view the internal lining of these organs

Treatment of PUD includes antibiotic medication to kill H pylori when it is present.

Drugs that inhibit stomach acid production, like proton pump inhibitors (PPIs), are given to promote healing.  Examples of PPIs are omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), esomeprazole (Nexium), and pantoprazole (Protonix).

Histamine (H-2) blockers also reduce the amount of stomach acid released and may reduce ulcer pain and promote healing. Examples are Tagamet (cimetidine), Zantac (ranitidine), Pepcid (famotidine), and Axid (nizatidine).

Antacids can provide rapid pain relief by neutralizing existing stomach acid. However, they are not considered useful enough to promote healing.

6. Gastroesophageal Reflux Disease (GERD)

Gastroesophageal reflux disease (GERD) is a common cause of epigastric pain.

GERD is a chronic digestive disease that occurs when stomach acid or stomach content flows back (reflux) into the esophagus.

Most healthy people experience acid reflux and heartburn once in a while. GERD should be suspected when these symptoms occur at least twice each week or interfere with daily life, .

The pain associated with GERD may be described as squeezing or burning. It may also radiate up to the chest, and sometimes to the back, neck, jaw, or arms.

Many people can manage the symptoms of GERD with lifestyle changes. Antacids are usually helpful too as they can neutralize gastric acid but the effects are usually short-lasting.

However, some patients may need prescription drugs, or even surgery, to reduce symptoms.

PPIs, H-2 blockers are commonly used to reduce symptoms.

Gastroscopy is a commonly used diagnostic tool when evaluating patients with epigastrial pain. It may detect GERD, gastritis, and peptic ulcer disease.

7. Gastritis

Gastritis is an inflammation affecting the lining of the stomach.

Similar to gastric ulcers, it is sometimes caused by an underlying infection with the H pylori bacteria. 

The symptoms include a gnawing or burning ache or pain in the epigastrium. Nausea and vomiting may also be present.

Common over-the-counter pain relievers, such as aspirin, ibuprofen (Advil, Motrin IB, others), and naproxen (Aleve, Anaprox) can cause gastritis. Stress and excessive alcohol consumption are also common underlying causes.

Medical treatment is essentially the same as that of peptic ulcer disease and GERD.

8. Pancreatitis

Pancreatitis is an inflammation of the pancreas. It can be both acute and chronic.

The main symptoms are upper abdominal pain, nausea, and vomiting.

The pain is characteristically dull, boring, and steady, and usually sudden in onset. It is most often located in the epigastrium and may radiate through to the back (9).

Gallstones and binge alcohol consumption are the most common underlying causes of acute pancreatitis.

9. Heart Attack and Acute Coronary Syndrome

Patients with imminent heart attack, also called acute coronary syndrome usually experience chest pain or tightness in the chest (10).

However, some patients may experience epigastric pain. There may even be a feeling of indigestion or fullness and gas.

10. Functional Dyspepsia 

Functional dyspepsia is a chronic disorder that may cause discomfort in the epigastrium.

It is characterized by a feeling of fullness following a meal, early satiation, and epigastric pain (11).

The disorder is defined as functional because there are no observable or measurable structural abnormalities found to explain the symptoms. Hence, it is sometimes called non-ulcer dyspepsia as well.

Upper Left Abdominal Pain

11. Disorders of the Spleen

Upper left abdominal pain is sometimes caused by diseases of the spleen.

Enlargement of the spleen (splenomegaly) and splenic infarction may cause right upper abdominal pain (12).

Splenic infarction is a condition in which blood flow supply to the spleen is compromised.

Lower Abdominal Pain

Lower abdominal pain in women is frequently caused by disorders of the internal female reproductive organs. These disorders are not covered here.

12. Kidney Stones (Urolithiasis)

Kidney stones can be both small and large. Some stones stay in the kidney and do not cause any symptoms.

Sometimes, a kidney stone travels down the ureter, the tube between the kidney and the bladder. If the stone reaches the bladder, it can be passed out of the body in urine.

A kidney stone can travel down the ureter, the tube between the kidney and the bladder. If the stone reaches the bladder, it can be passed out of the body in urine. If the stone becomes lodged in the ureter, it may cause severe pain.

If the stone becomes lodged in the ureter, it may block the urine flow from that kidney. This may cause very serious and intense pain.

The pain is usually a sharp, cramping pain in the back and side, often radiating to the lower abdomen and groin. The pain often starts suddenly and comes in waves.

Nausea and vomiting may be present as well.

In addition, the urine may be dark or red due to blood (hematuria).

13. Cystitis

Cystitis is an inflammation of the urinary bladder. It is usually caused by a bacterial infection.

Cystitis may cause pain in the lower mid-portion of the abdomen.

There may also be a persistent urge to pass urine and a burning sensation while urinating.

Furthermore, blood in the urine (hematuria) may be present and sometimes the urine is cloudy and has a strong smell.

Bacterial cystitis is usually treated with antibiotics

14. Pyelonephritis

Pyelonephritis is a urinary tract infection that often begins in the urine bladder and travels up to one or both kidneys.

The symptoms include fever, chills, pain in the back or side of the abdomen, or the groin. Frequent urination, nausea, and vomiting are also common.

The infection is usually caused by bacteria. Hence, antibiotics are the first line of treatment.

15. Acute Appendicitis

The appendix is a narrow, finger-shaped pouch that projects out from the colon

Acute appendicitis is an acute inflammation of the appendix and typically presents with pain around the navel. Usually, the pain radiates to the right lower quadrant of the abdomen.

The pain may increase with coughing, walking, or jolting movements.

Nausea and vomiting may be present, and there is usually a lack of appetite.

Acute appendicitis is usually treated by removing the appendix by open surgery or less-invasive keyhole surgery (laparoscopy) (20).

The appendix is a narrow, finger-shaped pouch that projects out from the colon. Acute appendicitis is an acute inflammation of the appendix.

16. Diverticulitis

Diverticula are small, bulging pouches that can form in the internal lining of the colon.

Diverticulitis is defined as an inflammation of one or more of these pouches.

The symptoms include left lower abdominal pain, nausea, vomiting, and fever.  Constipation, or less commonly, diarrhea may also be present.

Treatment usually includes antibiotics drugs.

Surgery is rarely needed unless complications are present.

Diffuse Abdominal Pain

Abdominal pain may often be diffuse and not located in a particular part of the abdomen.

17. Inflammatory Bowel Disease (IBD)

Inflammatory bowel disease (IBD) is a disease of a-unknown cause. It is believed to reflect an abnormal immune response to the intestinal microflora. Hence, it is classified as an autoimmune disease.

There are two major types of IBD, ulcerative colitis and Crohn’s disease.

Ulcerative colitis is limited to the colon whereas Crohn’s disease can affect any segment of the intestine.

The symptoms include abdominal pain and cramping, irregular bowel habits, and a passage of mucus with blood. Also, many patients experience weight loss, joint pain (arthralgia), sweats, and fatigue.

18. Intestinal Obstruction

Intestinal obstruction is a blockage that keeps food or liquid from passing through the small or large intestine.

There may be several underlying causes.  Sometimes bands of tissue (adhesions) form in the abdomen after surgery. Cancer of the small or large bowel may also cause obstruction.

The symptoms include a crampy abdominal pain that comes and goes in waves. Besides, there is a loss of appetite, swelling of the abdomen, vomiting, and inability to have a bowel movement or pass gas.

Treatment depends on the underlying cause.

19. Gastroenteritis

Viral gastroenteritis, sometimes called stomach flu, is an infection of the small or large intestine.

Symptoms include watery diarrhea, abdominal cramps, nausea, vomiting, and sometimes fever (13).

Usually, symptoms only last a day or two.

Bacterial gastroenteritis is usually caused by consuming food that is contaminated with bacteria. Typical examples include Campylobacter and Salmonella.

Because gastroenteritis is usually self-limited, medical care is primarily supportive. Drinking fluid (oral hydration) is important. However, sometimes, intravenous fluids may have to be administered.

Antibiotics are administered for some cases of bacterial gastroenteritis (14).

20. Mesenteric Ischemia

The mesentery is a fold of membrane that attaches the intestine to the abdominal wall and holds it in place (15).

Acute mesenteric ischemia is caused by inadequate blood flow through the mesenteric vessels. It is a potentially life-threatening condition.

The condition is characterized by severe abdominal pain, sometimes associated with bloody diarrhea.

Acute mesenteric ischemia must be treated immediately to prevent tissue death. Surgery may be necessary to remove parts of the intestine.

21. Cancer

Several cancers may be associated with abdominal pain. Examples are cancer of the stomach, the liver, the pancreas, the colon, and the rectum.

22. Irritable Bowel Syndrome (IBS)

Irritable bowel syndrome (IBS) describes a group of symptoms that affect the large intestine without a known cause.

IBS is a common disorder and occurs more often in women than in men.

Symptoms of IBS include cramping, abdominal pain, and bloating. Diarrhea or constipation may be present as well.

Before the diagnosis is made, other more serious underlying causes of the patient’s symptoms should be excluded.




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The CANTOS Trial – Is Targeting Inflammation the Solution to Heart Disease?

Estimated reading time: 10 minutes

The recently published results of the long awaited CANTOS trial may forever change our approach to the prevention and treatment of coronary artery disease (1). Inescapably, there is now proof that targeting inflammation, in this case by a drug, significantly improves outcome for certain very high-risk patients.

But, as so often in clinical research, things are not open-and-shut, and the picture is not as lucid as it seems.


Two or three decades ago, many experts predicted that the modification of risk factors, in particular, the treatment of high blood pressure and lipid disorders, would eliminate CAD in 10 – 20 years. Unfortunately, that prediction turned out to be wrong.

Although the death rate from coronary artery disease has dropped in most countries, the disease remains an important cause of death and disability worldwide. Even more worrying is the rising prevalence of obesity and type 2 diabetes which ultimately reverse the declining trend in mortality from cardiovascular disease.

Current drug therapies designed to slow the atherosclerotic process focus almost exclusively on reducing plasma levels of LDL cholesterol. However, experimental and clinical research supports that additionally targeting inflammation may be beneficial (2).

What Is Inflammation?

The body’s defenses are controlled by the immune system which is composed of biological structures and mechanisms that continuously protects us against diseases such as infections and cancer.

Inflammation is a protective response to injury or destruction of cells or tissues. It is one of the body’s most important defense mechanism. Without it, we would not be able to fight bacterial infections, injuries, and destruction of tissues.

Inflammation can be both acute and chronic. Acute inflammation is the initial response of the body to harmful stimuli.  Prolonged inflammation or chronic inflammation is characterized by simultaneous destruction and repair.

Inflammation is protective when it is appropriate. However, when inflammation is inappropriate or gets out of hand, it may cause disease.

Autoimmune disorders such as rheumatoid arthritis, Hashimoto’s thyroiditis, systemic lupus erythematosus, and type 1 diabetes are all associated with a dysfunction of the immune system. These disorders are characterized by an inappropriate immune response against cells and tissues in our body causing inflammation of tissues and organs.

Inflammation and Atherosclerosis

Inflammation plays a significant role in atherosclerotic cardiovascular disease (3). Modern theories on the initiation of atherosclerosis suggest that modified lipoproteins, such as oxidized LDL (OxLD), may play a central role in promoting the inflammatory reactions that characterize and drive atherosclerosis (4).

Leukocytes, the type of white blood cells typically involved in most inflammatory reactions in the body, appear to play an important role in atherosclerosis. Leukocyte recruitment to the arterial wall is an important initial step in the formation of atherosclerotic plaques.

Cytokines are small proteins that are important in cell signaling (5). The cytokines interleukin-6 (IL-6), IL-1, and TNFα are elevated in most, if not all, inflammatory states and have been recognized as targets of therapeutic intervention (6).

Interleukin-1β is a cytokine that is central to the inflammatory response and drives the so-called interleukin-6 signaling pathway.

Inflammatory biomarkers are used to determine whether systemic inflammation is present or not. Many observational and clinical studies have used high-sensitivity C-reactive protein (hs-CRP)  to test the relationship between inflammation and cardiovascular disease (7).

CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study)

The CANTOS trial examined whether reducing inflammation with canakinumab in patients with a history of a prior heart attack can decrease the risk of another cardiovascular event happening in the future.

Canakinumab is a human monoclonal antibody that neutralizes interleukin-1β (8). It is approved in the United States and Europe as a treatment for several rare inflammatory diseases and has proven to be well-tolerated in people with diabetes or arthritis.

A total of 10.061 patients with a history of myocardial infarction (heart attack) and an hs-CRP equal to or above 2 mg/L were included in the CANTOS trial. Patients with a history of chronic or recurrent infections and cancer were excluded from the trial. The median follow-up was 3.7 years.

Patients with a history of chronic or recurrent infections and cancer were excluded from the trial.

The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every three months) with placebo. Enrollment began in April 2011 and was completed in March 2014. The median follow-up was 3.7 years.

The CANTOS Trial Population

The mean age of the participants who underwent randomization was 61 years, 25.7% of the patients were women.

The median body mass of the participants was 29.9, 40.0% had diabetes, 79.9% had hypertension, and 93.4% were on lipid-lowering therapy.

Median LDL cholesterol was 82.0 mg/dl (2.1 mmol/L), median HDL cholesterol was 43.7 mg/dL (1.1 mmol/L), and median triglyceride level was 139 mg/dL (1.56 mmol/L).

The CANTOS Trial Results

Canakinumab reduced the hs-CRP level, compared to placebo, by 26% to 41% depending on the dose administered. Similar effects were observed for the interleukin-6 level.

Canakinumab did not reduce lipid levels from baseline although a slight reduction in triglycerides was found.

Here’s how the main results are reported in the paper (you’ll find an easier version below if you read further):

At a median follow-up of 3.7 years, the incidence rate for the primary end point (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the group that received the 50-mg dose of canakinumab, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group.

No significant effect, as compared with placebo, was observed with regard to the primary end point in the 50-mg group (hazard ratio, 0.93; P=0.30). By contrast, a significant effect for the primary end point was observed in the 150-mg group (hazard ratio vs. placebo, 0.85; P=0.02075, with a threshold P value of 0.02115). In the 300-mg group, the hazard ratio was similar to that in the 150-mg group, but the P value did not meet the prespecified threshold for significance (hazard ratio vs. placebo, 0.86; P=0.0314, with a threshold P value of 0.01058).

For the key secondary cardiovascular end point (the components of the primary end point plus hospitalization for unstable angina that led to urgent revascularization), the incidence rate was 5.13 events per 100 person-years in the placebo group, 4.56 events per 100 person-years in the group that received the 50-mg dose of canakinumab, 4.29 events per 100 person-years in the 150-mg group, and 4.25 events per 100 person-years in the 300-mg group. In the group that received the 150-mg dose of canakinumab (for which the P value met the significance threshold for the primary end point), the hazard ratio versus placebo for the secondary cardiovascular end point was 0.83 (P=0.00525, with a threshold P value of 0.00529).

No significant differences in the number of cardiovascular deaths or total mortality were observed between canakinumab and placebo.

Significantly more deaths were attributed to infection or sepsis in the pooled canakinumab groups than in the placebo group. Cancer mortality was significantly lower with canakinumab than with placebo.

Interestingly, the CANTOS group has in a separate paper published in the Lancet, published data suggesting that canakinumab could significantly reduce incident lung cancer and lung cancer mortality (9).

The event rate for the primary endpoint was 14.2% on canakinumab and  16.0% on placebo. This corresponds to an absolute risk reduction of 1.8% and a relative risk reduction of 11.3%. The number needed to treat (NNT) based on all dose groups vs. placebo is 56. Hence, 56 patients need to be treated with canakinumab for a median of 3.7 years to prevent one primary end-point event.

The Final Verdict

There are three important issues I want to highlight, not only because they tend to be overlooked, but because they provide the key to understanding the implications of the CANTOS trial.

The first issue deals with the study population, the second has to do with the statistical methods used, and the third will take us back to the real world to understand if and how the results will affect current clinical practice.

Who Are the CANTOS Patients?

The CANTOS trial was not a simple study of a pharmacological intervention in patients with coronary artery disease. It was a study of patients with a history of myocardial infarction on top of a chronic low-grade systemic inflammation. That is a huge difference.

But why do some patients with coronary artery disease have chronic low-grade inflammation whereas others don’t? Interestingly, the answer may be found by looking closer at the CANTOS study population.

Most patients included in the CANTOS trial were overweight, almost half of them may be defined as obese based on body mass index criteria, a high proportion had diabetes, HDL cholesterol levels were low, and triglycerides were high. So, to a large extent, these were patients with metabolic syndrome and insulin resistance.

Patients with metabolic syndrome have visceral obesity reflected by increased waist circumference, they have low HDL cholesterol and high triglycerides, they have prediabetes or diabetes, and they often have hypertension. Furthermore, the prevalence of obstructive sleep apnea and atrial fibrillation is high.

Adipose tissue (fat tissue) produces a number of bioactive substances, known as adipokines, which during fat tissue expansion may trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess fat mass and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases (10).

Unraveling the Statistics

Interestingly, the authors of the CANTOS trial decided to present the incidence rates in the study as events per 100 person years. In many studies, the length of exposure to the treatment is different for different subjects, and the person-year statistic is one way of dealing with this issue (11). However, it may make it hard to figure out the absolute risk reduction as well as the number needed to treat (NNT) which are numbers we usually want to see as well.

Person years is the summing of the results of events divided by time. The calculation of events per patient-year is the number of incident cases divided by the amount of person-time at risk. For example, if 1000 patients are followed for five years, there are 5.000 years of follow-up. If there are 100 events in the group, the rate would be 100 events per 5.000 patient years or 2 events per 100 patient years.

But, let’s figure out the absolute risk reduction for the primary endpoint (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) in the CANTOS trial.

A total of 955 events were reported for the primary endpoint in the canakinumab group (all doses) and 535 in the placebo group. The total number of patients on canakinumab was 6.717 and 3.344 on placebo.

Hence, it can be calculated that the event rate for the primary endpoint was 14.2% on canakinumab and 16.0% on placebo. This corresponds to an absolute risk reduction of 1.8% and a relative risk reduction of 11.3%. However, the authors report a 15% relative risk reduction by looking solely at patients in the 150-mg group.

I have calculated that the corresponding number needed to treat (NNT) based on all dose groups vs. placebo is 56. Hence, 56 patients need to be treated with canakinumab for a median of 3.7 years to prevent one primary end-point event.

Does anybody doubt that the juice ain’t worth the squeeze?

The Clinical Implications

The CANTOS Trial is a landmark study because it tested for the first time the hypothesis that blocking an important component of the inflammatory cascade involved in atherosclerotic heart disease will be translated into an improved outcome.

The positive results of the study certainly open new doors to the prevention and treatment of cardiovascular disease.

The data suggesting that canakinumab may reduce incident lung cancer and lung cancer mortality are of great interest but need to be confirmed by further studies.

However, the modest absolute clinical benefit and the high price of canakinumab can hardly justify its routine use in patients with coronary artery disease. Furthermore, more data is needed to understand the safety trade-offs involved in the long-term use of the drug.

Interestingly, the CANTOS trial has defined a high-risk subgroup of patients with coronary artery disease and metabolic abnormalities characterized by visceral obesity, insulin resistance, inflammation and adipocyte dysfunction.

The results of the study inevitably raise the question whether reducing inflammation by improving diet and lifestyle will provide similar results as treatment with an expensive drug with potential side effects.

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Loneliness, Social Isolation, and Poor Health

Estimated reading time: 8 minutes

Loneliness and social isolation are becoming problems of epidemic proportions. The statistics are chilling. Today, 25 percent of Americans have no one with whom to discuss matters important to them.

What is even scarier is that loneliness is killing us.

Studies show that loneliness and social isolation are associated with increased risk of early mortality (1). Being socially connected increases not only psychological and emotional well-being but also has a positive influence on physical health (2).

Although loneliness is usually associated with social isolation, it is important to discriminate between the two. Social isolation refers to a lack of contact with other people, while loneliness indicates a state of mind.

Despite these different definitions, there is significant overlap between social isolation and loneliness. Hence, the terms are often used interchangeably.

Changes in marital and childbearing patterns and the age structure of the U.S society are projected to produce a steady increase in the number of older people who lack spouses or children (3).

Since 1970, the composition of households and families and the marital status and living arrangements of adults in the U.S. both experienced marked changes. For example, the proportion of the population made up of married couples with children decreased, and the proportion of single mothers increased, while the median age at first marriage grew over time (4).

In 1940, 7.7 percent of households consisted of one person living alone. In 2000, this number was up to 25 percent (5).

By 2010, the number of people living alone is projected by the U.S. Census Bureau to reach almost 31,000,000, a 40 percent increase since 1980.

The negative health consequences of social isolation are particularly strong among some of the fastest growing segments of the population: the elderly, the poor, and minorities such as African Americans (6).

Loneliness

Loneliness is a subjective feeling of isolation, not belonging, or lacking companionship. It reflects a discrepancy between one’s desired and actual social relationships. A person can feel lonely despite living with a spouse or other family members. We can experience loneliness in a room full of people.

A recent survey suggests that 35 percent of adult Americans may be categorized as lonely (7).

Older adults were more likely to be lonely than younger individuals. Married respondents were least likely to be lonely (29%), and never-married respondents were most likely to be lonely (51%). Gender, education, and ethnicity were not related to loneliness. People with higher incomes were less likely to be lonely than those with lower incomes.

Lonely respondents were less likely to be involved in activities that build social networks, such as attending religious services, volunteering, participating in a community organization or spending time on a hobby.

Loneliness was a significant predictor of poor health. Those who rated their health as “excellent” were much less likely to be lonely than those who rated their health as “poor” (25% vs. 55%).

Perhaps no other age group feels the keen sting of loneliness more than the elderly

Social Isolation

Social isolation is defined as a state of complete or near complete lack of contact between an individual and society (8). It includes living alone, staying home for lengthy periods, having no communication with family, acquaintances or friends, and willfully avoiding contact with other humans.

Social isolation may have significant effects on health and well being.

Almost thirty years ago, House, Landis, and Umberson published a landmark review of prospective epidemiological studies of social isolation in humans (9). They reported that social isolation was a significant risk factor for morbidity and mortality. They even suggested that social isolation was as strong a risk factor as smoking, obesity, sedentary lifestyle, and high blood pressure.

But why is social isolation associated with poor health?

The “social control hypothesis” may provide some answers. The theory holds that good health behaviors may be promoted by direct social control (10). For instance, one study showed that among women, direct social control (i.e., how often someone tells you or reminds you to do something to protect your health?”) predicted increased physical activity three years later (11).

Being married is associated with an increased likelihood of engaging in health-promoting behaviors such as exercise (12), presumably because marital partners exert some influence over these behaviors.

The Relationship Between Loneliness, Social Isolation, and Poor Health

Many scientific studies have indicated an association between social isolation, loneliness and heart disease.

Studies have shown that loneliness is associated with diminished physical activity (13), depression (14), disrupted sleep and impaired daytime functioning (15), elevated blood pressure (16), impaired mental and cognitive function, and increased risk of dementia (17). Loneliness may even alter our immune response, increasing the risk of illness (18).

Furthermore, there is evidence that loneliness can contribute to functional decline and premature death independently of other physical, behavioral, or psychological factors (19).

A recent review of the association between marital status and cardiovascular disease shows better outcomes for married persons. Men who were single generally had the poorest results (20).

The study also found that smoking, a major risk to heart health, was highest among divorced people. Widowed people had the highest rates of high blood pressure, diabetes, and inadequate exercise. Obesity was most prevalent in those who were single or divorced, and widowed people suffered from the highest rates of diabetes, high blood pressure, and inadequate exercise.

It is quite likely that if you have a spouse, you may be more willing to look after yourself. You may be less liable to smoke and more compliant with a healthy diet and exercise. You may even be more willing to follow up medical appointments. The fact that married couples look after each other could be important.

The Roseto Effect

The story of the Rosetans may help to understand the importance of family relations and social surroundings for the risk of heart disease (21).

Roseto is an Italian-American town in eastern Pennsylvania. In the early 1960’s a local physician, Dr. Benjamin Falcone, who had been practicing in Roseto for 17 years pointed out that he rarely saw a case of a heart attack in any of the 1600 inhabitants of Roseto under age of 65. Subsequently, it was confirmed that from 1955 to 1965 the death rate from heart attack was markedly lower than in nearby communities and the rest of the country.

However, the usual risk factors were not less common in Roseto than elsewhere. The men spent their days doing hazardous labor in underground slate mines. Smoking was common. The traditional Italian food had been Americanized, and could not be considered heart healthy. So why weren’t the Rosetans dropping dead from heart attacks?

Dr. Stewart Wolf and coworkers described the social and family structure of the inhabitants of Roseto:

The Roseto that we saw in the early 1960s was sustained by the traditional value of southern Italian villagers. The family, not the individual, was the unit of their society. The community was their base of operations and each inhabitant felt a responsibility for its welfare and quality. Most households contained three generations.

Rosetans were proud and happy, generous, hospitable and ready to celebrate any small triumph of their citizens. The elderly were not only cherished but, instead of being retired from family and community responsibilities, they were promoted to the ‘supreme court’. There was no shortage of stress among Rosetans. They experienced many of the same social problems and personal conflicts as their neighbors, but they had a philosophy of cohesion with powerful support from family and neighbor and deep religious convictions to shield them against and counteract the stresses.

The Roseto effect is a term used to describe the phenomenon by which a close-knit community experiences a reduced rate of heart disease.

Interventions to Reduce Loneliness and Social Isolation

Many types of interventions have been developed to tackle social isolation and loneliness (22). Unfortunately, there is little evidence to show that they work. However, the quality of the evidence is weak, and further research is required to provide more robust data on the effectiveness of interventions.

A brochure intended to outline risk factors and steps seniors can take to avoid loneliness and isolation

A part of the problem is that the mechanisms by which loneliness and social isolation impact on health are not well understood.

National and international public health authorities are increasingly recognizing the importance of tackling social isolation and loneliness among older people.

The Campaign to End Loneliness was established in the UK in 2011 (22). It is a network of national, regional and local organizations and people working together through community action, good practice, research, and policy to ensure that loneliness is acted upon as a public health priority at national and local levels.

In 2016, a campaign to raise awareness of the growing problem of social isolation and loneliness in older Americans was launched in the United States by the National Association of Area Agencies on Aging (n4a) and the AARP Foundation (23). A brochure was created to outline risk factors and steps seniors can take to avoid loneliness and isolation (24).

The Bottom Line

Although loneliness is usually associated with social isolation, it is important to discriminate between the two. Social isolation refers to a lack of contact with other people, while loneliness indicates a state of mind.

Despite these different definitions, there is significant overlap between social isolation and loneliness. Hence, the terms are often used interchangeably.

Studies suggest that 35 percent of Americans may be categorized as lonely. With the rapidly growing number of older people, loneliness, and social isolation are expected to become more common

Loneliness and social isolation are associated with increased risk of early mortality. Hence, loneliness may be regarded as a hidden killer and may threaten public health as much as obesity and smoking.

Greater recognition is needed of the links between poor health and loneliness.

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Chronic Traumatic Encephalopathy (CTE) – A Disease of Athletes

Estimated reading time: 7 minutes

The prevalence of chronic traumatic encephalopathy (CTE) in American football players is shockingly high according to a  paper published online in JAMA (Journal of the American Medical Association) on July 25th (1).

The paper describes autopsy results from a convenience sample of 202 deceased football players who donated their brains for research. CTE was diagnosed in 87% of cases.

CTE was found in all but one of 111 (99%) participants who were former National Football League (NFL) players.

The most common cause of death for participants with mild CTE pathology was suicide (12 cases; 27%) and for those with severe pathology was neurogenerative disease (i.e., dementia related and Parkinson related) (62 cases; 47%).

The study provides the largest CTE case series described so far. All the participants were exposed to a relatively similar type of repetitive head trauma while playing the same sport.

However, as the authors of the paper point out, a major limitation is ascertainment bias associated with participation in the brain donation program. In other words, awareness of a possible link between repetitive head trauma and  CTE may have motivated players and their families with symptoms and signs of brain injury to participate in this research. Hence those without symptoms may be less likely to participate. Therefore, estimates of the real prevalence of CTE are not provided by this study.

In a recent interview, Daniel H. Deneshvar, one of the authors of the paper said (2):

Although at this point we cannot make any firm sweeping health statements about what types of hits cause CTE or about other risk factors, such as genetic risk, we can say that the fact that so many athletes develop CTE is very concerning, considering that we have children as young as 8 years old playing football and potentially subjecting themselves to this disease.

 

 

 

 

 

What is Chronic Traumatic Encephalopathy (CTE)?

CTE is a neurodegenerative disorder believed to be associated with exposure to repetitive head trauma. It is characterized by fibrillated tangles of hyerphosopholarated tau (p- tau) within the brain.

In humans, tau proteins are mostly found within the central nervous system where they may have an important stabilizing role. Both Alzheimer’s disease and Parkinson’s disease are associated with tau proteins that have become defective.

The term tauopathy is sometimes used to describe diseases caused by misfolding of the tau protein (3).

Although repeated physical trauma seems to be a prerequisite for the development of CTE, many athletes, including boxers and American football players, never develop the disease. So obviously, other factors are involved as well, some may be environmental and some may be genetic (4). In theory, a certain genetic predisposition might make some individuals who suffer repeated head trauma more vulnerable than others.

The Symptoms of CTE

CTE is believed to have two distinct initial clinical presentations: one with behavior or mood changes, typically at a relatively young age, and the other with cognitive symptoms. Several clinical subtypes have been suggested (5).

The symptoms are divided into three categories.

  • Neuropsychiatric: Increased impulsivity, explosivity, violence, rage, depression, apathy, substance abuse, and suicidal behavior.
  • Cognitive: Impaired attention, executive function, and memory.
  • Motor: Parkinsonism, difficulty swallowing (dysphagia), slurred speech (dysarthria), and poor coordination.

The early symptoms often include memory problems, irritability, depression, emotional lability, suicidal behavior, and substance abuse. Later, worsening of aggression, motor impairments, and dementia may occur.

The History of Chronic Traumatic Encephalopathy (CTE)

In the film Concussion from 2015, Will Smith portrays Bennet Omalu, a Nigerian born neuropathologist. Omalu discovered signs of CTE in Mike Webster, the Hall of Fame center for the Pittsburgh Steelers who died in 2002. This finding sparked a chain of events that ultimately forced the NFL to settle a class-action lawsuit from retired players and raised unprecedented awareness of the dangers of football head trauma

However, the history of CTE can be traced all the way back to 1928 when Harrison Martland described a “peculiar condition” described as “punch drunk” in boxers (7).

Markland wrote:

For some time fight fans and promoters have recognized a peculiar condition occurring among prize fighters which, in ring parlance, they speak of as “punch drunk.” Fighters in whom the early symptoms are well recognized are said by the fans to be “cuckoo,” “goofy,” “cutting paper dolls,” or “slug nutty.”

The phenomenon came to be known as ‘dementia pugilistica’ by Millspaugh in 1937 (8), and then the term ‘psychopathic deterioration of pugilists’ was introduced by Courville (9) The word pugil comes from Latin, meaning boxer.

In 1934, Parker described three three professional boxers with signs of neurological disease after their boxing careers were over which he referred to as “traumatic encephalopathy” (10).

In 1957, Macdonald Critchley wrote an article in the British Medical Journal describing the medical aspects of boxing from a neurological standpoint (11). Critchley wrote:

There is much in boxing to interest a practicing neurologist, and special attention should be focused upon (1) the phenomenon of groggy states as occurring during or after a contest, and (2) the condition known as traumatic progressive encephalopathy (or punch-drunkenness).

In 1969, Anthony Herber Roberts wrote a book called Brain damage in boxers: Study of the prevalence of traumatic encephalopathy among ex-professional boxers. He found that among 221 retired boxers studied, 11% had mild CTE, and 6% had moderate to severe CTE.

In 1994, Roberts and coworkers found deposits of beta amyloid protein deposits similar to Alzheimer’s disease in patients who had suffered a severe injury to the head (12). Subsequently, several investigators reported pathologic findings in the brain associated with chronic traumatic head injury, particularly among boxers (13).

In 2005 and 2006 Omalu published two papers describing CTE in two retired NFL players (14, 15). In 2010, he published his third case report article addressing a retired NFL player who had committed suicide by a gunshot to the head (16). Omalu concluded that his case series manifested similar clinical history of neuropsychiatric impairment with autopsy evidence of cerebral tauopathy.

The Bottom-Line

Although almost 90 years have passed since Millspaugh coned the term dementia pugilistica, research into CTE still seems to be in its infancy.

The diagnosis of CTE is most often based on autopsy findings, and there is no definitive diagnostic test for the disease in living people. However, CTE should be considered in the presence of a neurological and psychiatric decline in a previously healthy individual, in particular, if there is a history of head trauma.

Initially, CTE appeared to be primarily associated with boxing. The famous boxer Mohamed Ali was diagnosed with Parkinson’s disease in 1984. It has been widely argued, but never proven, that the multiple head injuries Muhammad Ali sustained during his boxing career could have caused his Parkinson’s disease.

Recently, American football has been associated with an increased risk of CTE. The list of former NFL players with signs of CTE at autopsy is shocking (see below) (17):

It seems pretty difficult nowadays to deny a link between CTE and repeated traumatic brain injury associated with sports like boxing, American football, and mixed martial arts like the Ultimate Fighting Championship (UFC).

What is frightening is that these sports are immensely popular and the amount of money involved is colossal. So, the risk of denial is palpable.

Never forget that CTE is a dreadful disease that commonly results in death. Furthermore, it causes grave suffering to family and friends of the victim.

Currently, there is no treatment available for CTE. Prevention is the only cure.



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Can Low-Fat Be Salvaged? – Updated WHI Dietary Modification Trial Results

A recent paper published in the American Journal of Clinical Nutrition provides updated results from the Women’s Health Initiative (WHI) Dietary Modification Trial (1). One of the questions raised is whether there is still hope for a low-fat dietary approach for the prevention of heart disease.

The primary aim of the WHI Dietary Modification Trial was to test whether behavioral intervention intended to produce a dietary pattern low in total fat, along with increased intakes of vegetables, fruits, and grains, would decrease the incidence of breast and colorectal cancer in postmenopausal women. A secondary aim was to test whether such a dietary intervention, which did not focus on the intake of specific fats, would also reduce the risk of cardiovascular disease (CVD) (2).

The study hypothesis was that a diet capable of effectively lowering LDL-cholesterol would reduce the risk of CVD.

A total of 48 835 postmenopausal women aged 50 to 79 years, of diverse backgrounds and ethnicities, were randomly assigned to an intervention (19 541 [40%]) or comparison group (29 294 [60%]) in a free-living setting. Study enrollment occurred between 1993 and 1998 in 40 US clinical centers; mean follow-up in this analysis was 8.1 years.

The intervention group received intensive behavior modification in group and individual sessions designed to reduce total fat intake to 20% of calories and increase intakes of vegetables/fruits to 5 servings/d and grains to at least six servings/d. The comparison group received diet-related education materials.

The study results, published in 2006, showed that this particular intervention did not significantly reduce the risk of coronary heart disease (CHD), stroke, or CVD in this particular population.

Today, eleven years after the original publication, the results of this large trial are still highly debated. Some believe the study proved that the diet-heart hypothesis was wrong while others pointed out that the lowering of LDL-cholesterol in the intervention group was too small to be able to make a difference.

In their recently published paper, Prentice and coworkers point out that CHD incidence may not have been reduced because of a risk elevation among the 3.4% of participants reporting CVD before trial involvement. It was also observed that the risk of CHD was higher for women with hypertension (43.2% of the trial population) than for women without hypertension.

Interestingly, updated CVD and all-cause mortality results for both the intervention and post-intervention periods, including mortality data through 2013 are provided in the paper.

The Updated WHI Dietary Modification Trial Results

The updated data on all-cause mortality during the trial intervention period did still not reveal any significant differences between the intervention and control groups. In other words, the low-fat intervention did not lower all-cause mortality.

However, interestingly, the effects of the low-fat dietary pattern intervention varied strongly based on whether hypertension or cardiovascular disease was present at baseline or not.

The CHD hazard ratio (HR) was significantly lower for participants with normal blood pressure than for hypertensive participants. That is, the low-fat intervention appeared more effective among those who had normal blood pressure. However, this benefit was partially offset by an increase in stroke incidence in the intervention group.

Interestingly, in women with prior CVD, the risk of CHD was increased in the low-fat interevntion group, yielding a marginal increase in total CVD risk.

The low-fat intervention reduced HDL-cholesterol and increased the triglyceride/HDL-cholesterol ratio, both of which may be considered negative. However, there were also positive effects including reductions in insulin levels and glucose along with favorable changes in weight, waist circumference, and blood pressure.

LDL-cholesterol at one year was lower in the intervention group by an estimated 2 mg/dL in women who were healthy but was larger by an estimated 15.9 mg/dL in women with prior CVD. The lowering of LDL-cholesterol in the intervention group appeared consistent throughout the intervention period after exclusion of women who were taking cholesterol-lowering medication at baseline.

Statin use rates during follow-up did not differ significantly between randomization groups.

Will the Updated Results Change Our View of the WHI Dietary Modification Trial

The updated results confirm the conclusion of the original trial; replacing dietary fat with carbohydrates does not lower CVD risk.

The authors of the paper, however, believe that their subset analyses may be of importance although they acknowledge the challenges associated with multiple testing. However, post-randomization confounding by statin use may offer a potential explanation for some of the differences.

As mentioned above, women with prior CVD seemed to do worse on a low-fat diet compared with the control group. However, the authors believe the results are uninterpretable (due to confounding by post-randomization statin use) although they underscore that they were not able to rule out the possibility that dietary changes in the low-fat intervention group may have contributed to the worse outcome.

On the other hand, the authors believe that the beneficial effect of the low-fat intervention among women with normal blood pressure and no CVD is unlikely to have been affected bay post-randomization statin-use. Hence, they conclude that total fat reduction is an important driver of the observed CHD reduction in these women. This could be mediated by the favorable effects on LDL-cholesterol, insulin, and glucose.

However, they also point out that this positive effect of the low-fat intervention may be tempered by a corresponding increase in stroke risk.

The paper’s final words are:

“These analyses, in which there is little potential for post-randomization confounding by cholesterol-lowering medications, suggest that CVD incidence rates in healthy postmenopausal women in the United States are quite sensitive to moderate dietary change. Intervention participants chose varying approaches toward achieving dietary goals, with a corresponding range of potential cardiovascular benefits and risks. Trial data are currently undergoing further analyses in an attempt to identify dietary pattern changes by women in the intervention group that retain CHD benefit while avoiding any adverse effects.”

Well, an interesting paper that raises several questions. But still, the conclusion from the original study remains intact.

It is well known that multiple comparisons may reveal an apparently statistically significant observation that may have arisen by chance. This statistical phenomenon has sometimes been called the look-elsewhere effect (3). If a certain diet is beneficial, why should it only work for women without hypertension? For me that’s a bit difficult to comprehend.

Hence, it is hardly justified to promote a low-fat high-carb diet of the type tested in the WHI trial for the purpose of preventing heart disease.

However, the authors appear to believe there remains a glimmer of hope that a truce of some kind can still be salvaged.



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