Hyperferritinemia

The measurement of serum ferritin is a laboratory test high demand for judging martial status. It makes it possible both to learn about the existence of a deficit in iron (hypoferritinémie) and that of an overload (hyperferritinemia).

The interpretation of an increase in serum ferritin levels, however, goes beyond the framework of excess iron and thus assumes a relevant analysis by the prescribing physician.

DIAGNOSIS:

Definition:

Ferritin is a protein like an eggshell can store iron in it, which makes the storage protein of excellence by iron, especially in hepatocytes and macrophage system (hepatosplenic).

But ferritin is also a protein of the inflammatory response, increasing production by macrophage activation situation.

These two functions, tissue iron storage and expression of inflammation, are the two main areas which may be reported pathophysiological hyperferritinemia.

Three other mechanisms may explain hyperferritinemia:

– Cell lysis, liver or muscle;

– An induction of the synthesis of ferritin by alcohol;

– Deregulation of ferritin synthesis due to mutations in the gene of ferritin.

Do not ignore a moderate hyperferritinemia:

Due to the extent of the normal range indicated by the analytical laboratories, with upper limits of normal in the order of 300-400 g / L in men and 200-300 mcg / L women, there is a risk of underestimating real hyperferritinemia when figures rub the top of this range slope. Thus, in women, the normal value is about 30 g / L before menopause and rises gradually to 80 on average after menopause.

This means that a rate of 200 can correspond, in women, a hyperferritinemia quite significant.

ETIOLOGY:

Hemochromatosis “classical” HFE:

In the absence of clearly suggestive context, the joint of the elevation of the saturation level of transferrin which constitutes the orientation determining element. Since, in hemochromatosis, elevated serum ferritin already constitution means a tissue excess iron, the saturation level of transferrin will always significantly high, usually ≥ 80%.

The confirmation of the diagnosis of hemochromatosis is therefore based mostly on the positive genetic test: C282Y mutation present in the homozygous state for asserting HFE hemochromatosis. The degree of elevation of ferritin is in this situation a great reflection of the degree of excess iron (in the absence of associated factors that could interfere in the increase, such as alcohol and / or a polymetabolic syndrome) : There was indeed in hemochromatosis a very good correlation between serum ferritinemia and liver iron concentration, which also explains that the monitoring of ferritin is the basis for monitoring the effectiveness of treatment with phlebotomy. In this context HFE, a composite profile heterozygosity (C282Y / H63D) can sometimes be the cause, but in general, the rate of hyperferritinemia is moderate (except elevation cofactors).

It should be noted that the negativity of genetic test does not exclude other two types, exceptional, of hemochromatosis:

– Juvenile hemochromatosis, by mutating the hemojuvelin (chromosome 1) also known as type 2 hemochromatosis or mutation of hepcidin (chromosome 19); juvenile hemochromatosis should be suspected whenever the patient is under the age of 30;

– Iron overload by mutation of the gene transferrin receptor type 2 (chromosome 7), sometimes called hemochromatosis type 3.

Dysmetabolic Syndrome:

Hyperferritinaemia Dysmetabolic is now the most common differential diagnosis of hemochromatosis: Hemochromatosis many erroneous diagnoses are in practice brought before typically frank hyperferritinemia (of the order of 600-1 000) which often leads the doctor to ask wrongly (that is to say without first checked the saturation of transferrin) HFE genetic testing, which mark such a simple C282Y heterozygosity (or H63D heterozygosity), these genetic results being mistakenly viewed as supporting the diagnosis of hemochromatosis … Moreover, it is not uncommon for a liver ultrasound monitoring is carried out and that his “liver overload” finding is considered diagnostic more argument, while c ‘ is a fat overload in question (the excess iron can never be detected by ultrasound guidance).

In fact, it is essential to remember that:

– The genetic test should be requested only after ensuring that there has elevation of transferrin saturation (≥ 45%, particularly ≥ 60% in men and ≥ 50% in women );

– The HFE hemochromatosis can not be held liable for hyperferritinemia without joint elevation of transferrin saturation (the only exception is the fortuitous coexistence of a marked inflammatory syndrome which not only increases the ferritin levels but decreases or normalizes serum iron and that of the transferrin saturation);

– A simple state of C282Y heterozygosity (let alone H63D) can never be held responsible for a significant increase in serum ferritin.

The only caveat is represented by reported cases of exceptional compound heterozygosity whose associated mutation C282Y is not H63D (thus giving the impression, given the outcome of routine genetic testing of C282Y heterozygosity “simplex “); but in such cases the transferrin saturation is frankly high, which is now seen in a setting that can not be a heterozygous C282Y.

Hyperferritinaemia Dysmetabolic stands out from the hyperferritinemia hemochromatosis by the following:

– The transferrin saturation is normal;

– Hepatic excess iron is in good standing very moderate (little more than 2 to 3 times the upper limit of normal in terms of liver iron concentration), highlighting the disproportionate nature in this syndrome, the hyperferritinemia compared to hepatosiderosis, which raises the problem of its pathophysiology might take more of macrophage activation that iron overload;

– There is of course a polymetabolic field, combining overweight, hyperlipidemia, non-insulin dependent diabetes, hypertension, hyperuricemia …

It goes without saying that when a genuine hemochromatosis is associated with a Dysmetabolic syndrome, its biological profile can be modified as with higher hyperferritinemia than would be the degree of excess iron.

Other causes:

Common causes:

Cytolysis:

It may be:

– Hepatic origin: whether acute hepatitis (especially) or chronic, hyperferritinemia can then be accompanied by a degree of hypersidérémie and elevation of transferrin saturation ( especially if there is associated with liver failure); hence the importance of coupling to ferritin control of transaminases (ALT and AST)

– Of muscular origin: cardiac or peripheral myolysis (rhabdomyolysis), hence the usefulness of joint control of muscle enzymes (creatine phophokinase, aldolase).

General inflammatory syndrome:

The hyperferritinemia is usually moderate (less than 500 mg / L) and is accompanied by hyposideremia (and a decrease in transferrin saturation). Therefore important to check the level of protein C-reactive before any hyperferritinemia.

Chronic alcoholism:

Hyperferritinemia (sometimes greater than 1000 mg / L) is in the chronic alcoholic observable in the absence of any cytolysis and iron overload (due to the ferritin synthesis stimulation by alcohol), associated in half of the cases to hypersidérémie.

After weaning, iron normalizes in less than a week as the decrease in ferritin is slower to stabilize after three months of abstinence.

Rare or exceptional causes:

Two of these cases are accompanied by visceral iron overload, the other not.

Situations with iron overload:

Hereditary aceruloplasminemia:

His presentation is readily hematologic as sluggish trend that evokes bleeding by the conjunction of hyposideremia and a decrease in transferrin saturation but comes with so totally unexpected for such supposed mechanism of a free hyperferritinemia.

He joins in neurological atmosphere (sometimes not expressed) and the diagnosis is based on the collapse of serum ceruloplasmin levels. This translates hyperferritinemia an often significant iron overload whose mechanism is defective cell output of iron (not a hyper-entry as in hemochromatosis HFE).

Ferroportin mutation:

This entity, newly identified, is associated with a mutation of a protein involved in particular in the output of the iron from the macrophage cells. Three characteristics allow the clinician to evoke:

– Serum biological profile is particular since mark in the absence of any inflammation and any aceruloplasminemia, by high elevated ferritin (sometimes very much greater than 1000 mg / L) contrasting with the normality or very moderate increase in transferrin saturation levels;

– Transmission type is dominant, so that a net hyperferritinemia is frequently observed in siblings and children;

– The tolerance of phlebotomy is poor due to a net anemic trend.

Histologically, the hepatic iron overload is very marked, and the difference of the HFE hemochromatosis, predominantly affects the macrophage cells (Kupffer cells).

Situations without visceral iron overload:

Gaucher disease:

During this thesaurosis macrophage, hyperferritinemia, of the order of 1 000-2 000 mg / L, is a common sign. Think about it especially when the serum hyperferritinemia without hypersidérémie or elevation of transferrin saturation is accompanied by splenomegaly.

Hyperferritinemia-cataract syndrome:

The trap is constituted by the family nature of hyperferritinemia, sometimes achieving phlebotomy “for hemochromatosis” in some family members. In fact, these phlebotomy are found to have been very poorly tolerated (with development of anemia), iron and saturation are normal, and the diagnosis is usually obtained by a simple examination oriented towards family ophthalmic history.

Sometimes, however, the personal history and / or family, may not be “talking” and it is then appropriate to ask an eye test that can discover a small cataract previously unsuspected clinically.

Viral macrophage activation syndrome:

In particular an infection by the Epstein-Barr virus or Herpes virus, an important hyperferritinemia can be observed.

Other conditions:

A major hyperferritinemia (> 10,000 mg / L) is an organic brand Still’s disease. Moderate hyperferritinemia, uncertain mechanism can be observed during the course of hyperthyroidism and malignant, visceral and hematological diseases.

TREATMENT HEMOCHROMATOSIS HFE:

The treatment of hemochromatosis HFE based on phlebotomy. The grooves are first weekly or fortnightly, removing a volume of 7 mL / kg of blood, which until now could not be used for transfusion. The pace is slowed down when bloodletting ferritin approach 300 mg / mL. The objective is to maintain serum ferritin close to 50 mg / L, with maintenance bled every 4 to 12 weeks depending on the case. There is no need to monitor the saturation of transferrin; but we must of course monitor blood counts prior to each bleeding to ensure that the patient is not anemic. The grooves are in principle in a French institution of blood (EFS) during a simple consultation, but day hospitalization is necessary for patients with heart disease (especially if restrictive heart disease hemochromatosis).

CONCLUSION:

In total, the pivot of hyperferritinemia diagnosis is the evaluation of the transferrin saturation if saturation is high, there is almost always an HFE hemochromatosis (provided there is no major cytolysis liver or muscle origin); if the saturation is normal hyperferritinemia can translate:

– In the context of common diseases: inflammatory syndrome or polymetabolic syndrome;

– Under rare conditions without iron overload: Gaucher disease or ferritin-cataract syndrome;

– In the context of rare diseases with iron overload: a hereditary aceruloplasminemia or mutation in ferroportin.