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

Chemotherapy: how much does it actually improve survival?

BMJ chemotherapy and survivalChemotherapy drugs have had little effect on cancer survival in adults according to an analysis just published in BMJ (British Journal of Medicine).

The author notes that although there have been advances in chemotherapy in recent years, a thorough examination of the data reveals that…

“Despite considerable investment and innovation, chemotherapy drugs have had little effect on survival in adults with metastatic cancer.”

In fact, the data on the survival benefits of chemotherapy are so disturbing that they raise questions about ethics, drug trials and approval, and patient consent.

The approval of drugs with such small survival benefits raises ethical questions, including whether recipients are aware of the drugs’ limited benefits, whether the high cost:benefit ratios are justified, and whether trials are providing the right information.”

Key messages include:

  • “Advances in chemotherapy have contributed little to population cancer survival

  • Responses in clinical trials may not apply to patients treated in the community

  • Evaluation outside trial centres is essential to ensure that scarce resources are not squandered

  • Stricter approval criteria are needed to achieve ethical treatment and reduce cancer costs

  • Ethical informed consent and empowerment of patients must be promoted”

The author strongly advises a more clinically sound and ethical way forward:
Many irregularities and competing interests—in pharma, in trials, in government approval, and in the clinical use of cancer drugs—impact ethically on the care and costs of patients with cancer. Non-representative clinical trials with imprecise endpoints and misinformed patients with unrealistic expectations compel interventions that are mostly not in their best interests. Spending a six figure sum to prolong life by a few weeks or months is already unaffordable, and inappropriate for many of the 20% of the (Western) population who will almost inevitably die from solid tumour metastases.”

 

Patients deserve better information and more supportive treatment….

Ethical cancer care demands empowerment of patients with accurate, impartial information followed by genuinely informed consent in both the clinical trial and therapeutic settings. Intensified prevention, earlier detection, more prompt and radical treatment of localised and regional disease, together with highly skilled, earlier, supportive care are the important yet underfinanced priorities in cancer control. Ethical impediments to sound practice need to be addressed and corrected. Above all, the efficacy bar for approval needs to be raised for both new and existing cancer drugs—by using more meaningful statistical and disease specific criteria of risk-benefit and cost-benefit. Finally, aggressively targeting the less than ethical actions of stakeholders in the heavily veiled medical-industrial complex may be the only way forward: current market driven rather than health driven priorities and practices do not benefit cancer patients.”

The entire paper can be downloaded here, and an illuminating, brief interview with the author can heard by clicking on the arrow in the upper left corner of the image below:

 

the-bmjThe editor-in-chief of BMJ in an accompanying editorial states:

“People with cancer are living longer now than 40 years ago. This is clearly good news. But how much of this improvement can we attribute to drug treatment? Not much, concludes Peter Wise this week in an article I humbly suggest all oncologists should read. The nearly 20% improvement in five year survival over the past four decades is probably mainly due to improved early diagnosis and treatment rather than developments in cytotoxic chemotherapy, he says. And patients are being badly misled by over-enthusiastic accounts of what chemotherapy can achieve. Many expect a cure. In reality they will gain on average only a few months of extra life.”

Moreover…

Unjustified enthusiasm for cancer drug treatments comes at huge cost, financial and personal (including treatment related deaths and reduced quality of life), and increased risk of dying in hospital rather than at home. Many patients don’t realise that opting for supportive rather than active treatment—often called “refusal”—is an option and may give them longer as well as better quality life than chemotherapy. Conflicts of interest among clinicians compound their reluctance to have tricky conversations.”

The editor summarizes the author’s recommendations in light of this data:

“Wise concludes with a call for higher bars for drug approval for new and existing drugs. Ethical cancer care demands empowerment of patients, he says, with accurate, impartial information followed by genuinely informed consent. And funds and attention should shift to prevention, early detection, prompt and radical treatment of localised and regional disease, and early provision of supportive care. Only then will cancer care serve patients rather than governments and industry.”

Levothyroxine therapy and normal TSH yet hypothyroid symptoms

JCEM levothyroxine fails to normalize thyroid T3Levothyroxine (LT4, synthetic thyroxine) is the standard therapy given by most physicians for hypothyroid. Yet clinicians experienced in functional case management of thyroid disorders know that patients may often continue to feel poorly due to inadequate T3 (triiodothyronine, the ‘active’ thyroid hormone converted from T4 outside the gland). A study just published in The Journal of Clinical Endocrinology and Metabolism offers undeniable evidence that many patients taking only levothyroxine are receiving inadequate treatment. Because TSH responds to T4 and not T3 levels, poor function persists even with normal TSH and . The authors state:

“The ideal therapeutic goal in hypothyroidism would be to restore clinical and biochemical euthyroidism via physiologic thyroid hormone replacement. This concept may seem straightforward, but there are subtleties that have only recently been recognized by the medical community. For the last four decades, the standard approach for thyroid hormone replacement in hypothyroidism has been administration of levothyroxine (LT4) at doses that normalize the serum TSH.”

Levothyroxine dogma persists despite prior evidence

An abundance of data contrary to the dogma has already been emerging for years (see these earlier posts: Thyroid hormone conversion affects hypothyroid treatment; Low ‘normal’ free T3 thyroid hormone predicts death in older patients even without overt hypothyroidThyroid in heart, metabolism, brain, kidney; vital importance of T3). Finally the dogma of standard therapy that has endured in fossilized resistance is being overcome.

“The hypothesis that LT4 ‘monotherapy’ will maintain an adequate serum pool of T4 and that the iodothyronine deiodinases will then provide physiologic regulation of T3 availability has been held with much conviction. The dogma in clinical thyroidology that LT4 monotherapy at doses that normalize serum TSH is sufficient to restore euthyroidism has come into question as evidence suggests a significant proportion of patients treated with LT4 continue to experience residual symptoms of hypothyroidism, including psychological and metabolic effects.”

Tremendous importance for public health

The authors underline the huge significance for public health:

“Hypothyroidism is a prevalent condition and levothyroxine is commonly prescribed; in 2015 levothyroxine was the single most commonly prescribed medication in the US. Thus understanding whether all parameters of hypothyroidism are universally restored by LT4 monotherapy has great clinical significance.”

They set about to determine whether LT4 at doses that normalize serum TSH is associated with normal markers of thyroid status and functional thyroid health by examining data for 9,981 participants with normal serum TSH were identified; 469 were LT4-treated from the giant US National Health and Nutrition Examination Survey. They used this to 9,981 participants with normal serum TSH were identified; 469 were LT4-treated.

Levothyroxine fails to adequately improve T3

Their data show clearly that in many cases levothyroxine monotherapy fails to ensure an adequate T3:T4 ratio and thyroid functional health:

Participants using LT4 had higher serum total and free T4 and lower serum total and free T3 than healthy or matched controls. This translated to ∽15–20% lower serum T3:T4 ratios in LT4 treatment, as has been shown in other cohorts. In comparison to matched controls, LT4-treated participants: had higher BMI despite report of consuming less calories/day/kg; were more likely to be taking beta-blockers, statins, and anti-depressants; and reported lower total metabolic equivalents. A serum TSH level below the mean in LT4-treated participants was associated with a higher serum free T4 but similar free and total T3; yet those with lower serum TSH levels exhibited higher serum HDL and lower serum LDL, triglycerides, and CRP. Age was associated with serum free T3:free T4 ratio in all participants; caloric intake was associated in LT4-treated individuals.”

The lower serum TSH in LT4-treated patients was associated with a different metabolic profile but not higher T3.  Commenting on the significance for quality of life they state:

“The major strength of the present studies is the availability of biochemical data as well as markers of quality of life (QOL) in a large population sample to assess for clinical relevance. There were major differences in 7 (out of a total of 21) objective (BMI, total cholesterol, HDL, LDL; beta-blocker, statin and antidepressant use), and 5 (out of a total of 31) subjective (nutrient intake, reported physical activity) clinical parameters between LT4 -treated participants and matched controls. While we recognize that these parameters are not specific markers of hypothyroidism and we cannot determine whether they were different between the groups prior to LT4 treatment, this does not mitigate the fact that these data present a strong challenge the dogma that having a normal serum TSH equates with euthyroidism in LT4 -treatment.

Clinical Note

It should go without saying that almost all hypothyroidism in developed countries is due to autoimmune thyroiditis (Hashimoto’s disease). Besides muddying the waters in terms of quantifying the functional effects, practitioners must bear in mind that the systemic burden of inflammation associated with autoimmunity has diverse negative effects, in addition to impairing type 2 deiodinase (D2) conversion of T4 to T3.

Commenting in Medscape Medical News, senior author Antonio C Bianco, MD, professor of medicine at Rush University Medical Center in Chicago, Illinois stated:

“Patients have told us this for years — they complain of having a hard time losing weight and feeling sluggish and depressed. Now, for the first time, we have documentation that supports the patients’ complaints, demonstrating that…[this] was not only in their minds, as some have suggested.”

The authors conclude:

“…NHANES participants with normal serum TSH levels on LT4 monotherapy exhibit lower serum T3:T4 ratios than healthy euthyroid controls. LT4 -treated individuals have higher BMIs despite reporting lower calorie intake corrected by body weight, report lower physical activity levels, and are more often taking statins, beta- blockers, and antidepressantsthe concept that establishing a normal serum TSH renders individuals on LT4 monotherapy clinically euthyroid should be revisited and QOL measures should be more highly prioritized in hypothyroidism research and professional guidelines.”

Autoimmune diabetes (type 1): half develops after age 30

EASD abstract on autoimmune diabetesAutoimmune diabetes (type 1), earlier thought to occur almost exclusively in the pediatric population, is dramatically increasing among adults. Data recently presented at the 2016 Annual Meeting of the European Association for the Study of Diabetes (EASD) and reported in Medscape confirms that it now occurs as frequently in adults over 30 as it does in children.

Onset of type 1 diabetes is just as likely to occur in people older than 30 years of age as in those younger, new research shows.”

This is a manifestation of the giant increase in autoimmune and autoinflammatory conditions present but too often overlooked in clinical practice.

Autoimmune diabetes lurks in the general population

MedscapePractitioners active in case management of autoimmune conditions are already aware of this, but to many it may come as a surprise.

“Obtained using genetic data from the UK Biobank, the startling results refute the long-held belief that type 1 diabetes is primarily a “juvenile” condition…Clinically, the findings are particularly relevant for primary care, where people who develop autoimmune-mediated diabetes in adulthood are often misdiagnosed as having type 2 and prescribed metformin instead of insulin.”

Dr Nicholas JM Thomas, of the Institute of Biomedical and Clinical Science, University of Exeter Medical School, United Kingdom, who presented the data, is quoted in Medscape:

“I think it’s an eye-opener and obviously has implications for how we diagnose and manage people and also the education people receive. We very much focus on childhood and adolescence and perhaps people diagnosed later don’t get the same education.”

Autoimmune diabetes can be mixed with type 2 (metabolic)

2016-10-23_17-29-31Experienced clinicians will recognize that HgbA1c going up in a lean adult almost always implies an autoimmune component. Harder to recognize is a person for whom both are occurring: there is insulin resistance with compensatory elevated insulin forcing the storage of calories as fat resulting in overweight or obesity but combined with further carbohydrate intolerance due to an autoinflammatory attack on beta cells, insulin, the GAD enzyme, or other factors that further damage blood glucose regulation. It can develop rapidly or slowly as LADA (latent autoimmune diabetes of adults).  I am seeing this in practice and I’m sure others paying attention are too.

Medscape further quotes Dr. Thomas:

“He advised that clinicians should at least be aware that adults can develop autoimmune diabetes, as either classic type 1 or the slower-onset phenomenon known as “latent autoimmune diabetes of adulthood (LADA).”

“It’s knowing this does happen, and therefore just keeping an open mind when you spot someone who’s not behaving like type 1 or not responding as you would anticipate when you go through the usual treatment guidelines for type 2,” he said, citing the example of British Prime Minister Theresa May, who was diagnosed with type 1 diabetes at age 56 and who “progressed very rapidly.”

He reiterated that type 1 diabetes is evenly distributed within the first 6 decades of life, but after age 30, the increase in type 2 diabetes makes the type 1 cases harder to recognize and treat correctly.

Diagnosis

Antibody measurements, particularly to the islet cells, insulin and glutamic acid decarboxylase 65 are a mainstay even though subject to the vulnerabilities of antibody expression. And there is a new approach:

“Dr Thomas and colleagues used a “robust, novel, genetic approach” using a risk score comprising 30 single nucleotide polymorphisms associated with type 1 diabetes (T1D-GRS).”

Firstly the clinician should be alert to impaired blood glucose control in adult patients who are not overweight or for whom the correct diet (LCHF) and targeted therapies are not yielding the result they should. This is a tipoff that the case has to be managed as autoimmune diabetes or LADA with the underlying causes for loss of immune tolerance investigated and targeted for therapy.

The session comoderator Catharine Owen, MD, associate professor of diabetes at the Oxford Center for Diabetes, Endocrinology, and Metabolism, United Kingdom, is also quoted in Medscape:

“I think it’s absolutely crucial for people to be aware that type 1 diabetes can present at any age. Physicians shouldn’t be complacent when people aren’t responding to oral agents, or they’re not bringing A1c down to target when they should.”

Leaky gut: inflammation, chronic fatigue and depression

Neuroendocrinology Letters--leaky gut and chronic fatigueLeaky gut‘ is abnormal intestinal permeability that occurs when the epithelial tissues that comprise the gut barrier have been damaged. When intact the gut barrier prohibits antigenic contents of the intestines from access to the gut-associated lymphoid tissue (GALT) right on the other side of the intestinal wall. Gut barrier integrity (absence of leaky gut) is crucial to prevent loss of immune tolerance (autoimmunity) since the GALT comprises 60-80% of all immune tissue in the body.

Normalization of leaky gut improves chronic fatigue

LPS (lipopolysaccharide from bacterial cell walls) is so highly antigenic that it’s used as an adjuvant in vaccines. Translocation of LPS across a damaged gut barrier elicits systemic inflammation, accompanied by oxidative and nitrosative stress. A study published in Neuroendocrinology Letters demonstrates how normalization of the antibody responses to LPS not only ameliorates but can predict the clinical outcome in chronic fatigue syndrome (CFS). The authors state:

“There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome (CFS).”

They investigated this by measuring serum concentrations of IgA and IgM to LPS of several gram-negative enterobacteria CFS patients, both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, while consuming a leaky gut diet during 10-14 months. They also measured corresponding result with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and after 10-14 months on the NAIOSs.

Good clinical response to lowered IgA and IgM

The improvement in CFS scores that they documented was very gratifying:

Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).”

The authors’ comments on their data can hardly be overemphasized for clinicians participating in case management of chronic fatigue and fibromyalgia:

“The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.”

High IgA response to normal gut bacteria fires up inflammation in CFS

Journal of Affective DisordersAn interesting study published in the Journal of Affective Disorders documents how LPS from commensal gut bacteria that translocates into the GALT provokes inflammation that drives CFS. The authors note:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by a) systemic IgA/IgM responses against the lipopolysaccharides (LPS) of commensal bacteria; b) inflammation, e.g. increased plasma interleukin-(IL)1 and tumor necrosis factor (TNF)α; and c) activation of cell-mediated immunity (CMI), as demonstrated by increased neopterin.”

These authors investigated the IgA/IgM responses to the LPS of 6 different enterobacteria by measuring serum IL-1, TNFα, neopterin, and elastase in 128 patients with ME/CFS and chronic fatigue (CF). When they correlated with biomarkers for inflammation, CMI and the symptoms of ME/CFS the results were noteworthy:

“Serum IL-1, TNFα, neopterin and elastase are significantly higher in patients with ME/CFS than in CF patients. There are significant and positive associations between the IgA responses to LPS and serum IL-1, TNFα, neopterin and elastase. Patients with an abnormally high IgA response show increased serum IL-1, TNFα and neopterin levels, and higher ratings on irritable bowel syndrome (IBS) than subjects with a normal IgA response. Serum IL-1, TNFα and neopterin are significantly related to fatigue, a flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability.”

This is extremely important in clinical practice due to the great functional significance of both systemic inflammation and autonomic nervous system regulation. The authors conclude:

“The findings show that increased IgA responses to commensal bacteria in ME/CFS are associated with inflammation and CMI activation, which are associated with symptom severity. It is concluded that increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients.”

Autoimmune attack on serotonin production

Another fascinating paper also published in the Journal of Affective Disorders reveals that bacterial translocation through the gut barrier into immune lymphoid tissue can provoke antibodies that attack 5-HT, the precursor of serotonin, contributing to chronic fatigue and depression. The authors state:

“Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation.”

The examined 117 patients with ME/CFS for autoimmune activity against 5-HT, measuring plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria. This was correlated with the fibromyalgia and chronic fatigue syndrome rating scale. Their data show a strong association:

“The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.”

This is very significant for clinicians involved in case management of fatigue, depression, chronic pain and autonomic dysregulation. The authors sum it up:

“The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions…These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.”

Leaky gut, LPS and depression

Yet another study in the same journal investigated increased IgA and IgM antibodies aimed at gut commensal bacteria specifically in depression. The authors measured antibodies directed against Hafnia alvei, Pseudomonas aeruginosa, Morganella morganii, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae in depressed patients and normal controls, and found a very significant correlation to symptoms of depression and fatigue:

“The prevalences and median values of serum IgM and IgA against LPS of these commensals were significantly higher in depressed patients than in controls. The IgM levels directed against the LPS of these commensal bacteria were significantly higher in patients with chronic depression than in those without. The immune responses directed against LPS were not associated with melancholia or recurrent depression. There was a significant correlation between the IgA response directed against LPS and gastro-intestinal symptoms.”

Clinical note

The treatment of chronic fatigue and depression demands a holistic, multidisciplinary approach. A core feature with a number of potential contributing causes that can vary in each case is up-regulation of immune pathways driving inflammation in the brain and against elements in neurotransmitter production. The authors highlight these considerations in their discussion:

“The results indicate that increased bacterial translocation with immune responses to the LPS of commensal bacteria may play a role in the pathophysiology of depression, particularly chronic depression…The findings suggest that “translocated” gut commensal bacteria activate immune cells to elicit IgA and IgM responses and that this phenomenon may play a role in the pathophysiology of (chronic) depression by causing progressive amplifications of immune pathways.”

Compounds that modulate neuroinflammation induced by LPS

Neurochemistry InternationalA wide range of therapeutic resources are available to the functional practitioner to employ, depending on the individual case, that can ameliorate autoimmune inflammation triggered by reactions to the LPS of bacteria translocated through a leaky gut. By way of one example among many, a paper published in Neurochemistry International shows that anthocyanins (polyphenolic compounds imparting a blue color, found in vegetation such as blueberries) can ameliorate inflammation triggered by reactions to LPS.

“Several studies provide evidence that reactive oxygen species (ROS) are key mediators of various neurological disorders. Anthocyanins are polyphenolic compounds and are well known for their anti-oxidant and neuroprotective effects. In this study, we investigated the neuroprotective effects of anthocyanins (extracted from black soybean) against lipopolysaccharide (LPS)-induced ROS-mediated neuroinflammation and neurodegeneration in the adult mouse cortex.”

This benign intervention produced a gratifying result:

“The immunoblotting and morphological results showed that anthocyanins treatment significantly reduced LPS-induced-ROS-mediated neuroinflammation through inhibition of various inflammatory mediators, such as IL-1β, TNF-α and the transcription factor NF-kB…Anthocyanins also prevent overexpression of various apoptotic markers, i.e., Bax, cytosolic cytochrome C, cleaved caspase-3 and PARP-1. Immunohistochemical fluoro-jade B (FJB) and Nissl staining indicated that anthocyanins prevent LPS-induced neurodegeneration in the mouse cortex.”

Of particular note to the clinician:

“Our results suggest that dietary flavonoids, such as anthocyanins, have antioxidant and neuroprotective activities that could be beneficial to various neurological disorders.”

Calcium supplementation may increase risk for dementia

NeurologyCalcium supplementation continues to come under scrutiny as evidence accumulates that it can increase the risk of inflammatory disorders, most notably cerebrovascular disease, likely by opposing the anti-inflammatory effects of magnesium. A study just published in the journal Neurology offers evidence that supplementation can increase the risk for dementia in women with cardiovascular disease. The authors set out to…

“…determine whether calcium supplementation is associated with the development of dementia in women after a 5-year follow-up.”

700 dementia-free women aged 70–92 years were examined at baseline and at follow-up 5 years later with comprehensive neuropsychiatric and physical examinations. 447 underwent CT scans at baseline. Dementia was diagnosed according to DSM-III-R criteria, and this was correlated with information on the use and dosage of calcium supplements.

Calcium supplementation dramatically increased the risk for dementia

Neurology 2The risk more was increased almost 7 times for the subset of women with a history of stroke, and tripled for those with white matter lesions, in comparison to similar subjects who did not supplement:

Women treated with calcium supplements (n = 98) were at a higher risk of developing dementia (odds ratio [OR] 2.10) and the subtype stroke-related dementia (vascular dementia and mixed dementia) (OR 4.40) than women not given supplementation (n = 602)….supplementation was associated with the development of dementia in groups with a history of stroke (OR 6.77) or presence of white matter lesions (OR 2.99), but not in groups without these conditions.”

Correspondence with previous studies

This was a relatively small study, but the findings correspond to earlier evidence that supplementation can increase the burden of systemic inflammation (some have been written about here). It opposes the absorption and action of magnesium, a likely mechanism accounting for these observations. Recall that osteoporosis is not a calcium deficiency disorder, rather a failure to maintain the protein matrix of bone to which the minerals attach. Though it was only subjects with a history of cerebrovascular disease or white matter lesions for whom the risk of dementia was markedly increased, clinicians should consider very carefully before recommending supplementation. The authors conclude:

Calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease.”

Thyroid autoimmunity and iron deficiency in pregnancy

European Journal of Endocrinology on thyroid autoimmunity in pregnancyThyroid autoimmunity and iron deficiency are both common in pregnancy, posing a risk for numerous adverse fetal and maternal outcomes, including miscarriage. A clinical study just published in the European Journal of Endocrinology the important connection between thyroid autoimmunity and low iron, both of which can be recognized at an early stage. The authors state:

“Thyroid disorders and iron deficiency (ID) are associated with obstetrical and fetal complications. Iron is essential for the normal functioning of thyroid peroxidase (TPO-abs) and ID is frequent during pregnancy. The aim of this study was to compare the prevalence of thyroid autoimmunity (TAI) and dysfunction during the first trimester of pregnancy in women with and without ID.”

They measured ferritin to determine iron status, TPO-abs (thyroid peroxidase antibodies) for thyroid autoimmunity, and thyroid-stimulating hormone (TSH) and free T4 (FT4) thyroid function. Note that their definitions for iron deficiency (ID) and thyroid autoimmunity (TAI) were extremely ‘generous’ with ID defined as ferritin <15µg/L and TAI as TPO-abs >60kIU/L. Practitioners in this country should also note their definition of subclinical hypothyroidism (SCH) as TSH was >2.5mIU/L.

Thyroid autoimmunity and iron deficiency are common

Their data also demonstrated a significant coupling between the two:

ID was present in 35% of women. Age and BMI were comparable between both groups. In the ID group, the prevalence of TAI and SCH was significantly higher, compared with that in the non-ID group (10% vs 6% and 20% vs 16% respectively). Ferritin was inversely correlated with serum TSH and positive with FT4 levels. In the logistic regression model, ID remained associated with TAI after correction for confounding factors. The association with SCH was absent after correction for the confounders in the logistic regression model, but remained present in the linear regression model.”

MedscapeMedscape Medical News comments on these findings:

“While previous studies have indicated that iron deficiency during pregnancy can affect from 24% to 44% of women, this is the first to show the secondary effect of an increased prevalence of thyroid autoimmunity.”

Thyroid autoimmunity poses serious maternal and fetal risks. Also stated in Medscape:

“Senior author Kris G Poppe, MD, PhD, head of the Endocrine Clinic, University Hospital CHU St-Pierre, Brussels, Belgium, told Medscape Medical News that this finding is important because thyroid autoimmunity in pregnant women increases the risk of miscarriage, preterm delivery, and low birth weight compared with unaffected women.”

For important points on the multiple adverse affects of thyroid autoimmunity on pregnancy and the neonate see the earlier post Subclinical hypothyroidism in pregnancy. Standard of care for pregnancy planning and management should always include testing ferritin, thyroid antibodies and function.

The authors conclude:

ID was frequent during the first trimester of pregnancy and was associated with a higher prevalence of TAI, higher serum TSH, and lower FT4levels.”