Iron-rich blood and metabolic syndrome

Hyperferritinemia Is Associated with Insulin Resistance and Fatty Liver in Patients without Iron Overload
Original source: PLoS ONE 3(10): e3547
Authors: Robert Brudevold (corresponding author), Torstein Hole, Jens Hammerstrøm
Publication date: October 28, 2008
DOI (digital document ID): 10.1371/journal.pone.0003547
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Over the past ten years, the investigators have seen a rise in patients with hyperferritinemia (high blood ferritin) -- excess iron in the blood. A certain amount of this is to be expected given the increasing awareness of hereditary hemochromatosis -- a genetic condition in which the blood retains an overload of iron. High blood ferritin is also seen in cases of inflammation and in cancer. Over the same period, there has been an increase in patients whose high ferritin levels cannot be explained by these conditions. Most of these patients are overweight, middle-aged men.

Previous research suggested links between elevated ferritin levels and non-alcoholic fatty liver disease (NASH -- in technical terms, non-alcoholic steatohepatitis), and between high ferritin and insulin resistance. Both NASH and insulin resistance are often seen in patients with metabolic syndrome. The authors chose to examine this possible link in more detail.

They examined forty consecutive patients referred to them for hyperferritinemia. After examination, 34 patients remained with unexplained hyperferritinemia -- 1 woman and 33 men. Fasting blood samples were taken and analyzed for iron, liver enzymes, c-reactive protein (a marker for inflammation), and c-peptide (a marker for insulin production). Liver biopsies were obtained for 29 of the patients, and liver iron stores were assessed for 16 of them.

The majority of the patients had either markers for metabolic syndrome, or could be clinically diagnosed as having metabolic syndrome, showing increased body mass index, elevated diastolic blood pressure, and insulin resistance. Nineteen of the 29 patients biopsied had steatosis (fatty livers). Only four patients showed increased levels of iron in their livers -- of which two could be explained by alcohol consumption. Ferritin levels were higher in subjects with insulin resistance than in those without.

Fourteen of 16 patients normalized ferritin levels after phlebotomy (removal of an amount of blood -- a standard medical procedure for persons with hemochromatosis), but after a while, their ferritin levels rose again. Those who changed lifestyle (diet and exercise) -- first-line therapy for patients with metabolic syndrome -- had stabler ferritin levels. Since NASH is often seen in obese patients and in patients with metabolic syndrome, this evidence supports the theory associating NASH with increased ferritin levels.

These observations suggest that fatty livers and insulin resistance, but not increased iron storage in the liver, may be frequently seen in patients referred to specialists because of high ferritin levels. The authors conclude that ferritin levels seem to be higher in people with insulin resistance and suggest that high ferritin levels are markers of metabolic syndrome with NASH and insulin resistance, rather than iron overload.

Reliability:
There were very few subjects examined in this study, and no indication of how common this complaint is within the population affected by insulin resistance and/or metabolic syndrome. Because of this, there is a possibility of skewed data.

The tests support previous research, adding information to the existing body of knowledge and suggesting directions for further research.

The authors are associated with accredited medical institutions and the article is published in a peer-reviewed journal.

Practical Applications:
Understanding the entire extent of physiological changes associated with metabolic syndrome can help doctors and pharmacists better understand both metabolic syndrome in general and how best to treat the individual patients.

While the population studied is small, it supports our understanding that lifestyle management -- maintenance of a stable, healthy weight through diet and exercise -- is of vital importance for maintaining or improving our overall health.

Ethics note: All patients gave oral consent to the examination program and to the use of clinical data for research purposes.

This synopsis was based on the entire article.

Mediterranean Diets: low-carb versus low glycemic load

Spanish Ketogenic Mediterranean diet: a healthy cardiovascular diet for weight loss
Original source: Nutrition Journal 2008, 7:30
Authors: Joaquin Perez-Guisado (corresponding author), Andres Munoz-Serrano, and Angeles Alonso-Moraga
Publication date: 26 October 2008
DOI (digital document ID): 10.1186/1475-2891-7-30
Requires subscription? No
Publicly-available abstract: Yes

Enhancement of a modified Mediterranean-style, low glycemic load diet with specific phytochemicals improves cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia in a randomized trial
Original source: Nutrition & Metabolism 2008, 5:29
Authors: Robert H Lerman (corresponding author), Deanna M Minich, Gary Darland, Joseph J Lamb, Barbara Schiltz, John G Babish, Jeffrey S Bland, and Matthew L Tripp
Publication date: 4 November 2008
DOI (digital document ID): 10.1186/1743-7075-5-29
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Both of these studies looked at variants of the Mediterranean Diet, followed over a period of 12 weeks (three months). The Spanish study emphasized the use of virgin olive oil as the primary source of dietary fat, green vegetables and salads as the primary source of carbohydrates, and fish as a primary source of protein. The US study is a follow-on to a previous study comparing a low-glycemic-load Mediterranean diet with added soy protein and phytosterols (plant-based fats) to the American Heart Association's diet plan. In this study, the diet is supplemented with plant-derived substances (phytochemicals) that they believe will improve insulin sensitivity and reduce cardiovascular and metabolic risk factors.

In the Spanish study, 31 obese people (BMI approximately 36) in their mid- to late-thirties were studied. They were not given caloric limits, but their diets included approximately 2 tablespoons of virgin olive oil (2 teaspoons per meal), 1-2 glasses wine daily (half at lunch and half at dinner),
green vegetables and salads to a maximum of 30 g carbohydrate per day, and unlimited protein. Non-nutritive sweeteners were allowed on this diet. Protein was divided into "fish" and "non-fish" (meat, fowl, eggs, shellfish and cheese), with "fish" and "non-fish" being consumed on separate days, and at least four "fish days" per week. In addition, subjects were allowed up to two cups of coffee or tea per day, and required to drink at least three liters of water per day. The subjects were given a standard multivitamin-and-mineral supplement and a calcium supplement; they were also asked to check their urine for ketones using ketostrips.

• Results: After 12 weeks, the subjects lost about 14 kg (30-35 lb), lowered their blood pressure (by about 15 points (millimeters mercury) systolic and 9 points diastolic), lowered their total cholesterol about 10%, significantly dropped their triglyceride levels (from about 218 down to 114 mg/dl), and reduced their fasting blood glucose level about 16 mg/dl. In addition, LDL ("bad") cholesterol levels dropped about 8%, and raised their HDL ("good") cholesterol about 9%. While the subjects were not heavy enough to have moved from "obese" to "overweight" in this time frame, the measured changes moved the patients' statuses from "prehypertension" to "normal blood pressure", from "prediabetic" to "normal", and from "high cholesterol" to "normal cholesterol". Based on the factors used to diagnose it, these subjects would be considered to no longer have metabolic syndrome. The researchers did not measure the beginning and ending percentages of body fat versus muscle mass, but their visual observation suggests that the weight lost was primarily fatty tissue.
• Limitations: The study had a number of limitations, including small size, short duration, highly-selected population, no measurement of total caloric intake, and the possibility that weight loss alone, as well as any of the factors of the program -- either by itself or in combination with others -- may have accounted for these changes. The authors suggest further study with a larger group of people, for a longer period of time, and also comparison with other low-carb diets.

The US researchers' initial viewpoint is that modern diets induce tissue inflammation, resulting in metabolic syndrome. They state that a number of active ingredients in medicinal plants target the pathways of this inflammation, and believe that the addition of these active agents to a low-glycemic-load adaptation of the Mediterranean diet can assist the body in repairing this damage. The US study included 49 patients with metabolic syndrome, average age 53 years, average BMI approximately 34. All subjects had high LDL cholesterol and triglycerides, and had at least two of the other signs used to diagnose metabolic syndrome (low HDL cholesterol, stage I hypertension or drug-treated hypertension, large waist size, and impaired fasting glucose. Half were put on a modified Mediterranean diet alone; the other half were put on the modified diet with the inclusion of phytochemical supplements. The two groups were split out in a way to minimize the initial differences between them.
In this version of the Mediterranean diet, wine was limited to 1 glass per day. Whole grains were allowed, but only one serving per day. Vegetables were mostly limited to very low glycemic load vegetables, with a maximum of one "occasional" serving of a small category of
phytochemical-rich vegetables with a moderate glycemic index (55-70). The only sweeteners allowed were stevia and low-glycemic agave nectar syrup.
The group receiving phytochemical supplementation received a nutritional supplement beverage (powdered) and supplement tablets. All subjects were required to engage in moderate aerobic exercise (at 70-75% target heart rate) for at least 2.5 hours per week. Food cravings, as well as food intake and satiety levels, were monitored (patient-generated logs and surveys). The results were analyzed, accounting for the effects of weight loss, consuming fewer calories, and consuming lower levels of carbohydrate.

• Results: At the end of 12 weeks, the diet-alone subjects lost about 5.7 kg (about 12.5 lb), and the supplemented group about an extra half-pound. While both groups showed lowered total cholesterol, LDL, and triglycerides, the group receiving the supplements saw greater reductions in these readings. Only the group with the supplements had increased HDL cholesterol. The group receiving the supplements were able to lower both systolic and diastolic blood pressure by about 6 points, while those receiving diet alone were only able to lower their systolic blood pressure, by about 4 points. Hemoglobin A1c (HbA1c), a measure of long-term blood glucose levels, went down in both groups, but fasting blood glucose did not drop in the group receiving supplements. Twice the number of subjects in the group receiving supplements were able to move from "having metabolic syndrome" to "normal".

Reliability:
The authors in the Spanish study are associated with the Genetics department of the University of Cordoba and do not report any conflicts of interest. Their bibliographic references are from peer-reviewed journals, mostly in the realm of nutrition.

The authors in the US study all work for the MetaProteomics, a research subsidiary of Metagenics, a company which produces and sells dietary plans, including a number of dietary supplements and meal replacement formulas, which it states will improve the health, weight,
and longevity of people with metabolic syndrome and cardiovascular disease. The MetaProteomics subsidiary is aimed at research into human proteins and how specific chemicals in foods are used by the human body. The bibliographic references are from peer-reviewed journals, and their source research is aimed more at finding the causes of cardiometabolic disease as well as specific chemicals that might lessen the probability of developing these diseases. As employees of a subsidiary of Metagenics, the authors' research is aimed at developing new products (both diets and supplements) for Metagenics to sell.

Both studies are limited in small sample size over short amounts of time; additionally, the Spanish study considers fewer variables.

There are significant differences in the two low-glycemic/low-carb "Mediterranean diets" studied: the Spanish study centers on healthy proteins and fats, while the US study aims more at trying to determine the effect of an anti-inflammatory diet and of the phytochemical
supplements the company sells.

Practical Applications:
Both versions of "Mediterranean diet", unsupplemented, showed favorable changes in cholesterol levels and blood glucose levels. The Spanish study showed greater changes in weight loss, blood pressure, triglycerides, and HDL cholesterol than the US study including supplements; however, the limitations of both studies does not indicate how effective either diet is at maintaining long-term health, or how safe they are over long periods of time.

Any highly-restrictive diet has its limitations, and even some less-restrictive diets may not be suitable for your personal medical conditions. Please consult your doctor and nutritionist before making any large-scale changes to your diet.

This synopsis and comparison was based on the full articles.

Are adverse effects of some diabetes drugs related to their suppression of sex hormones?

Are the adverse effects of glitazones linked to induced testosterone deficiency?
Original source: Cardiovascular Diabetology 2008, 7:30
Authors: M. Carruthers (corresponding author), T. R. Trinick, E. Jankowska, and A.M. Traish
Publication date: 15 October 2008
DOI (digital document ID): 10.1186/1475-2840-7-30
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors pose a theory that the various adverse effects of diabetes drugs in the class called "glitazones" -- including rosiglitazone (RGZ -- brand name Avandia) and pioglitazone (PGZ -- brand name Actos) -- may be related to a separate known action of these drugs -- their suppression of sex hormones. These side effects include heart disease, swelling, weight gain, and anemia.

Glitazones act on sex hormones by reducing the levels to which they are released and by making the body less sensitive to them. These sex hormones are responsible for directing new cell growth to become blood vessels, skin, muscle, and other types of structural cells, rather than fat cells. This might give further weight to an existing theory of how obesity might cause diabetes (called "Ungar's theory of the 'Lipocentric Pathway to Hyperglycemia'"(1)). The authors note evidence that low testosterone levels in men can cause a number of the same side effects that are being observed in diabetes patients treated with glitazones; furthermore, that diabetes and/or cardiovascular disease are often seen to develop where testosterone production has been suppressed in order to treat prostate cancer. Much of this can be tied to the abdominal weight gain related to low testosterone levels. Treatment with testosterone in these cases has been shown to reduce the side effects and lower the statistical occurrence of cardiovascular disease among patients showing a number of these metabolic symptoms.

The authors note a number of known effects of rosiglitazone and troglitazone (Resulin, which has been removed from the US market) on sex hormones and on the development and maturation of new body tissues.

The authors suggest that this hypothesis might be tested by double-blind, placebo-controlled clinical studies examining the endocrine profiles, and levels of sex hormones, in people with Type 2 diabetes both before and while/after being treated with a glitazone. Additionally, studies on treating diabetic men with testosterone might show us whether this might counteract (or at least lessen) the adverse effects of glitazones. They also suggest further research into exactly how glitazones inhibit sex hormones.

Reliability:
The authors are associated with a number of universities and medical research institutes throughout the world. The hypothesis was published in a peer-reviewed journal. The authors are posing a theory, rather than a statement of fact, and suggesting ways that others could determine whether or not their theory is correct.

Practical Applications:
If the theory is correct, and if administering testosterone to men can completely counteract the adverse effects of Avandia and similar medications, that would make Avandia a relatively safer choice to treat Type 2 diabetes than it is now.

For further reading:
(1) Roger H. Unger, MD Reinventing type 2 diabetes: pathogenesis, treatment, and prevention. Journal of the American Medical Association (JAMA), 2008;299(10):1185-1187.
Full text requires paide subscription.
First 150 words available free.

"Evidence-Based Medicine", Patient Pages, Journal of the American Medical Association (JAMA)

This synopsis was based on the entire article.

Is Uric Acid level a risk indicator?

Uric Acid and Cardiovascular Risk
Original source: New England Journal of Medicine Volume 359 — October 23, 2008 — Number 17
Authors: Feig (corresponding author), D. I., Kang, D.-H., Johnson, R. J.
Publication date: October 23, 2008
DOI (digital document ID): (not available)
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
The original publication is a review article: it summarizes a number of previous publications concerning uric acid (a waste product that our blood carries to our kidneys for excretion) and possible links to high blood pressure (hypertension), diabetes, metabolic syndrome, kidney disease, and cardiovascular disease.

The authors note that the average levels of uric acid in the blood have been rising, along with our risks of these diseases. This does not necessarily mean that one or more of these diseases cause uric acid levels to rise, or that high uric acid levels raise the risk of developing cardiovascular disease, kidney disease, diabetes, metabolic syndrome, etc.

The authors examine research in which uric acid levels are examined in the cases of people and test animals with kidney disease, hypertension, metabolic syndrome, and kidney disease. Some observations include the possibility that high consumption of fructose is a factor in increased uric acid levels, and that increased uric acid levels may be partly responsible for the development of hypertension, insulin resistance, and weight gain. High uric acid levels may also be a factor in, or a result of, impaired kidney function.

In all of these cases, lowering uric acid levels -- particularly with the drug allopurinol -- seems to alleviate the symptoms of the other conditions. However, these studies were conducted in small, specific groups of people and animals. The researchers are not sure that this is necessarily from lowering uric acid levels rather than specifically from the use of allopurinol (other drugs to lower uric acid levels did not provide as dramatic results). They note that allergy or sensitivity to allopurinol can be fatal, so it's not necessarily a drug of choice. They state that more research needs to be conducted -- both on the whole-body effects of uric acid levels and of possible alternatives to allopurinol.

Reliability:
Review articles are based on taking previously-published research and examining it in a new light. Sometimes this means taking small studies from a lot of different groups and compiling or comparing them; sometimes it means creating a general overview of a topic. In this case, the authors reference a number of publications (follow the links in the "References" list) and their conclusions, come up with a theory (that high blood levels of uric acid may be the cause of other metabolic diseases), and point this out as something that needs further testing to prove whether this is true, or just coincidence.

Practical Applications:
Uric acid is one of the items measured in a standard "metabolic panel" blood test -- the blood test most of us get every time go to the doctor for a check-up. It is one of the waste products that is processed by our kidneys into urine. High uric acid levels have been associated with gout, which -- like metabolic syndrome -- is one of many conditions that are associated with obesity. If researchers can prove a definite cause-and-effect relationship between high uric acid levels and other metabolic conditions, it may give doctors another set of tools to improve the health of some people with cardiovascular disease, diabetes, and/or metabolic syndrome.

This synopsis was based on the CME version of the complete article.

Metabolic syndrome increases risk of heart attack and stroke

Effect of metabolic syndrome or type II diabetes mellitus on the occurrence of recurrent vascular events in hypertensive patients
Original source: Journal of Human Hypertension (2008) 22, 358–365
Authors: A L M Vlek, Y van der Graaf, W Spiering, F L J Visseren (corresponding author), SMART study group
Publication date: published online 14 February 2008
DOI (digital document ID): doi:10.1038/jhh.2008.5
Requires subscription? Not for this article
Publicly-available abstract: Yes

Synopsis:
People with high blood pressure and vascular disease (diseases of the blood vessels) are at increased risk for recurrences of vascular disease, and for developing additional cardiovascular diseases such as heart disease, stroke, peripheral artery disease, and aneurysms. This study aims to find out whether having metabolic syndrome, and/or Type 2 diabetes, increases those risks even further.

Over 2000 people who were part of the Second Manifestations of Arterial Disease study (SMART) were followed for up to 10 years afterward for death, strokes, and heart attacks. These were used to calculate the risks of cardiovascular disease for people with high blood pressure only, for high blood pressure and metabolic syndrome, and for people with high blood pressure and diabetes.

Of this group, patients with metabolic syndrome (but without diabetes) had higher rates of stroke, heart attack, and sudden deaths related to cardiovascular issues. Patients with Type 2 diabetes had even higher risks than those with metabolic syndrome (but without diabetes). The increased risk of people with metabolic syndrome was not explainable by diabetes.

Further lowering of blood pressure did not seem to reduce the increased risk of heart attack and stroke in patients with metabolic syndrome.

Because people with metabolic syndrome have been shown to have higher risk of cardiovascular disease, investigators suggest more attention should be paid to diagnosing metabolic syndrome and treating it aggressively.

Reliability:
A large number of people were observed over a relatively long period of time. The authors work in a university medical center. The research was published in a peer-reviewed journal. The results should be relatively reliable.

Practical Applications:
Patients and healthcare providers should pay more attention to identifying the signs of metabolic syndrome and treating it with diet, exercise, and drugs (where appropriate).

Health insurance and life insurance actuaries will want to account for this relationship in their risk tables when determining coverage and premiums.

This synopsis was based on the entire article.

Metabolic syndrome increases risk of heart disease and diabetes

Metabolic syndrome risk for cardiovascular disease and diabetes in the ARIC study
Authors: C M Ballantyne (correpsonding author), R C Hoogeveen, A M McNeill, G Heiss, M I Schmidt, B B Duncan and J S Pankow
Original source: International Journal of Obesity Volume 32, Supplement 2, pp. S21-S24
Publication date: May, 2008
DOI (digital document ID): doi:10.1038/ijo.2008.31
Requires subscription? Not for this article
Publicly-available abstract: Yes

Synopsis:
The investigators studied over 15,000 middle-aged Americans in four communities for a period of approximately ten years to try to determine the role of metabolic syndrome in the development of cardiovascular (heart and artery) disease and diabetes. The particular study is called Atherosclerosis Risk in Communities (ARIC).

Metabolic syndrome is diagnosed by the presence of three or more of the following characteristics: waist circumference greater than 40" in men or 35" in women; high triglycerides (over 150 mg/dl); low HDL or "good cholesterol" (less than 40 mg/dl in men or 50 mg/dl in women); high blood pressure (over 130/85 mm Hg); and high fasting glucose levels.

The investigators studied the numbers of those with and without metabolic syndrome to determine how much greater a risk someone with metabolic syndrome has of developing atherosclerosis, heart disease, stroke, or diabetes.

• ARIC participants who had metabolic syndrome were two to three times more likely to have coronary heart disease than those without, with the highest additional risk in black men and white women.
• The walls of the carotid arteries of persons with metabolic syndrome were about 5% thicker than those without.
• The increased risk of stroke for those with metabolic syndrome was an additional 35-40 cases per 10,000 person years.
• Of those participants with three or more indicators of metabolic syndrome, who did not have diabetes, those with obesity and/or elevated fasting glucose levels had significantly increased risk of developing diabetes.

Reliability:
This is a large study, conducted over a long period of time, and the article was published in a peer-reviewed journal. Both this, and the academic credentials of the authors, result in high levels of confidence in the results.

Further reading:
More information on the design of the ARIC study and publications based on information collected during the study can be found at the ARIC home page.

This synopsis was based on the entire article.