Suicide and biomarkers of gastrointestinal inflammation

Suicide and gastrointestinal inflammation

Suicide mostly occurs in association with neuropsychiatric disorders characterized by neuroinflammation (brain inflammation). Neuroinflammation often results from perturbations of the brain-gut axis, with pro-inflammatory immune signaling from the gut to the brain. An important study just published in Psychiatry Research offers data showing the connection between biomarkers of gastrointestinal inflammation and recent suicide attempt. The authors were motivated by the intent to validate biomarkers to help assess, treat and prevent suicide attempts.

Most attempting suicide have an illness associated with neuroinflammation

“Psychological autopsy and epidemiological studies indicate that more than 90% of people who die by suicide have a diagnosable psychiatric illness, particularly major depression, bipolar disorder, or schizophrenia…The identification of blood-based markers would provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts.”

It is an urgent clinical need to identify causes that promote dysregulated activation of the immune system against the neuronal antigens.

The GI tract is often the source of immune activation against the brain

Biomarkers of gastrointestinal inflammation are frequently increased in neuropsychiatric disorders.

“Many individuals with schizophrenia and mood disorders have evidence of immune activation suggesting that immune dysregulation may be part of the etiopathology of these disorders. Studies by our group and others indicate that the gastrointestinal tract is often the primary source of this immune activation as evidenced by increased levels of markers of gastrointestinal inflammation in individuals with serious mental illness.”

IBD (inflammatory bowel disease) and celiac disease appear to increase risk for suicide.

“Furthermore, increased rates of suicide and suicide attempts have been found in some populations of individuals with celiac disease or inflammatory bowel diseases.”

But previous studies have focused on a lifetime history rather than attempts, so the authors set out to:

“…examine the association between levels of markers of gastrointestinal inflammation and a recent suicide attempt in individuals with schizophrenia, bipolar disorder or major depressive disorder in comparison with non-psychiatric controls.”

Elevated IL-6

Interleukin-6 (IL-6), a key pro-inflammatory cytokine which can arise from the GI tract, is associated.

“Results from other investigators indicate that inflammation may be associated not only with a proclivity for a psychiatric disorder, but specifically with suicidal behavior. Studies have found an association between a suicide attempt history and the level of cytokines such as IL-6 which are cell signaling molecules involved in the immune response and which can arise from inflammation from many sources, including the gastrointestinal tract”

Gluten and brain inflammation

Neuroinflammation triggered by non-celiac gluten sensitivity is also implicated:

“Gliadin is a component of gluten, found in wheat and related cereals. Antibody response to dietary gliadin is associated with celiac disease, an immune-mediated enteropathy, and with non-celiac wheat sensitivity and is thought to indicate intestinal inflammation and/or intestinal barrier dysfunction. We have found increased levels of antibodies to gliadin in individuals with schizophrenia and with bipolar disorder and in individuals with acute mania during a hospital stay…”

Additionally, loss of tolerance to a commensal yeast may promote neuroinflammation.

“We also have studied the antibody response to yeast mannans represented by antibodies to Saccharomyces cerevisiae (ASCA), a commensal organism present in some foods and in the intestinal tract of many individuals. Elevated ASCA levels are associated with increased intestinal inflammation. We have previously found increased levels of ASCA in individuals with mood disorders.”

Pathogens and loss of immune tolerance

Various pathogens present at low levels can elicit a persistent cross-reaction to self-antigens, including brain antigens, in individuals disposed to loss of immune tolerance.

“An association between elevated antibodies to Toxoplasma gondii, an apicomplexan parasite, and suicide attempts have also been reported. In a recent study, we found that individuals with serious mental illness who had a lifetime history of a suicide attempt had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV); we also found an association between the levels of these antibodies and the number of suicide attempts.”

Significant link found

Association between suicide and markers of GI inflammation

The authors examined data for 282 participants: 90 with schizophrenia, 72 with bipolar disorder, 48 with major depressive disorder, and 72 non-psychiatric controls; who were enrolled in ongoing studies of the role the immune response to infections in individuals with serious psychiatric disorders. Biomarkers measured included IgA antibody to yeast mannan from Saccharomyces cerevisiae (ASCA), IgG antibody to gliadin, IgA antibody to bacterial lipopolysaccharide (LPS) from E. coli O111:B4, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and levels of C-Reactive protein.

“We found a statistically significant difference between the recent attempters and the control group in levels of IgA ASCA; the level in the recent attempt group was significantly higher…We also found that the level of IgG antibodies to gliadin was significantly higher in the recent attempters vs. the control group…We also found that the level of IgA antibodies to bacterial lipopolysaccharide (LPS) was significantly higher in the recent attempters vs. the control group…In terms of CRP, we found that there was a significantly higher level in the past attempter group.”

Predicting risk and protecting patients

These findings offer a valuable opportunity for clinicians to gauge and ameliorate risk of suicide in patients with serious neuropsychiatric disorders.

“The markers of gastrointestinal inflammation are of interest because they can be readily measured in blood samples. In addition, some of the markers studied here may be an attractive target for therapeutic intervention since intestinal inflammation can be modulated by dietary interventions as well as the administration of available prebiotic, probiotic, and antibiotic medications.”

The authors conclude:

“Suicide, for which a previous suicide attempt is the greatest risk factor, is a major cause of death worldwide and is highly prevalent in patients with serious mental illness. Unfortunately, the ability to predict suicide remains limited and no reliable biological markers are available. The identification of blood-based markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.”

For additional categories of importance in evaluating neuropsychiatric risk see The Parents’ Guide to Brain Health.

Corticosteroids even short term increase adverse events

Corticosteroids, prescribed for as many as one in five Americans in commercial insurance plans, can significantly increase the risk for adverse effects even when given short term, as found in a study recently published in BMJ (British Medical Journal). The authors note that though the severe adverse effects of longer term use or oral corticosteroids is well known, little has been understood about short term risks.

“…long term use of corticosteroids is generally avoided, given the risks of serious acute complications such as infection, venous thromboembolism, avascular necrosis, and fracture, as well as chronic diseases such as diabetes mellitus, hypertension, osteoporosis, and other features of iatrogenic Cushing’s syndrome…Indeed, corticosteroids are one of the most common reasons for admission to hospital for drug related adverse events…In contrast with long term use, however, the risk of complications from short term use is much less understood, and evidence is generally insufficient to guide clinicians.”

Corticosteroids often used where evidence is lacking

Until now little is know about the potential harms of short term use for the range of outpatient conditions for which they are often prescribed.

“…anecdotally corticosteroids are also used often in the short term to treat many other prevalent conditions where evidence is lacking, such as non-specific musculoskeletal pain and rashes. Despite such pervasive indications for use of oral corticosteroids, little is known about the prescribing patterns of short term use of these drugs in the general adult population, or their potential harm.”

Thus they set out to correlate short term use in an outpatient population and the risk of acute adverse events by analyzing data for 1,548,945 subjects who were prescribed oral corticosteroids for less than 30 days (non-oral forms were excluded from this study).

“We chose three acute events listed as adverse events on the Food and Drug Administration mandated drug label for oral corticosteroids (sepsis, venous thromboembolism, fracture). Given the inherent challenges related to confounding, we employed a self controlled case series (SCCS) design. This design has been used to examine drug and vaccine safety.”

The most common prescription was a six day methylprednisolone “dosepak”, most commonly given for upper respiratory tract infections, spinal conditions, and intervertebral disc disorders, allergies, bronchitis, and (non-bronchitic) lower respiratory tract disorders by family medicine and general internal medicine practitioners, but also by specialists in emergency medicine, otolaryngology, and orthopedics.

Significantly higher rates of sepsis, venous thromboembolism, and fracture

The authors identified a serious risk:

“Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001).”

It defies common sense to use an agent that suppresses the immune system during an infection in all but the rare cases of severe immune excess, especially when there are numerous, more benign alternatives.

Quoted in Medscape Family Medicine, lead author Akbar K. Waljee, MD, an assistant professor of gastroenterology at the University of Michigan in Ann Arbor, states:

“On the basis of these findings, Dr Waljee recommended prescribing the smallest possible amount of corticosteroids for treating the condition in question. “If there are alternatives to steroids, we should be use those when possible,” he said in the release. “Steroids may work faster, but they aren’t as risk-free as you might think.”

From the study:

  • This study of 1.5 million privately insured adults (18-64 years) in the US found that one in five patients in an outpatient setting used short term oral corticosteroid over a three year period (2012-14)

  • Within 30 days of corticosteroid initiation, the incidence of acute adverse events that result in major morbidity and mortality (sepsis, venous thromboembolism, fracture) increased by twofold, to fivefold above background rates

  • Greater attention to initiating prescriptions of these drugs and monitoring for adverse events may potentially improve patient safety

The authors conclude:

“Oral corticosteroids are frequently prescribed for short term use in the US for a variety of common conditions and by numerous provider specialties. Over a three year period, approximately one in five American adults in a commercially insured plan used oral corticosteroids for less than 30 days. The short term use of these drugs was associated with increased rates of sepsis, venous thromboembolism, and fracture; even at relatively low doses.”

Prediabetes, chronic inflammation and hemoglobin A1c

PrediabetesPrediabetes, blood glucose is slightly higher than normal but not enough to qualify for diabetes, is associated with an increased systemic burden of inflammation and elevated risk for cardiovascular, cancer, dementia and other diseases. The first study described in this post, published in the European Journal of Nutrition, highlights the link between prediabetes, chronic inflammation and mortality from a range of diseases tied to HgbA1c (hemoglobin A1c, glycosylated hemoglobin), the key biomarker for glucose regulation. The authors state:

Chronic inflammation is associated with increased risk of cancer, cardiovascular disease (CVD), and diabetes. The role of pro-inflammatory diet in the risk of cancer mortality and CVD mortality in prediabetics is unclear. We examined the relationship between diet-associated inflammation, as measured by dietary inflammatory index (DII) score, and mortality, with special focus on prediabetics.”

Pro-inflammatory diet plus prediabetes (increased HgbA1c)

Of great significance is the effect they reveal when a pro-inflammatory diet, measured by the dietary inflammatory index (DII) score, is consumed when there is elevated HgbA1c. They categorized 13,280 subjects between the ages 20 of and 90 years according to whether or not they were prediabetic, which they defined as a HgbA1c percentage of 5.7–6.4. Their data highlighted this connection between all-cause mortality, a pro-inflammatory diet and prediabetes:

“The prevalence of prediabetes was 20.19 %. After controlling for age, sex, race, HgbA1c, current smoking, physical activity, BMI, and systolic blood pressure, DII scores in tertile III (vs tertile I) was significantly associated with mortality from all causes (HR 1.39, 95 % CI 1.13, 1.72), CVD (HR 1.44, 95 % CI 1.02, 2.04), all cancers (HR 2.02, 95 % CI 1.27, 3.21), and digestive-tract cancer (HR 2.89, 95 % CI 1.08, 7.71). Findings for lung cancer (HR 2.01, 95 % CI 0.93, 4.34) suggested a likely effect.”

The authors conclude:

“A pro-inflammatory diet, as indicated by higher DII scores, is associated with an increased risk of all-cause, CVD, all-cancer, and digestive-tract cancer mortality among prediabetic subjects.”

 Prediabetes and cardiovascular risk

Research published in The BMJ (British Medical Journal) focusses on the substantial impact of prediabetes on the risk of heart attack and ischemic stroke. The authors set out to…

“…evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality…”

…by analyzing 53 prospective cohort studies with 1,611,339 individuals that passed the screening tests for validity. In this study they applied several definitions of prediabetes:

“Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L = 101-124 mg/dL), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L = 110-124 mg/dL), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L = 141-198 mg/dL during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol [5.7-6.4%] according to ADA criteria or 42-47 mmol/mol [6.0-6.4%] according to the National Institute for Health and Care Excellence (NICE) guideline.”

Their data show that prediabetes with a ‘mildly’ elevated HgbA1c was clearly associated with increased cardiovascular risk:

“Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol [5.7-6.4%] or 42-47 mmol/mol [6.0-6.4%] were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.”

Interestingly, risk of stroke does not emerge from these data, suggesting other factors promoting vascular inflammation. The authors conclude:

“…we found that prediabetes defined as impaired fasting glucose or impaired glucose tolerance is associated with an increased risk of composite cardiovascular events, coronary heart disease, stroke, and all cause mortality. There was an increased risk in people with fasting plasma glucose as low as 5.6 mmol/L [100 mg/dL]. Additionally, the risk of composite cardiovascular events and coronary heart disease increased in people with raised HbA1c. These results support the lower cut-off point for impaired fasting glucose according to ADA criteria as well as the incorporation of HbA1c in defining prediabetes.”

HgbA1c and risk of all-cause and cause-specific mortality without diabetes

Similar results were obtained in a study published in Scientific Reports. Here the authors concluded:

“We found evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer in this meta-analysis. The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. This fact reveals a clear threshold effect for the association of HbA1clevels with mortality. In addition, from the perspective of mortality benefit and health care burden, it suggests that the most appropriate HbA1c level of initiating intervention is approximately 5.7%…higher HbA1c level is associated with increased mortality from all causes, CVD, and cancer among subjects without known diabetes. However, this association is influenced by those with undiagnosed diabetes or prediabetes .Because of limited studies, the results in relation to cancer mortality should be treated with caution, and more studies are therefore warranted to investigate whether higher HbA1c level is associated with increased cancer mortality.”


Immunotherapy can take 3 years to desensitize to allergens

Sublingual immunotherapyImmunotherapy can induce tolerance for allergens, but what is a realistic time frame? A study recently published in JAMA demonstrates that 3 years of sublingual desensitizing treatment is effective, but 2 years is no different than placebo. This research helps practitioners working in the larger context of immune plasticity, and patients, to consider pragmatic parameters for case management. The authors note:

“Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment.”

But since reducing the inconvenience and expense of treatment is always desirable, the they set out to…

“…assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up.”

3 years of immunotherapy effective, 2 years comparable to placebo

In a randomized double-blind, placebo-controlled, 3–parallel-group study of adult patients with moderate to allergic rhinitis that was severe enough to interfere with normal daily activities and sleep), thirty-six subjects received 2 years of sublingual immunotherapy (SLIT; daily tablets containing 15 µg of a major allergen and monthly placebo injections), another 36 received subcutaneous immunotherapy (SCIT; monthly injections containing 20 µg of the allergen and daily placebo tablets); and 34 received double placebo. The nasal allergen challenge was performed before and at 1 and 2 years during treatment; and at 3 years, which was1 year after treatment concluded. Their data make clear that, while the effectiveness of 3 years of treatment is well established, 2 years of treatment did essentially nothing.

“Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score [total nasal symptom score] for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]).”

In other words, there were no significant differences between the placebo group and the treatment groups, or between the two treatment groups, despite the finding that SCIT appeared to be more effective than SLIT at reducing TNSS after 1 year.

Medscape Family Medicine quotes an editorial by Linda S. Cox, MD:

“…the cumulative costs of symptomatic drug treatment for perennial or seasonal allergic rhinitis can be significant over time,” because it is a chronic condition. Therefore, any analysis of allergen-specific immunotherapy must take into account its potential for long-term disease modification. However, she warns, any cost-benefit assessment of allergen-specific immunotherapy must include “the duration of treatment required for optimal long-term efficacy.” The time commitment requirement may be an important factor in patients’ decisions to initiate therapy.” Therefore, it is important to clarify the optimum duration of treatment. The findings of this study suggest that “2 years is not sufficient for SLIT treatment to induce long-term clinical efficacy.”

Clinical note

This study leaves open the question as to whether adjunctive forms of immunomodulation can accelerate sustained benefit or improve outcomes in other ways, but it does offer one reference by which clinicians and patients can appreciate the dynamic and time frame of therapies addressing immune and neuroplasticity.

The authors conclude:

“Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up.”

Magnesium mediates insulin resistance, diabetes risk

Magnesium, insulin resistance and diabetesMagnesium is required for hundreds crucial functions, not least of which are its calming, parasympathetic nervous system supporting and anti-inflammatory effects. Patients in our practice are also informed that a good magnesium level is necessary for insulin receptor function, further evidence for which has just been published in the journal Diabetologia. The results of this study demonstrate a causal role for low magnesium in diabetes and prediabetes, especially through insulin receptor resistance.

Magnesium and diabetes

An association with diabetes has long been observed, but questions have remained regarding whether this is a cause or an effect. For this reason the authors investigated its role in prediabetes.

“Previous studies have found an association between serum magnesium and incident diabetes; however, this association may be due to reverse causation, whereby diabetes may induce urinary magnesium loss. In contrast, in prediabetes (defined as impaired fasting glucose), serum glucose levels are below the threshold for urinary magnesium wasting and, hence, unlikely to influence serum magnesium levels. Thus, to study the directionality of the association between serum magnesium levels and diabetes, we investigated its association with prediabetes. We also investigated whether magnesium-regulating genes influence diabetes risk through serum magnesium levels. Additionally, we quantified the effect of insulin resistance in the association between serum magnesium levels and diabetes risk.”

 Prediabetes and insulin resistance

They examined data from 8555 subjects for an association with prediabetes/diabetes, and further sought to determine if genes influence diabetes risk through serum magnesium levels. They also aimed to determine how much of the effect is mediated through insulin resistance  by HOMA-IR). Their data show a robust role in regulating insulin receptor function and effect on diabetes risk.

A 0.1 mmol/l decrease in serum magnesium level was associated with an increase in diabetes risk (HR 1.18 [95% CI 1.04, 1.33]), confirming findings from previous studies. Of interest, a similar association was found between serum magnesium levels and prediabetes risk (HR 1.12 [95% CI 1.01, 1.25]). Genetic variation…significantly influenced diabetes risk and for CNNM2, FXYD2, SLC41A2 and TRPM6 this risk was completely mediated by serum magnesium levels.”

Condensing these results they state:

“In this large population-based cohort, we found that over a median follow-up of almost 6 years, low serum magnesium levels are associated with an increased risk of prediabetes, with comparable risk estimates to that of diabetes. Furthermore, we found that common genetic variants in magnesium-regulating genes influence diabetes risk and that this risk is mediated through serum magnesium levels.”

In the clinic

Practitioners are aware of two well-known facts: serum magnesium is a poor, insensitive biomarker for sufficiency; and clinical insufficiency is extremely common. (Even RBC membrane levels are not as dependable as the EXA test—see under ‘Useful Links’.) Thus when serum magnesium is suboptimal it should be diligently attended to by the clinician.

The authors conclude:

“…we found that low serum magnesium levels are associated with an increased risk of prediabetes, with similar effect estimates as compared with diabetes. The effect of serum magnesium on prediabetes and diabetes risk is partly mediated through insulin resistance. Furthermore, common genetic variation in magnesium regulating genes TRPM6, CLDN19, SLC41A2, CNNM2 and FXYD2 significantly modify the risk of diabetes through serum magnesium levels. Both findings support a potential causal role of magnesium in the development of diabetes...”

Cytomegalovirus: neglected problem endangers pregnant women, children

Medscape Cytomegalovirus

Cytomegalovirus (CMV) hasn’t gotten the press accorded to Zika, yet it infects 2%-4% of pregnant women and is transmitted to the fetus. The resulting congenital infection in 40% of these cases can result in a host of serious problems that include brain maldevelopment and microcephaly. An article recently published in Medscape Family Medicine draws needed attention to his common but poorly recognized hazard.

“Congenital CMV is well recognized as a common, endemic congenital infection, infecting over 30,000 newborns each year in the United States. Although many newborns congenitally infected with CMV may have no symptoms or sequelae, up to 8000 each year will have in utero growth restriction; petechiae; liver and spleen disease; thrombocytopenia; congenital and progressive hearing loss; vision loss; brain maldevelopment syndromes; microcephaly; and permanent neurodevelopmental and motor disabilities such as cerebral palsy. In addition, fetal and neonatal death from in utero CMV occurs in approximately 400 babies each year.”

Cytomegalovirus awareness is low

Most people have heard of Zika but very few are aware of cytomegalovirus though it is a far more widespread problem.

“…despite this well-recognized and well-accepted public health impact, only 9%-15% of women of childbearing age, including those with graduate degrees and those entering medical school, have even heard of CMV.”

“CMV Knowledge Vaccine”

Just knowing that cytomegalovirus is a common infection and serious hazard in pregnancy is the start. Then there are three simple precautions based on the fact that young children commonly excrete CMV in their saliva and/or urine for a year and transmit it to their parents 45-53% of the time, often without either manifesting any symptoms. The paper cites three recommendations to reduce exposure:

  1. Not sharing food, drink, straws or eating utensils with young children;

  2. Not kissing young children on or around the mouth or lips; and

  3. Washing hands well after changing all diapers (wet with urine or dirty with stool) and wiping runny noses or mouth drool.

Unfortunately, the American College of Obstetrics and Gynecology (ACOG) has not supported active education of women about CMV risk. The author concludes:

The greatest risk reduction strategy available now to prevent CMV transmission to pregnant women is education about CMV. Patients; healthcare professionals, especially obstetricians and midwives; and public health agencies should be partners in providing women with factual information and allowing them to make informed choices regarding their pregnancy health and prevention of CMV. In other words, spread the word, not the virus.”

HgbA1c (hemoglobin A1c) predicts prediabetes better than glucose

HgbA1c predicts prediabetesHgbA1c (hemoglobin A1c) is hemoglobin that has been ruined by glycation (bonding with sugar). It has long been recognized as a biomarker for average glucose over an approximately three month time span as well as a metric for the degree of damaging glycation occurring throughout the body. Now further evidence for its superior value as a predictor for prediabetes is presented in a study just published in The Lancet Diabetes & Endocrinology.The authors…

“…compared the risk of future outcomes across different prediabetes definitions based on fasting glucose concentration, HbA1c, and 2 h glucose concentration during over two decades of follow-up in the community-based Atherosclerosis Risk in Communities (ARIC) study. We aimed to analyse the associations of definitions with outcomes to provide a comparison of different definitions.”

HgbA1c compared to fasting and 2 hour glucose

They compared several prediabetes definitions in their ability to predict major long-term health problems. They analyzed data from over seven thousand subjects drawn from four communities across the USA who participated in the Atherosclerosis Risk in Communities (ARIC) study. HgbA1c was pitted against fasting and 2 hour postprandial glucose:

“Fasting glucose concentration and HbA1c were measured at visit 2 and fasting glucose concentration and 2 h glucose concentration were measured at visit 4. We compared prediabetes definitions based on fasting glucose concentration (American Diabetes Association [ADA] fasting glucose concentration cutoff 5·6–6·9 mmol/L and WHO fasting glucose concentration cutoff 6·1–6·9 mmol/L), HbA1c (ADA HbA1ccutoff 5·7–6·4% [39–46 mmol/mol] and International Expert Committee [IEC] HbA1c cutoff 6·0–6·4% [42–46 mmol/mol]), and 2 h glucose concentration (ADA and WHO 2 h glucose concentration cutoff 7·8–11·0 mmol/L).”

HgbA1c better identifies those at risk for diabetes and serious complications

Chronic kidney disease, cardiovascular disease and death were more accurately predicted by HgbA1c than by fasting glucose:

“After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality than did fasting glucose concentration-based definitions (all p<0·05). The C-statistic for incident chronic kidney disease was 0·636 for ADA fasting glucose concentration clinical categories and 0·640 for ADA HbA1c clinical categories. The C-statistics were 0·662 for ADA fasting glucose clinical concentration categories and 0·672 for ADA HbA1c clinical categories for atherosclerotic cardiovascular disease, 0·701 for ADA fasting glucose concentration clinical categories and 0·722 for ADA HbA1c clinical categories for peripheral arterial disease, and 0·683 for ADA fasting glucose concentration clinical categories and 0·688 for ADA HbA1c clinical categories for all-cause mortality. Prediabetes defined using the ADA HbA1c cutoff showed a significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared with prediabetes defined with glucose-based definitions.”

Clinical Significance

HgbA1c study reviewed in Medscape Family Medicine

Medscape Family Medicine remarks:

“The researchers found that using an HbA1c-based definition, those identified as having prediabetes were 50% more likely to develop kidney disease, twice as likely to develop CVD, and 60% more likely to die from any cause compared with those with normal HbA1c.”

The authors, quoted in Medscape Family Medicine, comment on the practical significance of their findings:

“When someone is told they have prediabetes, we hope it will cause them to make changes to their habits in order to prevent the development of diabetes and its complications,” added the study’s senior author, Elizabeth Selvin, PhD, MPH, a professor in the Bloomberg School’s department of epidemiology.

“Being identified as having prediabetes can also make it easier to receive weight-loss and nutritional counseling as well as reimbursement for these services. Intensive lifestyle changes and weight loss can reduce the risk of diabetes, so it is critically important we identify those persons who are at high risk.

At the same time, we also don’t want to overdiagnose people. Using the hemoglobin A1c test allows us to more accurately identify those persons at highest risk,” she added.

This is important information for physicians and it is also important information for professional organizations. Coming to a global consensus on how to define and diagnose prediabetes would really help move the field forward — and help patients all over the world,” she concluded.”

The authors conclude:

“Our results suggest that prediabetes definitions using HbA1c were more specific and provided modest improvements in risk discrimination for clinical complications. The definition of prediabetes using the ADA fasting glucose concentration cutoff was more sensitive overall.”

Brain health is maintained by immune system activity

the-scientistDramatic advances in understanding how brain health is maintained by the immune system are described in an excellent article published recently in The Scientist that accompanies the brief video presentation by neuroscientist Michal Schwartz shown below. Only recently has it been recognized that brain immune function is integrated with the systemic immune system.

Until recently, the brain and the spinal cord were considered immune-privileged sites, strictly cordoned off from immune cells unless something went terribly wrong. Researchers knew, for example, that multiple sclerosis (MS) was caused by T cells that breach the selective border called the blood-brain barrier (BBB), enter the CNS, and attack the myelin sheath covering neurons. Even microglia, specialized macrophage-like immune cells that scientists had recognized as normal CNS residents since the 1960s, were mainly studied in the context of disease.”

Now the pervasive role of the immune system in brain function and maintenance is being observed:

“But over the past two decades, researchers have recognized that the entire immune system is very much a part of a functional CNS, with vital roles in cognition, injury repair, neurodegenerative disease, and sensory systems. Microglia pervade the CNS, including the white and gray matter that constitute the organ’s parenchyma. Other immune cells, including T cells, monocytes, and mast cells, reside in the brain and spinal cord’s outer membranes, known as the meninges, and circulate in cerebrospinal fluid (CSF).”

Immune cells in the brain help repair damage

It was formerly thought that immune cell activity in the brain was only harmful.

Macrophages, for example, can damage neurons by secreting cytokines, proteases, or reactive oxygen species, but in rat and mouse models of spinal cord injury, they also produce transforming growth factor-beta (TGFβ), which promotes wound healing,5 and interleukin 10 (IL-10) which helps resolve inflammation. By the late 2000s, researchers recognized that different subtypes of macrophages can benefit neuronal growth in rodents, and that some were critical to recovery. Views also began to change on the clinical side after the 2004 Corticosteroid Randomization After Significant Head Injury (CRASH) study showed that corticosteroids didn’t help brain injury patients recover, but increased their risk of disability and death.”

Cells of the adaptive immune system residing in the tissue lining of the ventricles can also assist in repair.

Her team also showed that T cells present in this lining, called thechoroid plexus, secrete cytokines such as interferon gamma (IFNγ), which allows selective passage of CD4+ T cells and monocytes from the blood into CSF within the ventricles.  In a model of spinal cord bruising, mice deficient for the IFNγ receptor had reduced immune cell trafficking across the choroid plexus and poor recovery of limb movement. And last year, Kipnis’s team reported that IL-4 produced by CD4+ T cells in the CNS signals neurons to regrow axons after spinal cord or optic nerve injury.”

Immune cells in the brainAn intact blood-brain barrier (BBB), however, is essential:

“His team also found that microglia reinforce the BBB, which is composed of endothelial cells, pericytes, and astrocytes. Microglia fill in spaces left by astrocytes killed or damaged during injury. Without a robust barrier, McGavern says, unwanted immune cells may flood the parenchyma and do more harm than good.”

Immune cells residing in the CSF and choroid plexus

Immune cells residing in the CSF and choroid plexus

Brain needs both anti-inflammatory and pro-inflammatory activity for cognition

Neuroinflammation is well known to be a core feature of neurodegenerative disorders, but inflammatory immune activity is also required for healthy cognition.

“…Rivest used two-photon microscopy to monitor monocytes in blood vessels of living mouse brains, and he watched as the cells migrated toward and cleared amyloid-β deposits within veins. When the researchers selectively depleted monocytes, the mice developed more amyloid-β plaques in the cortex and hippocampus. And when they knocked out the innate immune signaling protein MyD88, which mediates signals from several monocyte-activating receptors, the mice also experienced more amyloid-β accumulation, accompanied by accelerated cognitive decline.”

Even in the classic disease of neuroinflammation, MS, immune cell activity is necessary:

“Rivest’s team found that microglia-forming monocytes are beneficial in a model of MS, where microglia are found within the inflammatory lesions. Last year, the researchers reported that inhibiting monocytes from entering the CNS reduced the clearance of damaged myelin and impeded proper remyelination.”

Evidence for the immune system’s role in preventing neurodegeneration continues to mount:

“Schwartz has similarly found evidence for the immune system’s ability to protect against neurodegeneration. Last year, she and her colleagues reported that the choroid plexus epithelium was less permissive to immune cell trafficking in a mouse model of Alzheimer’s disease than in wild-type mice, due to anti-inflammatory signals produced by regulatory T cells (Tregs). They found that depleting Tregs in Alzheimer’s mice allowed macrophages and CD4+ T cells into the brain, reduced the number of amyloid-β plaques, and improved cognition. Similarly, blocking the T-cell checkpoint protein PD1, which normally supports Treg survival while suppressing the activity of other T cells, reduced amyloid-β plaques in mouse brains and improved the animals’ scores in a learning and memory water maze test.”

Clinicians should be alert to evaluate and support balance

Too much neuroinflammation is clearly adverse.

“But there’s a reason that scientists have believed that immune activity contributes to Alzheimer’s damage: microglia, perhaps best known for trimming back synapses, have the potential to become overzealous, and excessive synapse pruning can cause neural damage in a variety of CNS diseases. By blocking the cells’ proliferation in mice, Diego Gomez-Nicola of the University of Southampton in the U.K. has successfully alleviated symptoms of Alzheimer’s disease, amyotrophic lateral sclerosis, and prion disease. And earlier this year, Beth Stevens of the Broad Institute and her colleagues reported that inhibiting a protein that tags synapses for microglial pruning halted over-pruning and loss of synapse signaling strength in two mouse models of Alzheimer’s disease.”

Regulation of stress is critical

Stress has a major effect on which way the ‘two-edged sword’ swings.

“Kipnis says regulation of stress may be linked to T cells’ role in learning. Stress can signal macrophages to secrete proinflammatory cytokines, some of which block a protein called brain-derived neurotrophic factor (BDNF), which astrocytes need to support learning and memory. CD4+ T cells in the meninges make more IL-4 cytokine after mice have been trained in a water maze—a stressful exercise for the animals—suggesting the signaling molecule might let macrophages know when the brain is dealing with the stress of learning something new, not the stress of an infection. “They tell macrophages, ‘Don’t overshoot,’” says Kipnis. In mice whose meninges are depleted of CD4+ T cells and thus deficient for IL-4, macrophages secrete proinflammatory factors unchecked in times of stress, disrupting their ability to learn and form memories.”

But excess suppression of inflammatory activity in the brain could have unwanted consequences as in the case of mast cells:

“Best known for their involvement in allergic responses in the upper airway, skin, and gastrointestinal tract, mast cells have been found in the meninges as well as in perivascular spaces of the thalamus, hypothalamus, and amygdala. They are known to quickly recruit large numbers of other immune cell types to sites of inflammation, and to play a role in MS. But mast cells also release serotonin into the hippocampus, where the molecule aids neurogenesis, supports learning and memory, and regulates anxiety.”

A ‘goldilocks zone’ for immune activity in the brain

As in every condition clinical evaluation must embrace the whole context…

“Thus, like microglia, mast cells are a double-edged sword when it comes to neural health. It’s a reflection of the entire immune system’s love-hate relationship with the CNS, Kipnis says. “Saying the immune system is always good for the brain, it’s wrong; saying it’s always bad for the brain, it’s wrong. It depends on the conditions.”

Neuroscientist Michal Schwartz — Breaking The Wall Between Body and Mind


Thyroid disorders in children and adolescents: clinical review

JAMA Pediatrics: Thyroid disordersThyroid disorders are widespread and can occur at any age. An excellent clinical review just published in JAMA Pediatrics offers a comprehensive and detailed yet succinct review of the various types that occur in children and adolescents. The authors state:

“Normal thyroid gland function is critical for early neurocognitive development, as well as for growth and development throughout childhood and adolescence. Thyroid disorders are common, and attention to physical examination findings, combined with selected laboratory and radiologic tools, aids in the early diagnosis and treatment.”

They provide a “provide a practical review of the presentation, evaluation, and treatment of thyroid disorders commonly encountered in a primary care practice” based on 479 articles relevant to…

“…the incidence, pathophysiology, laboratory evaluation, radiological assessment, and treatment of hypothyroidism, hyperthyroidism, thyroid nodules, and thyroid cancer in children and adolescents. Eighty-three publications were selected for inclusion in this article based on their relevance to these topics.”

They cover these topics:

  • Congenital hypothyroidism
  • Acquired hypothyroidism
  • Hyperthyroidism
  • Thyroid nodules

Autoimmune thyroiditis is by far the most common

Pediatric thyroid examReaders here surely know that autoimmunity prevails as the leading cause of hypothyroidism in developed countries. As part of the ‘epidemic’ of loss of immune tolerance it can occur amidst a constellation of other autoimmune phenomena, some noted here:

Autoimmune hypothyroidism (Hashimoto thyroiditis) is the most common cause of acquired hypothyroidism in children, adolescents, and adults. The prevalence of autoimmune hypothyroidism in childhood is an estimated 1% to 2% with a 4:1 female predominance. Approximately 50% of cases have a family history of autoimmune thyroid disease… An additional autoimmune disorder in the same patient is also associated with an increased risk, most commonly diabetes, alopecia, vitiligo, and celiac disease.”

Interestingly, hypothyroidism is not typically associated with weight gain in this population:

“The most common symptoms of hypothyroidism are fatigue, cold intolerance, constipation, and menstrual irregularities. Children may present with pubertal delay or, in cases of severe longstanding hypothyroidism, precocious puberty. A goiter is the most common physical examination finding. Other examination findings include bradycardia, delayed reflexes, and myxedema of the face and extremities. Hypothyroidism causes poor linear growth and/or growth failure and, if undiagnosed, may compromise adult height. However, contrary to common belief, hypothyroidism is rarely the etiology of weight gain. In fact, excess weight gain is associated with mild elevations in thyrotropin (between 5 and 10 mIU/L), with normalization of the thyrotropin level after achieving weight loss.”

Thyroid examination and diagnosis

I recommend that practitioners desiring a review of thyroid examination and diagnosis in the pediatric patient peruse the entire paper for details on the examination and diagnosis of each condition.

Pediatric endocrinologist Andrew J. Bauer, MD, on of the authors, demonstrates an exam on a healthy child and others illustrating the main diagnoses in this helpful video…

Ketone supplementation and the ketogenic diet for cancer

Clinical Cancer ResearchKetone enhancement by diet and supplementation can dramatically improve cancer survival. An easily implemented low carb high fat approach can produce results comparable to a more strict diet and be further enhanced by ketone supplementation.

Glucose consumption at a ravenous rate is characteristic of the peculiar metabolism of cancer cells. Fresh evidence for the ‘Warburg Effect’ the metabolic theory of cancer is eclipsing the earlier ascendant somatic mutation theory. Accordingly, ketogenic LCHF (low carb high fat) diets are gathering momentum in the treatment and prevention of malignancies. A study recently published in Clinical Cancer Research offers evidence that an easily implemented LCHF ketogenic diet supplemented with MCTs (medium chain triglycerides; sHFLC) may render significant benefit in the treatment of glioblastoma, a very malignant and metabolically active brain cancer, while being easier to maintain than a more strict ketogenic diet. The authors state:

“Dysregulated energetics coupled with uncontrolled proliferation has become a hallmark of cancer, leading to increased interest in metabolic therapies. Glioblastoma (GB) is highly malignant, very metabolically active, and typically resistant to current therapies. Dietary treatment options based on glucose deprivation have been explored using a restrictive ketogenic diet (KD), with positive anticancer reports. However, negative side effects and a lack of palatability make the KD difficult to implement in an adult population. Hence, we developed a less stringent, supplemented high-fat low-carbohydrate (sHFLC) diet that mimics the metabolic and antitumor effects of the KD, maintains a stable nutritional profile, and presents an alternative clinical option for diverse patient populations…We report a dietary intervention that produces low circulating glucose while elevating ketones and results in a substantial reduction in GB cellular proliferation.”

Glucose metabolism and the Warburg Effect

The bizarre metabolism of cancer cells has been recognized has an especially promising vulnerable target for treatment.

“Glucose metabolism and the Warburg Effect have gained traction as a potential tumor weakness and exploitable treatment area. Where normal cells utilize glucose for high-yield energy production in the mitochondria (1:36ATP), tumor cells demand higher levels of glucose for diminished energy production, via lactate in the cytosol (1:4ATP) and nucleotide synthesis in the pentose phosphate pathway. This metabolic characteristic, termed the Warburg Effect, is an essential byproduct of rapid cellular proliferation and promoted during tumorigenesis by oncogenic metabolic reprogramming. Hence tumor cells acquire the ability to sustain proliferative signaling mechanisms, which subsequently promotes malignant glycolysis. “

Ketogenic diet

The ketogenic diet has been around has been demonstrated to be safe and effective but in its strict form can be difficult to maintain.

“Research into dysregulated cellular metabolism has given rise to the notion that dietary therapies for cancer patients may have significant clinical utility. GB has been proposed to be a promising candidate for dietary intervention due to its substantial reliance and utilization of glucose. At the forefront of dietary anticancer therapy is the ketogenic diet (KD), which is a high-fat, low-carbohydrate, low-protein diet, used for decades to treat refractory epileptic seizures. Extreme carbohydrate restriction mimics a fasting state, resulting in reduction of blood glucose and induction of ketone bodies (e.g., b-hydroxybutyrate/BHB). Ketone bodies are suitable energy replacements for normal cells with functional mitochondria, but have been shown to be unsuitable for tumor cells, as tumor cell mitochondrial functions are dysregulated. Existing preclinical data support the KD and a calorie-restricted KD (RKD) in the treatment of brain cancer by diminishing tumor growth and increasing animal survival. Clinical report, case reports, and pilot trials have demonstrated that the KD is safe, has low toxicity, and is applicable to cancer patients.”

But because of challenges to implementation of the strict ketogenic diet the authors sought to investigate the effect of a more easily maintained less restrictive LCHF diet with supplemented with medium chain triglycerides (MCT).

“…a less restrictive KD-like diet that would exhibit the same physiologic phenotype and antitumor efficacy. By supplementing a high-fat, low-carbohydrate (sHFLC), moderate protein diet with specialized medium-chain triglycerides [MCT; 60%(30%):30%:10%::Fat(MCT): Protein:Carb], we hypothesize that a more balanced diet can be implemented, resulting in diminished tumor progression. MCTs were specifically chosen based on carbon chain lengths (C8: C10::97%:3%), which allow them to rapidly diffuse from the gastrointestinal tract into the hepatic portal system and travel directly to the liver where they are converted into ketone bodies). We believe it is possible to provide a more nutritionally complete, flexible, and palatable anticancer diet with the sHFLC, which could target a diverse patient population and increase patient compliance.”

Tumor cell growth significantly reduced

tumor-volume-with-high-fat-low-carb-low-glucose-ketogenicThey tested glioblastoma cells both in vivo and in vitro resulting in a significant decrease in the proliferation of both the tumor cells, and very importantly the tumor stem cells.

Lowering glucose concentrations resulted in a significant reduction in Ki-67 and MCM2 expression, in both PG and LG as well as a significant increase in active caspase-3 between NG and LG. Therefore, alterations in glucose availability, to levels equivalent to a low glucose state, are sufficient to slow the proliferation of gliomaspheres while concomitantly increasing apoptosis…Quantification of the self-renewing stem cell symmetrical division rate demonstrated a significant decrease in cancer stem cell expansion under reduced glucose conditions. The combination of diminished stem cell division rates, cellular fold expansion, and proliferation markers indicates that lowering glucose affects not only the putative stem cell population, but also the non-stem cell population.”

Low carb high fat benefits comparable to strict ketone diet

This is a very important point for practical implementation of an effective therapeutic diet.

“Animals placed on the sHFLC and KD had a significant reduction in blood glucose, above hypoglycemic levels, compared to controls, with no difference between the sHFLC and KD. Blood ketones were significantly increased in mice maintained on the sHFLC and KD to a safe level, with a statistical difference between the groups.”

The employed a glucose ketone index (GKI) to compare dietary interventions:

“To compare blood glucose and ketone levels among different anticancer dietary therapies, a simple glucose ketone index (GKI) is used. The GKI is a single number, and can be used both clinically and preclinically, to identify a therapeutic zone. On the basis of this formulation, our average calculated GKIs are 24.4 ± 7.14, 3.1 ± 1.07, and 1.94 ± 0.67 for the control, sHFLC and KD, respectively.”

Adding metformin yielded no additional benefit

Those following the topic of metformin as an anticancer therapy should note that it appears to be rendered unnecessary by this dietary approach:

“It has been proposed that a potential combinatorial treatment of metformin with carbohydrate restriction could result in enhanced antitumor efficacy. Mice fed the KD and sHFLC alone demonstrated a significant increase in survival compared with the control-fed mice, statistically equal to metformin alone. In both xenograft models, metformin alone was able to reduce blood glucose, reduce tumor progression, and increase survival, yet the combination sHFLC diet and metformin showed no additive or synergistic effects…These data indicate that the sHFLC diet is capable of increasing animal survival while minimizing tumor burden, is as effective as metformin, and may mechanistically overlap in AMPK-mediated inactivation of the mTOR pathway.”

Most importantly…

“The sHFLC diet slows tumor progression, increases survival, and reduces tumor burden in subcutaneous and orthotopic xenograft models.”

Low carb high fat with MCT oil much easier to maintain than strict ketogenic

Low carb high fat supplemented with MCT oil is as effective as the stricter ketogenic diet and has nutritional advantages.

“Here, we demonstrate that a high-fat, low-carbohydrate diet supplemented with MCT oil (sHFLC) is able to slow tumor progression and increase survival. In vivo, the sHFLC diet was similar to the ketogenic diet (KD) in antitumor efficacy, but showed nutritional advantages in body weight, organ enzyme levels, and lipid profile. Finally, we demonstrate that the sHFLC diet affects the mTOR signaling pathway by reducing expression of upstream regulators and translational downstream effectors…We designed the sHFLC diet for long-term sustainable maintenance of GB and for increased flexibility and palatability.”

Clinical note: Clearly, glucose control is crucial in case management for treatment and prevention of malignancies.

Excess glucose, as seen in GB patients with persistent hyperglycemia, leads to poor patient survival. It has also been suggested that diets with a high glycemic index may increase the risk of tumorigenesis, and low-carbohydrate, high-protein diets that limit circulating glucose can delay cancer development and progression.”

Moreover, regarding the hugely important issue of restricting cancer stem cell expansion:

“Treatment of GB stem cell lines with a constant physiologic concentration of BHB (4 mmol/L), as seen in KD patients, resulted in reduction of clonogenic frequency and symmetrical stem cell divisions, suggesting that elevated ketones affect the putative cancer stem cell population.”

Effective for diverse malignancies

Because a dependence on glycolysis is characteristic of all cancers these principles can be broadly applied.

“The combination of reduced glucose and increased ketone bodies has shown an enhanced anticancer effect…The KD mimics these biologic effects and has been proposed as a treatment for GB and other cancers…numerous groups have investigated the antitumor efficacy of a KD and an RKD in several types of cancer. RKD in experimental mouse models of glioma has been shown to be antitumorigenic, antiangiogenic, and pro survival, while also being anti-invasive, anti-inflammatory, and proapoptic by targeting signaling pathways related to glucose and glutamine metabolism. In animal models, feeding with the KD ad libitum has been reported to increase survival and reduce tumor growth. Other preclinical animal models such as gastric cancer, colon cancer, and metastatic cancer have used the KD, reporting similar antitumorigenic effects.”

Effects on the mTOR pathway is especially important:

“The mTOR pathway is one of the largest and most utilized pathways in cellular signaling, with two complexes (mTORC1/mTORC2) that have demonstrated a role in tumorigenesis. Recently, it’s been shown that inhibition of both mTORC1/mTORC2 signaling results in dramatically reduced cell viability in glioma cell lines, as well as inhibition of tumor growth in vivo. In our assessment of the sHFLC diet’s effects on the mTOR pathway, we found significant reduction in both mTORC1/mTORC2 signaling…Taken together, these findings indicate that inhibition of the mTORC1/2 pathway can be achieved through dietary intervention, resulting in a potent anti-cancer treatment.”

The authors conclusions highlight fundamental concerns in case management:

“Our work demonstrates that there is a distinct relationship between metabolism and proliferation that can be exploited by changing the energy sources in the body. Further research into the biochemical reactions of metabolic intermediates may shed more light on how ketone bodies are differentially utilized by tumor cells, as the role of mitochondria in tumor propagation and carcinogenesis is multifaceted and incompletely understood. Nevertheless, we effectively show that a combination of low glucose and high ketones results in negative proliferative effects on gliomaspheres, which can be translated in vivo with the sHFLC diet. This diet reduces overall tumor burden and increases survival, equivalent to a strict 1:6 KD, and has a complete nutritional profile. Hence we propose that dietary therapy, such as the sHFLC diet, could be utilized in the management of GB.”

The Warburg effect, foundation of the benefits of a low glycemic ketogenic diet

international-journal-of-cancerAn excellent study published in the International Journal of Cancer documenting decreased tumor cell viability and prolonged survival with supplemental ketones includes a fine review of the Warburg effect.

 “A century ago, Otto Warburg discovered that cancer cells display a unique metabolic phenotype of lactate fermentation in the presence of oxygen. This phenotype, known as the Warburg effect, enables tumor visualization using fluorodeoxyglucose positron emission tomography (FDG-PET) scans owing to the elevated rate of glucose consumption in most cancers. Metabolic therapies can exploit this phenotype, offering novel therapeutic directions aside from the classically targeted cytotoxic and gene-based therapies. The Warburg effect exposes a fundamental weakness of cancer cells, reliance on excess glucose for survival and maximal proliferation. Fasting, calorie restriction (CR) and the carbohydrate-restricted ketogenic diet have been successfully used to limit glucose availability and slow cancer progression in a variety of animal models and human studies.”

Importantly, the ketogenic effect is additive to the benefits of low glucose…

“Previously, the anticancer effects of these dietary manipulations have largely been attributed to decreased circulating blood glucose, which limits energy substrates for cancer cells. New evidence suggests, however, that the physiological state of ketosis and elevated circulating ketones also have anticancer effects.”

Ketogenic effect may be primary

For anti-cancer effects elevated ketones may be even more important than low glucose.

“Recently, Fine et al. demonstrated that a carbohydrate-restricted ketogenic diet inhibited disease progression and promoted partial remission in patients with advanced metastatic cancers from various tissue origins. [10] On average, the patients did not exhibit a drop in glucose from baseline, suggesting that decreased glucose availability was not the sole or primary cause of efficacy. Interestingly, the study found that the most important factor dictating the patients’ response to therapy was the degree of elevated ketosis from baseline. Indeed, a prominent metabolic shift to higher levels of ketosis correlated with reduced disease progression, stable disease or partial regression.”

Cancer as a mitochondrial disorder

The metabolic theory of cancer (as opposed to the somatic mutation theory) posits mitochondrial dysfunction as an instigator in the shift of normal to cancer cells.

“Although ketone bodies are efficient energy substrates for healthy extrahepatic tissues, cancer cells cannot effectively use them for energy. Widespread mitochondrial pathology has been observed in most if not all tumors examined, including decreased mitochondrial number, abnormal ultrastructural morphology, mitochondrial swelling, abnormal fusion–fission, partial or total cristolysis, mtDNA mutations, altered mitochondrial membrane potential and abnormal mitochondrial enzyme presence or function, among others.These defects in mitochondrial structure and function impair respiratory capacity and force a reliance on substrate-level phosphorylation for survival. As ketone bodies are metabolized exclusively within the mitochondria, cancer cells with impaired mitochondrial function are unable to efficiently metabolize ketone bodies for energy. Indeed, unlike healthy cells, ketone bodies fail to rescue glioma cells from glucose withdrawal-induced death.”

Ketone bodies oppose cancer in multiple ways

A ketogenic diet does more than just starve cancer cells…

  1. “Ketone bodies inhibit glycolysis, thus decreasing the main pathway of energy production for cancer cells.
  2. Cancer cells thrive in an environment of elevated reactive oxygen species (ROS) production but are very sensitive to even small changes in redox status. Ketones decrease mitochondrial ROS production and enhance endogenous antioxidant defenses in normal cells, but not in cancer cells. Ketone metabolism in healthy cells near the tumor may inhibit cancer cell growth by creating a less favorable redox environment for their survival.
  3. Ketone bodies are transported into the cell through the monocarboxylate transporters (MCTs), which are also responsible for lactate export. It has been shown that inhibiting MCT1 activity or inhibiting lactate export from the cell dramatically decreases cancer cell growth and survival. Ketones may impair cancer cells indirectly by competitive inhibition of the MCTs, decreasing critical lactate export from the cell.
  4. Recently, Verdin and coworkers demonstrated that βHB acts as an endogenous HDAC inhibitor at millimolar concentrations easily achieved through fasting, CR or ketone supplementation such as with a ketone ester (KE). Thus, ketone bodies may elicit their anticancer effects by altering the expression of oncogenes and tumor suppressor genes under control of the cancer epigenome.”

“Clearly, ketone bodies exhibit several unique characteristics that support their use as a metabolic therapy for cancer.”

Ketones oppose metastasis

Effectiveness against metastasis is critical for successful cancer therapy.

The Warburg effect is especially prevalent in aggressive cancers and metastatic cells. Metastasis, the spreading of a primary tumor to distal locations, is the primary cause of cancer morbidity and mortality and is responsible for more than 90% of cancer-related deaths.”

Ketones can be easily increased by diet and supplementation, so authors set out to investigate in vivo effectiveness:

It is possible to raise blood ketone levels without the need for carbohydrate restriction by administering a source of supplemental ketones or ketone precursors. 1,3-Butanediol (BD) is a commercially available food additive and hypoglycemic agent that is converted to βHB by the liver. The KE [ketone ester] elevates both AcAc and βHB in a dose-dependent manner to levels beyond what can be achieved with the KD or therapeutic fasting. Oral administrations of BD and KE have been shown to elevate blood ketones for at least 240 min in rats. As ketone bodies appear to elicit anticancer effects, and metastasis is the most significant obstacle in the successful treatment of neoplasms, we tested the efficacy of ketone supplementation in the VM-M3 cell line and mouse model of metastatic cancer.”

They measured proliferation and viability in highly metastatic cells cultured in the presence and absence of β-hydroxybutyrate (βHB). Also adult male inbred VM mice were implanted subcutaneously with firefly luciferase-tagged syngeneic VM-M3 cells and fed a standard diet supplemented with either 1,3-butanediol (BD) or a ketone ester (KE) which are metabolized into βHB and acetoacetate. They then monitored tumor growth in vivo bioluminescent imaging, and documented Survival time, tumor growth rate, blood glucose, blood βHB and body weight.

Ketone supplementation prolonged survival and reduced tumor burden

Tumor burden with ketone supplementation

Effect of supplemental ketones on tumor bioluminescence. (CR calorie restriction, BD 1,3-butanediol, and KE ketone ester).

The results were amazing, even without reducing glucose and calorie restriction:

Ketone supplementation decreased proliferation and viability of the VM-M3 cells grown in vitro, even in the presence of high glucose. Dietary ketone supplementation with BD and KE prolonged survival in VM-M3 mice with systemic metastatic cancer by 51 and 69%, respectively (p < 0.05). Ketone administration elicited anticancer effects in vitro and in vivo independent of glucose levels or calorie restriction.”

The authors discuss the profound clinical implications:

“The Warburg effect is the most ubiquitous cancer phenotype, exhibited by most if not all cancer types. Exploiting the metabolic deficiencies of cancer cells should be prioritized, because this therapeutic strategy would likely prove effective against most cancers. Mitochondrial dysfunction underlies many aspects of cancer metabolic deficiency and prevents cancer cells from effectively using ketone bodies for energy. In our study, ketone supplementation decreased VM-M3 cell proliferation and viability, confirming similar results demonstrated in other cancer types in vitro. Therefore, we hypothesized that dietary administration of ketone body precursors would inhibit disease progression in vivo. Indeed, dietary administration of ketone precursors, BD and KE, increased mean survival time by 51 and 69%, respectively, in VM-M3 mice with metastatic cancer. These data support the use of supplemental ketone administration as a feasible and efficacious cancer therapy, which should be further investigated…”

Although carbohydrate restriction has other important metabolic benefits, ketone supplementation was effective in prolonging survival even without it.

“Ketone supplementation decreased blood glucose after acute administration, decreased body weight with chronic administration and sustained ketosis in vivo, even when administered with a high-carbohydrate rodent chow in both healthy (VM/Dk) and cancer (VM-M3) mice. Our study demonstrates the ability of dietary administration of BD and KE to significantly elevate ketone bodiesin vivo for at least 12 hr in healthy VM/Dk mice and 7 days in VM-M3 cancer mice.”

Moreover, ketone supplementation on its own reduces weight, diminishes appetite and improves insulin sensitivity.

“It is important to note that the metabolic changes associated with acute and chronic ketosis are vast and can dramatically affect blood metabolite concentrations. In previous studies, chronic BD and βHB administration has been shown to decrease food intake in the rat and pigmy goat. Similarly, Veech and coworkers demonstrated that feeding a KE-supplemented diet increased malonyl-CoA, an anorexigenic metabolite known to decrease food intake. Ketone-induced appetite suppression may account for the decreased blood glucose and body weight seen in treated VM-M3 cancer mice. Additionally, prior studies suggest that ketones increase insulin sensitivity, which may be contributing to the decreased circulating blood glucose in KE-fed mice…Furthermore, chronic ketosis enhances ketone utilization by tissues, known as keto-adaptation, resulting in lower blood ketone concentrations.”

A ketogenic high fat diet with ketone supplementation may be more effective than calorie restriction

In the past, dietary treatment in cancer has emphasized carbohydrate or calorie restriction to exploit the Warburg effect, but this may not be the best approach.

“Interestingly, although CR [calorie restriction] decreased blood glucose and elevated blood ketones, CR mice exhibited a trend of increased latency to disease progression and increased survival that was not statistically significant from controls in our study. As described, some data suggest that elevated ketones are responsible for much of the anticancer efficacy of the ketogenic diet.Perhaps elevating ketones with exogenous sources such as ketone supplementation or a ketogenic diet, rather than elevating ketones endogenously through lipolysis such as occurs with CR, provides a more effective anticancer strategy. Additionally, ketone supplementation may preserve lean muscle mass to a greater degree than CR, and may therefore support overall health of the organism in this way…These data support the in vitro and in vivo conclusions of Fine et al. suggesting that ketone bodies can inhibit cancer progression independently of other factors such as carbohydrate restriction or CR.

Enhancement of radiation and chemotherapy

Ketogenic diet and ketone supplementation can enhance the cytotoxic effects of the increase in ROS (reactive oxygen species) by radiation and chemotherapy.

“The ketogenic diet has been shown to enhance the efficacy of both radiation and chemotherapy in vivo. As supplemental ketones mimic the physiological ketosis induced by the ketogenic diet, combining supplemental ketone therapy with standard of care could produce similar effects, even if administered with a SD [standard diet]. Furthermore, the neuroprotective effects of ketone metabolism have been widely documented. Ketone metabolism protects normal cells from oxidative damage by decreasing mitochondrial ROS production and enhancing endogenous antioxidant defenses. Radiation and chemotherapy work in large part by inducing ROS production in the tumor, but simultaneously incur damage to normal tissue. Ketone metabolism by healthy tissue would likely mitigate some of the adverse side effects of standard of care as ketones have been shown to protect against oxidative stress.”

The authors’ conclusion needs to be appreciated by any practitioner involvement in cancer case management:

Our data strongly suggest that supplemental ketone administration could provide a safe, feasible and cost-effective adjuvant to standard care that should be further investigated in preclinical and clinical settings.”

Exploiting Cancer Metabolism with Ketosis—Dr. Angela Poff