Ketogenic Diet Rapidly Reduces Liver Fat in Non-Alcoholic Fatty Liver Disease

stages of liver damage

Non-alcoholic fatty liver disease is an important contributor to cirrhosis, i.e., scarring in the liver that impairs liver function. In the study at hand, a ketogenic diet reduced liver fat by 31% over just six days. I don’t have many details of the diet used, but it reduced carbohydrates to 20 grams/day.

Significance

Ketogenic diet is an effective treatment for nonalcoholic fatty liver disease (NAFLD). Here, we present evidence that hepatic mitochondrial fluxes and redox state are markedly altered during ketogenic diet-induced reversal of NAFLD in humans. Ketogenic diet for 6 [days] markedly decreased liver fat content and hepatic insulin resistance. These changes were associated with increased net hydrolysis of liver triglycerides and decreased endogenous glucose production and serum insulin concentrations. Partitioning of fatty acids toward ketogenesis increased, which was associated with increased hepatic mitochondrial redox state and decreased hepatic citrate synthase flux. These data demonstrate heretofore undescribed adaptations underlying the reversal of NAFLD by ketogenic diet and highlight hepatic mitochondrial fluxes and redox state as potential treatment targets in NAFLD.

Abstract

Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes and their regulators in humans by using positional isotopomer NMR tracer analysis. Ten overweight/obese subjects received stable isotope infusions of: [D7]glucose, [13C4]β-hydroxybutyrate and [3-13C]lactate before and after a 6-d KD. IHTG was determined by proton magnetic resonance spectroscopy (1H-MRS). The KD diet decreased IHTG by 31% in the face of a 3% decrease in body weight and decreased hepatic insulin resistance (−58%) despite an increase in NEFA concentrations (+35%). These changes were attributed to increased net hydrolysis of IHTG and partitioning of the resulting fatty acids toward ketogenesis (+232%) due to reductions in serum insulin concentrations (−53%) and hepatic citrate synthase flux (−38%), respectively. The former was attributed to decreased hepatic insulin resistance and the latter to increased hepatic mitochondrial redox state (+167%) and decreased plasma leptin (−45%) and triiodothyronine (−21%) concentrations. These data demonstrate heretofore undescribed adaptations underlying the reversal of NAFLD by KD: That is, markedly altered hepatic mitochondrial fluxes and redox state to promote ketogenesis rather than synthesis of IHTG.

Source: Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease | PNAS

Steve Parker, M.D.

PS: If you have the Advanced Mediterranean Diet, 2nd edition, you already have the Ketogenic Mediterranean Diet as one of two options.

What’s the Best Type of Exercise to Reduce Obesity?

Steve Parker MD
Resistance training on left; treadmill on right can be high intensity

From Obesity Reviews:

Current international guidelines recommend people living with obesity should be prescribed a minimum of 300 min of moderately intense activity per week for weight loss. However, the most efficacious exercise prescription to improve anthropometry [measurements and proportions of the body], cardiorespiratory fitness (CRF) and metabolic health in this population remains unknown. Thus, this network meta‐analysis was conducted to assess and rank comparative efficacy of different exercise interventions on anthropometry, CRF and other metabolic risk factors.

* * *

Results reveal that while any type of exercise intervention is more effective than control [no particular exercise, if any], weight loss induced is modest. Interventions that combine high‐intensity aerobic and high‐load resistance training exert beneficial effects that are superior to any other exercise modality at decreasing abdominal adiposity, improving lean body mass and increasing cardiorespiratory fitness. Clinicians should consider this evidence when prescribing exercise for adults living with obesity, to ensure optimal effectiveness.

Source: What exercise prescription is optimal to improve body composition and cardiorespiratory fitness in adults living with obesity? A network meta‐analysis – O’Donoghue – – Obesity Reviews – Wiley Online Library

So, “combine high‐intensity aerobic and high‐load resistance training” to reduce body fat and increase fitness.

Steve Parker, M.D.

 

Determination of Brain Death by Neurologic Criteria

Wish I were here

This is for my personal use. Not for my typical readers. From the World Brain Death Project:

Abstract

Importance

There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries.

Objective

To formulate a consensus statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel.

Process

Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery.

Evidence Synthesis Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed.

Recommendations

Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH <7.30 and Paco2 ≥60 mm Hg. If the clinical examination cannot be completed, ancillary testing may be considered with blood flow studies or electrophysiologic testing. Special consideration is needed for children, for persons receiving extracorporeal membrane oxygenation, and for those receiving therapeutic hypothermia, as well as for factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability.

Conclusions and Relevance

This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.

Source: Determination of Brain Death/Death by Neurologic Criteria: The World Brain Death Project | Critical Care Medicine | JAMA | JAMA Network

Daily Users of Proton Pump Inhibitors Have Double the Risk of COVID-19

Are you tired of this pic yet?

Click for details.

You should assume there’s a good reason or two why we have acidic stomach juice. One reason is to prevent infection. I see too many patients who are put on these drugs for a good reason, but they keep taking them after the drug has finished its job. An “as needed” H2 blocker like Pepcid may be a reasonable substitute for PPIs. Check with your personal physician.

I have nothing against Prilosec in particular. It can be very helpful. It’s one of several PPIs on the market.

Steve Parker, M.D.

Ketogenic Diet More Effective Than Low-Fat for Obesity and Diabetes

One of many ketogenic salads

From The Journal of Nutrition:

For >50 y, dietary guidelines in the United States have focused on reducing intakes of saturated and total fat. However, rates of obesity and diabetes rose markedly throughout this period, with potentially catastrophic implications for public health and the economy. Recently, ketogenic diets have received substantial attention from the general public and nutrition research community. These very-low-carbohydrate diets, with fat comprising >70% of calories, have been dismissed as fads. However, they have a long history in clinical medicine and human evolution. Ketogenic diets appear to be more effective than low-fat diets for treatment of obesity and diabetes. In addition to the reductions in blood glucose and insulin achievable through carbohydrate restriction, chronic ketosis might confer unique metabolic benefits of relevance to cancer, neurodegenerative conditions, and other diseases associated with insulin resistance. Based on available evidence, a well-formulated ketogenic diet does not appear to have major safety concerns for the general public and can be considered a first-line approach for obesity and diabetes. High-quality clinical trials of ketogenic diets will be needed to assess important questions about their long-term effects and full potential in clinical medicine.

Source: Ketogenic Diet: Evidence for Optimism but High-Quality Research Needed | The Journal of Nutrition | Oxford Academic

     Steve Parker, M.D.

PS: A ketogenic diet is one of the options in The Advanced Mediterranean Diet, 2nd edition.

Low to Moderate Alcohol Drinking Linked to Improved Cognitive Function in Adults

Jameson’s in a hotel bar near Chicago

From JAMA network:

These findings suggested that low to moderate alcohol drinking was associated with better global cognition scores, and these associations appeared stronger for white participants than for black participants.

Source: Association of Low to Moderate Alcohol Drinking With Cognitive Functions From Middle to Older Age Among US Adults | Dementia and Cognitive Impairment | JAMA Network Open | JAMA Network

     Steve Parker, M.D.

Do Antibody Infusions Work Against COVID-19?

artist rendition of coronavirus
See the spikes? Or are they golf tees?

A monoclonal antibody given to patients with mild COVID-19 reduced symptom severity and the odds of needing hospitalization.

About 10 days ago the hospital where I work started giving intravenous antibodies to COVID-19 patients in the emergency department. These are folks with COVID-19 symptoms and a positive COVID PCR test within the last three days but they’re not sick enough to warrant admission. My impression is that the infusion is monoclonal antibodies, different from the convalescent plasma we were offering to inpatients several months ago.

The antibody used in the study at hand is “LY-CoV555 (also known as LY3819253), a potent antispike neutralizing monoclonal antibody that binds with high affinity to the receptor-binding domain of SARS-CoV-2,” and “was derived from convalescent plasma obtained from a patient with Covid-19.” I assume scientists figured out a way to synthesize that antibody in a lab.

Click on Abstract for full details.

Abstract

BACKGROUND

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (Covid-19), which is most frequently mild yet can be severe and life-threatening. Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization.

This was a very small study; only a little over a hundred patients in each of three treatment groups (three different doses) and the placebo group.

METHODS

In this ongoing phase 2 trial involving outpatients with recently diagnosed mild or moderate Covid-19, we randomly assigned 452 patients to receive a single intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo and evaluated the quantitative virologic end points and clinical outcomes. The primary outcome was the change from baseline in the viral load at day 11. The results of a preplanned interim analysis as of September 5, 2020, are reported here.

RESULTS

At the time of the interim analysis, the observed mean decrease from baseline in the log viral load for the entire population was −3.81, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was −0.53 (95% confidence interval [CI], −0.98 to −0.08; P=0.02), for a viral load that was lower by a factor of 3.4. Smaller differences from placebo in the change from baseline were observed among the patients who received the 700-mg dose (−0.20; 95% CI, −0.66 to 0.25; P=0.38) or the 7000-mg dose (0.09; 95% CI, −0.37 to 0.55; P=0.70). On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo. The percentage of patients who had a Covid-19–related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group.

CONCLUSIONS

In this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501. opens in new tab

Another study looked at the use of a cocktail containing two monoclonal antibodies in non-hospitalized patients. Researchers concluded:

In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629. opens in new tab.)

Click for details.

Their report indicated that those who received the antibodies were less likely to need subsequent medical visits. But they didn’t put that in their concluding paragraph so I will assume it didn’t reach statistical significance.

Neither of these studies reported reduction in death rates.

+ + +

Obesity, particularly BMI 35 or higher, is risk factor for serious COVID-19 disease. If obese, you’ve had almost a year to work on it. How ya doin’? I can help if needed. See the book below.

Steve Parker, M.D.

What About Melatonin for COVID-19?

Photo by Anna Shvets on Pexels.com

Melatonin is a commonly-available over-the-counter sleep aid. In 2020, the Cleveland Clinic did epidemiological study that linked melatonin usage with a 30% reduced risk of contracting COVID-19. Clinical psychologist Michael J Breus, Ph D has an article at Psychology Today on the use of melatonin as a preventative or treatment for COVID-19.

Melatonin, of course, is best known as a sleep regulator. But melatonin also plays an important role in regulating the immune system. One way it does so is by influencing the production of small proteins known as cytokines, which act as signalers from the immune system to cells around the body. Cytokines can be inflammation producing (pro-inflammatory cytokines) or inflammation restricting (anti-inflammatory cytokines). Melatonin has been shown to reduce the production of pro-inflammatory cytokines. Melatonin also is well known to be an antioxidant, neutralizing free radical cells and limiting oxidative stress and damage, which contribute inflammation.

Pro-inflammatory cytokines serve an important purpose, in marshaling the inflammatory response that fights off viruses, bacteria, and other pathogens. That’s the protective mechanism of inflammation at work. But for the pro-inflammatory cytokine response to be beneficial, it must be proportional to the threat. A too vigorous response of pro-inflammatory cytokines creates a dangerous amount of inflammation—and can actually serve to spread the viral infection, rather than tamping it down. It is this inflammatory overreaction and viral spread that appears to take place in the most serious cases of COVID-19.

I spent 10 minutes on the Internet trying to find the appropriate dose of melatonin for its possible preventative and treatment powers. But no luck. It’s likely in the range of 1 to 10 mg/day, typically taken at night or bedtime. For insomnia in my hospitalized patients, I start at 1.5 mg. Most of my colleagues use a much higher dose. Dr Josh Farkas at emcrit.org suggests that the treatment dose is 5 mg/day.

As always, check with your personal physician first.

Steve Parker, M.D.

COVID-19: Do Lock-Downs Work?

artist's rendition of coronavirus
Artist’s rendition of Coronavirus

If you’re looking for evidence that stay-at-home orders and business closures don’t help control COVID-19, here it is:

In summary, we fail to find strong evidence supporting a role for more restrictive non-pharmacological interventions in the control of COVID in early 2020. We do not question the role of all public health interventions, or of coordinated communications about the epidemic, but we fail to find an additional benefit of stay-at-home orders and business closures.

– John P.A. Ioannidis, et al.

Despite Pasta, You Can Still Lose Weight With a Mediterranean Diet

spaghetti squash, spaghetti
Spaghetti squash is an alternative to pasta

The title above sums it up. If you’re eating pasta frequently and trying to lose weight, you do have to be careful not to over-eat. In other words, you generally have to restrict calories. In the study at hand, I don’t know how many daily calories were allowed since I haven’t read the full report. Here’s the abstract:

Background & aims

The effect of pasta consumption within a low-energy [read: calorie-restricted] Mediterranean diet on body weight regulation has been scarcely explored. This paper investigates the effect of two Mediterranean diets, which differed for lower or higher pasta intake, on body weight change in individuals with obesity.

Methods & Results

Forty-nine volunteers finished a quasi-experimental 6-month two–parallel group dietary intervention. Participants were assigned to a low-energy high pasta (HP) or to a low-energy low Pasta (LP) group on the basis of their pasta intake (HP ≥ 5 or LP ≤ 3 times/week). Anthropometrics, blood pressure and heart rate were measured every month. Weight maintenance was checked at month 12. Body composition (bioelectrical impedance analysis, BIA), food intake (24-h recall plus a 7-day carbohydrate record) and the perceived quality of life (36-item short-form health survey, SF-36) were assessed at baseline, 3 and 6 months. Blood samples were collected at baseline and month 6 to assess glucose and lipid metabolism. After 6-month intervention, body weight reduction was −10 ± 8% and −7 ± 4% in HP and LP diet, respectively, and it remained similar at month 12. Both dietary interventions improved anthropometric parameters, body composition, glucose and lipid metabolism, but no significant differences were observed between treatment groups. No differences were observed for blood pressure and heart rate between treatments and among times. HP diet significantly improved perception of quality of life for the physical component.

Conclusions

Independent of pasta consumption frequency, low-energy Mediterranean diets were successful in improving anthropometrics, physiological parameters and dietary habits after a 6-month weight-loss intervention.

Source: Body weight of individuals with obesity decreases after a 6-month high pasta or low pasta Mediterranean diet weight-loss intervention – Nutrition, Metabolism and Cardiovascular Diseases

Steve Parker, M.D.