HIGH FERRITIN - to understand once and for all (by Dr. Leandro Minozzo)

Excellent text by Dr. Leandro Minozzo, original in full at http://www.leandrominozzo.com.br/blog/?p=558

(Posted in  June 29, 2013 - I recommend you visit the site and follow it)

“A clinical and nutrological approach to an increasingly common problem that causes a lot of concern, especially among middle-aged men.

It's not one, two or three patients who seek medical attention frightened after opening the envelope with their laboratory test results and finding a high ferritin level. Many, even on their own, arrive with a restrictive diet, demonizing poor beans, lentils and, of course, red meat. “Doctor, I haven't eaten barbecue for two years because of this ferritin!” - a man told me the other day. It sounds simple, but imagine the fear the result caused him; after all, we're in Rio Grande do Sul and a barbecue every now and then is almost necessary. It even sounds like a fad or a new pandemic, given the number of people who have the change. But what is behind this high ferritin value? Does the patient necessarily need to stay away from iron-rich foods? Where is the danger? Is bloodletting always indicated? Let's go. I'll try to clear up some doubts, reassure you as much as possible and advise you that the best course of action is to take your medical follow-up calmly, step by step, in other words - keep this in mind - in stages.

I'll start by defining what ferritin is and what its functions are - this understanding is fundamental to understanding the message I want to convey today. Ferritin is a protein produced mainly by the liver, whose basic functions are to carry iron and mediate the inflammation process. As it is involved in iron transportation, it is natural that there should be a proportionality in the protein's levels with those of the mineral. For this reason, one of the clinical uses of the test is, for example, in assessing iron reserves in patients with anemia or in situations at risk of iron deficiency, such as children and pregnant women; low ferritin levels in these cases indicate low iron reserves.

As for the question of the presence of an acute or chronic inflammatory process or activation of the immune system, as with other biochemical markers, ferritin rises - in other words, when we are dealing with flu, pneumonia, cancer, gastroenteritis and even a simple cold, the levels rise rapidly. In these cases, ferritin production can even triple without there being any increase in the body's iron content. Other conditions that lead to an increase in this marker are alcoholism and liver diseases, such as cirrhosis, hepatitis and steatosis - the all-too-common accumulation of fat in the organ. Also causes of hyperferritinemia (high ferritin) are the increasingly common obesity and metabolic syndrome (a combination of visceral fat accumulation, insulin resistance, high blood pressure and changes in cholesterol and triglyceride levels). To make this issue of the causes of elevated ferritin clearer, I bring you a recent Australian study, pointing out that only 10% of the cases of elevated ferritin are associated with iron overload - all those other diseases I've just mentioned account for 90% of the cases. (Read that last sentence again!)

Here are two important points: (1) other conditions increase ferritin and, therefore, (2) this increase doesn't always mean iron overload - a condition that isn't that common.

I then move on to the second question, about immediate changes in eating habits. There is no need to restrict iron-rich foods after opening the test envelope and finding a high ferritin level. This is because it is not a definitive test for diagnosing excess iron. Before changing the diet, an altered result should lead the patient and their doctor to a careful, step-by-step investigation. Once again, I would like to stress the need for this investigation to be organized in stages, so as to avoid rash decisions, errors in diagnosis and unnecessary bloodletting or diets.

Initially, a question should be raised and answered: was the patient suffering from an inflammatory condition (a cold or arthritis in the knee, for example) when the test was carried out, or could a chronic illness be causing this increase? It is always advisable to repeat the test, advising patients to go three days without drinking alcohol and not to exercise intensely the day before. If the ferritin level is high again, and in order to deepen this analysis, in addition to the anamnesis (clinical interview) and physical examination, the doctor can order other fairly simple tests, such as transferrin saturation, ultrasensitive C-reactive protein and ESR. The former is more reliable in detecting iron overload and should always be ordered, while the latter are related to the body's inflammatory state. To illustrate and make things easier to understand, that man who hadn't eaten a barbecue in two years had high ferritin and C-reactive protein, but low transferrin saturation (<30%), so he didn't have iron overload and wouldn't need to undergo any dietary restrictions.

And what is the danger of an “elevated ferritin” laboratory result and excess iron?

In recent years, research has shown the negative impact of iron overload and its consequent accumulation of free radicals on the functioning of various organs and the development of degenerative diseases. At a glance, I would highlight damage mainly to the liver, heart and blood vessels, joints, glands such as the thyroid, pancreas and testicles. These degenerative diseases include atherosclerosis (fatty build-up in the arteries), diabetes and Alzheimer's disease. There is also an increased risk of developing certain cancers and premature ageing. Molecular biology studies show that excess iron reduces the length of leukocyte telomeres - a marker of accelerated ageing.

There are several factors motivating this recent research, including the increasing number of patients with excess iron.

As for the problem itself, it is initially a mathematical question of the imbalance between the intake and elimination of the mineral. In order to function well, an adult male needs around 8 mg of iron a day, of which he absorbs just over 10%, while the Western diet offers around 6 mg for every thousand calories consumed, or around 18 mg in a common 3,000 calorie diet. Unlike other minerals, iron is easily absorbed by the digestive tract and, on the other hand, is more complicated to eliminate, basically by flaking off the intestinal wall. We are better at absorbing than eliminating iron from our bodies. Some people have genetic characteristics that predispose them to absorbing iron even more easily and others consume foods that also enhance the absorption of the metal, such as excess saturated fat.

Speaking of genetics, there is a reasonably rare and predominantly asymptomatic disease called Haemochromatosis - its prevalence varies between 1 case in 200-500 adults in the USA - which is characterized precisely by the ease with which the mineral accumulates (2-3 times more) and which, when left untreated, can lead to other problems such as cirrhosis (25% of those affected) and liver cancer, joint deformities, heart disease, hypothyroidism, diabetes and hypogonadism - which means low levels of sex hormones. The diagnosis is made through blood tests, including a genetic test for the C282Y and H63D mutations, imaging tests (magnetic resonance imaging) or even a liver biopsy. With the diagnosis of hemochromatosis, or an iron overload - which can happen without the presence of the disease - bloodletting is not always the first course of action; it is dependent on the values found in the tests and the presence of lesions or the associated malfunctioning of some organ.

Iron overload is seen when:

• transferrin saturation is above 45%;

• presence of iron accumulation on liver biopsy or MRI (e.g. FerriScan or with protocols for this purpose) - this is because 90% of the body's iron is deposited in the liver;

• by quantitative phlebotomy (absence of anemia after 16 weekly “bleedings” - which is equivalent to removing at least 4 g of iron).

Because genetic testing is difficult to access (many health insurance plans don't cover it and it costs at least 280 reais), it is suggested that men use transferrin saturation as a screening test for the disease. A Norwegian study showed that two measurements above 55% have a sensitivity of 90% and specificity of 99.6% for finding the genetic alteration C282Y - typical of hemochromatosis. Of course, our population genetics and those of the Norwegians are very different and there is no similar research here, so this accuracy of transferrin saturation cannot be transferred to Brazilians. However, in patients with high levels of transferrin saturation, the indication of genetic testing takes on greater weight.

Returning to what to do, as has been shown, an investigation is needed to determine whether there really is excess iron, whether there is hemochromatosis and how the most commonly affected organs are. If indicated, therapeutic bloodletting (phlebotomy) is usually carried out in blood banks, on medical advice, and shows excellent results. Initially, excess iron is removed with several bleedings, after which 2 to 6 are performed annually for maintenance. In some cases, when the patient has no contraindications, even frequent blood donations can be indicated as a preventative measure to avoid iron overload. There are medications that reduce body iron, called chelators, but these are reserved for very specific situations.

The great danger of bloodletting (phlebotomy): the target may be wrong!

In the presence of iron overload and the patient being able to tolerate the withdrawal of blood, as we have seen, the indication for bloodletting is correct and useful. As for the dangers of treatment with phlebotomies, I would highlight the risk of developing anemia in people who don't have iron overload, the fear that some genetic disease runs in the family and the risks of venous injuries, such as wounds and phlebitis. However, the great danger of the wrong indication for bloodletting is that you miss the chance to intervene in another cause of increased ferritin other than iron overload - I'm referring to hepatic steatosis, obesity or hepatitis B or C, for example.

But then, if I have high ferritin and low transferrin saturation, don't I need to worry? The question of metabolic hyperferritinemia.

Yes, it does. Even when iron overload is not present, high ferritin should always be seen as a warning sign. Why? You're remembering that one of the functions of this protein is to be a marker of the inflammatory process, so something is wrong and you need to find out what it is. In addition, excess ferritin in this situation is associated with the risk of developing a dangerous disease: diabetes. Several recent studies have shown a link between high levels of this protein and an increased risk of the disease.

A Korean study, now from 2013, followed 2,000 men over 4 years. Those with high ferritin levels had a 2-fold greater risk of becoming diabetic. Two other meta-analysis studies, also this year, but from China and England, confirmed the same trend: a 1.6 to 1.7 times greater risk of developing diabetes in those with higher ferritin levels. This latest study, carried out by the University of Cambridge, analyzed 12 studies and a total of 185,462 participants.

Apart from the question of diabetes, researchers point out that a high level of the marker could indicate problems in the treatment of other diseases. In a study published this year, researchers suggested that ferritin could even influence the progression of breast cancer, through its involvement in inflammatory pathways. Also in relation to breast cancer, another recent study from 2012 showed that women with high ferritin levels (>250) before receiving chemotherapy had a worse response rate and a shorter survival.

As far as men's health is concerned, Chinese research from October 2013 showed an inverse relationship between ferritin levels and total and free testosterone levels, i.e. the higher the levels of this marker, the lower the hormone levels. The interesting thing is that this relationship, like that of insulin resistance, stimulates a vicious metabolic cycle, since secondary hypogonadism accentuates the findings of metabolic syndrome and hepatic steatosis, which further increases ferritin levels and may facilitate the appearance of iron overload. This overload, in turn, impairs the functioning of the testicles, leading to low testosterone levels. Well, I hope I haven't put anyone's mind at rest. The message is that scientific evidence will soon reinforce the high ferritin marker as a predictor of male hypogonadism (the so-called “andropause”) - which is not good, but not good at all!

In short, high ferritin is an important warning sign! It means something is wrong!

Iron, insulin, fatty liver and diabetes

Now I'm going to focus a little on how excess iron harms our health. Possibly, the changes in your metabolism lead to what we call insulin resistance - a phenomenon characterized not by a lack of the hormone, but by a difficulty in the cell receptors to “accept” it, which causes the pancreas to have to produce even more insulin. This is an early stage in the development of diabetes and is one of the characteristics of metabolic syndrome. Together, alterations in iron metabolism and insulin resistance favor the appearance of a common condition that has gained clinical importance in recent years: hepatic steatosis - the accumulation of fatty acids in the liver. Far from being an occasional finding on an ultrasound scan, this condition represents a health problem and is a marker for the development of problems such as statohepatitis, cirrhosis, high blood pressure, carotid plaques and diabetes.

Two other pathophysiological pathways, i.e. those that explain the onset of disease, also find a place in this relationship between high ferritin and diabetes: oxidative stress (remembering that excess iron facilitates the appearance of reactive oxygen species, or free radicals) and inflammation. These two processes act to perpetuate excess iron, increased ferritin levels, hepatic steatosis and the onset of diabetes. This is so true that one of the only ways to treat hepatic steatosis is to supplement with high doses of a powerful antioxidant, vitamin E at 800 U a day.

As for the relationship between excess iron and diabetes, it has become more evident with research proving that removing the metal is related to an improvement, which is always important, in markers of inflammation, insulin resistance and blood glucose levels and, above all, glycated hemoglobin, which is one of the main therapeutic targets in this disease.

Iron-containing foods aren't the only villains!

With regard to the nutrological aspects of excess iron, in many cases it is recommended to restrict your intake of the mineral, as well as taking care when using food supplements that may contain it, or that have vitamin C in their formula - remembering that this vitamin greatly facilitates the absorption of iron in the intestines. Among other measures, I'd like to mention the “digestive duo”: some research suggests that drinking coffee and green tea immediately after a meal containing iron reduces the absorption of the mineral. Foods rich in calcium, such as milk, can also have the same effect.

Recent research has shown, however, that it's not just the consumption of iron-rich foods that causes increases in ferritin. We now know that various metabolic conditions favor the liver's lack of control in dealing with the metal. Through the production of a hormone called hepcidin, the liver is among those responsible for this control. Hepcidin works by helping the body to reduce iron levels. A type of sugar, however, called fructose, impairs the functioning of the organ and leads to an increase in ferritin levels, uric acid, intrahepatic fat (inside the organ) and insulin resistance. This explains, for example, why people who don't consume large quantities of red meat have high ferritin levels - all they have to do is consume too many soft drinks, boxed juices, sweets, honey and fruit. Another major villain of healthy eating, corn syrup used in industrialized products, is also rich in fructose.

Another villain in this matter of damaging the liver in the way it deals with iron is the excess consumption of saturated fat (>7% of total daily calories). This is found in fried foods, frozen foods, cookies, ice cream and fast food in general.

Returning to the question of immediately restricting iron in the diet, there's no point in immediately cutting out meat or beans - they can even be an important ally when we propose a dietary re-education (they are rich in fiber and protein). One detail is that when eaten with red meat, the amount of iron from the beans is more easily ingested. I therefore recommend eating them away from meat. When done properly, nutrological advice needs to take into account various aspects of liver metabolism, food composition and very careful analysis of tests. Pay close attention to the next paragraph.

Diet for “Liver Fat” - I have organized nutrological principles for reducing ferritin when normal transferrin saturation (or what is called metabolic hyperferritinemia) is associated with hepatic steatosis:

• diet with no more than 7% of caloric value coming from saturated fat;
• low fructose content;
• carbohydrates with a low glycemic index;
• controlled level of sodium (1500 mg);
• at least 30 grams of fiber a day;
• adequate levels of PUFA, especially omega-3;
• control over the amount of iron ingested;
• insert green tea and plenty of calcium-rich foods;
• indication of the amount of protein in 1 gram per kg of weight per day;
• supplementation of vitamins E and D in the presence of hepatic steatosis or low levels of the latter;
• antioxidants if necessary;
• use of metformin when insulin resistance, pre-diabetes or diabetes;
• restriction on the consumption of alcoholic beverages (maximum of 1 dose per day);
• indication of aerobic and resistance exercises;
• use of substances such as silymarin, caffeine and turmeric according to medical assessment;
• do not use an iron pan.

Put the fear of high ferritin aside and go to your doctor for a more thorough assessment. Often the test can be repeated and come back normal or much lower. If in doubt, you can consult a hematologist - he or she is a specialist in blood disorders and can help define the diagnosis of hemochromatosis and the treatment to be given. Gastroenterologists, nutrologists and some clinicians with an interest in the subject can also help you. If you find it difficult to understand nutrological recommendations - I know that not all of them are easy - seek out a nutrition professional. In my opinion, a situation like this, when you have an altered test, is an excellent opportunity to get closer to your doctor and review various details that may be going unnoticed and will soon cause serious problems. Fortunately, science keeps giving us valuable signs to take care of ourselves, reconsider our routine and value our health. This is one of them: high ferritin.

List of complementary tests useful in the investigation of hyperferritinemia:

• total abdominal ultrasound (to detect hepatic steatosis);
• CBC, repeat ferritin, transferrin saturation, glycemia, glycated hemoglobin, insulin, tgo, tgp, gamma gt, HbSAg, anti-HCV, uric acid, lipid profile, total and free testosterone (or SHBG + albumin), estradiol (in men), TSH, free T4;
• FAN, genetic testing for hemochromatosis, liver biopsy, MRI to detect hepatic iron may also be of value, if necessary.

A big hug,

Dr. Leandro Minozzo - Nutrologist and General Practitioner

11 topics to take home:

1) High ferritin (between 300 and 1000) in most cases does not indicate excess iron;

2) There is a disease called Hemochromatosis that causes metal overload;

3) Various diseases increase ferritin: flu, colds, hepatitis, tumors and inflammation in general;

4) Three increasingly common conditions lead the reasons for high ferritin levels: diabetes, pre-diabetes and hepatic steatosis (fat in the liver);

5) Iron restriction is not always necessary when the ferritin level is altered;

6) Consumption of saturated fat and fructose (fruit sugar, soft drinks, corn syrup, honey and processed foods) also increases ferritin;

7) In some situations, therapeutic bloodletting (phlebotomy) and even blood donation every 3 months is indicated;

8 ) According to an Australian study, high ferritin is not related to excess iron in 90% of cases;

9) Another very useful test in cases of excess iron is transferrin saturation. Values above 45% indicate the need to repeat the test in 30 days; if the value remains high, genetic testing is indicated;

10) The wrong indication for bloodletting can obscure the diagnosis and treatment of other diseases.

11) A test showing high ferritin is a very serious indication that something is wrong with your health. There is a double risk of diabetes. See your doctor!

Please note: The explanations contained in this text and on the blog are not a substitute for consulting a doctor. I apologize to professionals who do in-depth research on the subject for having had to reduce complex concepts in order to bring them closer to the readers' understanding.

Read more:

Article on chronic inflammation (click herei)

Albert Einstein Hospital: http://www.einstein.br/einstein-saude/pagina-einstein/Paginas/hemocromatose-a-doenca-do-excesso-de-ferro.aspx; Int J Obes (Lond). 2008 Nov;32(11):1665-9; World J Gastroenterol. 2012 Aug 7;18(29):3782-6; Haematologica March 2009 94: 307-309; Full Text; Clin Nutr. 2012 Dec 28. pii: S0261-5614(12)00281-6, Diabetes Metab Res Rev. 2013 May;29(4):308-18.

http://www.bcguidelines.ca/pdf/hemochromatosis.pdf (British Columbia Medical Association guideline - Canada/2013)