In this situation I would be happy to make the diagnosis of hereditary haemochromatosis. The idea of treating patients with HH is to prevent iron overload rather than wait until they become iron overloaded. 

In this situation I will treated (and i treat them) as the C282Y homocigoty patients.

But in case of doubt, I will perform an abdominal ecography and T2* RMN.

Actualy there is no reason for liver biopsy, except the presence of malignant suspected mass

Thank you for your answers. Would you proceed differently if the patient would have a confounding factor such as an inflammatory state (for example, rheumatoid arthritis) or metabolic syndrome with a fatty liver on ultrasound? Both can raise the ferritin level.

Of course!

Ferritin is an strong inflammatory acute phase reactant.Hiperferritin is an sign and it is not synonimus of iron overload. In western developed countries fatty liver and hypermetabolic syndrome are the most frequent causes of hyperferrtinenmia and they both are nor associated with iron overload. In those situations, T2* NMR will help to screen.

Dr Alberg,

We all agree that a diagnosis of HH type1 is justified based on the compound heterozygous Y/D genotype and on the biochemical phenotype (elevated % sat. and ferritin).  For me, that justifies a deironization treatment aimed at first normalizing ferritin and second and foremost, at the permanent normalization of the % saturation which is the first to be affected during iron excess.  

In 2016, liver involvement should be considered a very late finding of HH and should only be of historical interest in our medical textbooks. What is the clinical phenotype in your patient?  Any joint pains?  Any hind foot complaint?  Those, alert for HH and may sometimes masquerade as RA (so-called pseudo-RA).  They occur many years before elevation of ferritin but % sat. may be elevated.  In early RA, the iron profile is different: that of an hyperhepcidin state vs HH pseudo-RA, that of a hypohepcidin state.

I am preparing a paper on specific joint manifestations as early signs of HH, occurring even before the biochemical phenotype shows up.  Hence my interest in this discussion.  Best wishes

In this situation (hyperferritinemia, raised TSI and C282Y/H63D) you must determine the LIC by MRI (Rennes; Alustiza) because you must treat disease (increased LIC) not a polimorphysm or a gene mutation. To have an HFE gene mutation (including C282Y/C282Y, with a low penetrance) do not implies to develope disease.

We have developed an algorythm for the diagnosis of high liver iron concentration in patients with increased iron biomarkers (seum ferritin and/or TSI): patients with raised ferritin and TSI must be studied by MRI to determine LIC.

 http://www.jfhod.com/Data/PDF/Livre-resumes-2016-V2.pdf (in french).

 CO 82, page 142. raised ferritin and STI and HFE gene mutation different to C282Y/C282Y: study LIC by MRI.

Good morning Dr Castiella,

Thanks for the web reference (>400 web pages on my IPad).  Could  you indicate which presentations/posters relate to HH?

In the patient of Dr Alberg, although we are not given the liver info, I would get the LIC MRI but would treat the patient notwithstanding the results of the LIC or the LFTs and, I would definitively not need a liver biopsy.  Why? In my very simplistic understanding, hyperferritinemia in this context, is the liver shouting "HELP" having reached the limit of its usual Iron storage capacity.  The raised % TSat. tells me that the transport system is already constantly overloaded and that justifies the phlebotomies because the level of tolerance of the chondrocyte environment are much lower than those of the hepatocyte environment.

I agree that we should not be treating only on the basis of the HFE genotype, because other genes are probably required for liver or joint pathology to appear.  On the other hand, we should not wait for major organ damage or failure before starting treatment.  Indeed, in the case of HH arthritis, iron overload is only one facet of the problem.  Because, the site specific joint problems also occurs in the so-called "silent HD mutations" where most of the time the iron biochemical phenotype is absent (i.e. we cannot prove excess iron). Other loss-of-function genes are probably co-inherited for the clinical phenotype to appear.  Those HD patients with HH arthritis may never have abnormal iron profile or liver problems but they have joint problems that will be compounded by the excess iron should it occur intermittently.  Those we do not know how to treat because phlebotomies are not a logical approach.  Waiting for gene therapy....

In other word, in rheumatology, HH shows up years before it does in gastroenterology and that is why I wrote that liver problems are a late event that should now be largely preventable if the iron treat is recognized and treated earlier.

I realized that what precedes may go against some current practices regarding the indication for deironization.  Thanks again for sharing your thoughts and reading mine.

Best wishes

Henri A. Ménard MD FRCP(C), Emeritus Professor of Medicine, McGill U.

Dr Castiella.

Félicitations pour votre beau travail👌👍.  Please send me the full paper when you publish it so that I can share it and discuss it with our hepatologists.  It seems to work well for YY patients with a positive biochemical phenotype.

I would still recommend treating Dr Alberg's patient.  Ten years ago, I had a similar patient with idiopathic hindfoot OA and we showed iron liver damage by biopsy (There were no imaging techniques available then) even if she had always been liverwise asymptomatic.  She is still doing well, no joint or liver progression with enough phlebotomies to maintain % TSat. normal.  Ferritin had normalized months before the former.  I also had 12 years ago, a YY patient with normal % TSat. and ferritinemia that I did not treat and who is happily living staying away from GI and joint doctors.  So, when patient come directly in rheumatology, in my decision to treat, I put a lot of emphasis on % T Sat in the context of a predisposing genotype.  Of course, when the patient is referred from GI It is late into the disease and treatment is already on.  It is usually too late to save the joints.  So, it is possible that we are not taking about the same phase of the evolution of HH and that LIC by MRI may be more useful in GI than in Rheum.  More research is needed.

Best.

HM.

Dear Professor: the reference is in page 142 (CO.82).

http://www.jfhod.com/Data/PDF/Livre-resumes-2016-V2.pdf (in french).

I agree with you in the fact that liver biopsy is not longer necessary with diagnosis purposes in HH and, in my humble opinion, nowadays is it not necessary for prognosis (fibroscan, olynyk fibrosis index for HH, platelets 1000; hypertransaminasemia). Furthermore, Falize et al (hepatology 2006; 44: 472-7) demostrated the reversibility of cirrhosis in HH after treatment with phlebotomies: 36 HH patients. ("Among the 13 patients who had F3 fibrosis on their initial liver biopsy, 3 had F0, 6 had F1, and 2 had F2 on their second liver biopsy. Among the 23 patients with cirrhosis on their initial liver biopsy, 1 had F0, 4 had F1, 3 had F2, and 2 had F3 on their second liver biopsy"). 

I think that we must treat the patient on the basis of the LIC results. Among C282Y/C282Y patients, only 10% of women and 20-30% of men will develop a liver iron surchrage. Taken into account that C282Y/C282Y mutation in the HFE gene is the most frequent mutation in caucasian population, with a frequency of more than 1patient  from 100-200 screening patients in some European populations (Ireland), the population with phlebotomies for a theoric prevention would be incredibly high (and that only for C282Y/C282Y population; add C282Y/H63D (less of 5% of HH cases) and H63D/H63%(1% of HH cases). We know that more than the 70% of the excess of the iron absortion goes to the liver, as the principal target in the human body. This normally occurs prior to the involve of the heart, joints, pancreas  or the hypofisis. As an hepatologist, I rarely see patients with joints problems in HH.

In an Australian study with 31,192 subjects of northern European descent,  genotyped for HFE C282Y and H63D, "male and female compound heterozygotes had a similar prevalence of hemochromatosis-related morbidity to wild-types. One of 82 males and zero of 95 females had documented iron overload-related disease".  "Although compound heterozygotes might maintain elevated iron indices during middle age, documented iron overload-related disease is rare" (Hepatology. 2009 Jul;50(1):94-101. doi: 10.1002/hep.22972.).

In an Australian recent work, "an arthropathy consistent with that commonly attributed to HH was found to occur in 24% of patients with definite/probable HH. The association observed between this arthropathy, homozygosity for C282Y, and serum ferritin concentrations at the time of diagnosis suggests that iron load is likely to be a major determinant of arthropathy in HH and to be more important than occupational factors".(Arthritis Rheum. 2011 Jan;63(1):286-94. doi: 10.1002/art.30094.)

Kind Regards,

Agustin Castiella, MD, PhD. mendaro Hospital. Spain. 

Dear Dr Castiella,

Precision Medicine deals with PANOMICS of which PHENOMICS is the contribution of the clinician.  The latter is both essential and neglected.

The hepatology experience is that many patients with HFE mutations and excess iron will not evolve toward fibrosis and cirrhosis.  The current thinking is that there is/are other gene(s) involved in the tissue specific expression of the disease, excess iron being an important initiating/aggravating factor.  Functional genomic research is exploring those issues.  

As clinicians, in 2016, we must target EARLY emergent symptoms and prevent disease.  In rheumatology, the HH arthritis literature you cited is textbook compatible i.e. it is LATE arthritis of the ORGAN FAILURE/CIRRHOSIS-EQUIVALENT type.  No treatment except joint replacement will help at that stage.  We do not want to see that anymore.

.Indeed, it is clear (from GJ Carrol 2006, HA Ménard 2005 and 2010, both cited in P Kiely, Scand J Rheum. 2016 in press) that MSK involvement is the earliest and, is most damaging to quality of life in HH type1 patientsI  More specifically idiopathic hindfoot involvement, which is rare in rheumatology, is the clue to identify the HFE mutations either C-Y or H-D with/without the biochemical phenotype, respectively.  Thus, no need to screen the whole population or treat the asymptomatic abnormal tests.  We follow Sir William Osler's advice:  "The patient is the entity, not the disease"

We thus use careful CLINICAL PHENOMICS to direct GENOMICS..  That bothersome hindfoot occurs long before joint organ failure and becomes treatable (or not) by phlebotomy thus preventing chondrocyte death and OA (preliminary data).  It usually occurs long before the asymptomatic liver gets involved.  In vitro, transfection of normal human chondrocytes with the HFE mutations is very deleterious to their physiology even in a normal concentration  of iron.  We see other usually protective genes become dysfunctional (V Martelli et al., Abstract ACR Chicago, 2010, unpublished data).  Thus, like in the liver, in the joint, there are other genes than HFE that allow site expression of the disease.  I would not be surprized if those putative genes were tissue specific as what we have seen is a different gene as that associated with liver fibrosis.

In conclusion, hemochromatosis is a systemic metabolic disease affecting all cells and organs.  With the modern approach of Precision Medicine, I believe we will be redefining that disease and soon will rewrite the textbooks as the patient will be exposed to PANOMICS and SYSTEMS BIOLOGY.

The research fellow who was associated with that research effort is now working in Madrid at Gregorio Maranon Hosp.  If I visit her in Spain, I will make an effort to come to your place to continue our discussion and maybe give a talk to your rheumatology colleagues. 

Best regards and thanks for reading this too long piece.

Henri André Ménard, MD, FRCP (C)

McGill University Health Center,

Montréal, Qc, Canada. 

I am a carrier of hereditary hemochromatosis of the type commented by heterozygous composite and very aggressive voices. I am a descendant of European. I have all the diseases due to hereditary hemochromatosis. Besides, I was also diagnosed with Addison's Disease. They are all of genetic origin. How do you explain this case at the scientific level? I was diagnosed in late 2014.

I look forward to a scientific answer, because there is not yet a study of all the diseases I have been diagnosed, and this would help other people.

M.Sc. Engineer Cristina Fischer

Depending on family history (liver cancer, cirrhosis, etc), medication history that could contribute to damaging the liver and a MRI,CAT,Ultrasound should be performed to see if biopsy is needed.

Possibly have others in the family get tested for the genes

Hemochromatosis "symptoms" vary and appear at different stages and ages - I know from experience

Also was the test done at a genetics lab or a "consumer DNA/Family history" company ?

I have a collection of publications on H63D here also

http://georgenet.net/bloodhemo/FILES/index.php?path=H63D/

http://georgenet.net/bloodhemo/FILES/index.php?path=Genetics/

Hope it helps

George