Hereditary Hemochromatosis Often Presents as a Rheumatic Problem And Its Clue is an Unexplained Hind Foot Complaint
Posted April 1st, 2015 by webadmin
By Dr Henri A. Ménard, Professor of Medicine and Rheumatologist, McGill University Health Center, Montreal, and Medical Advisor to the Canadian Hemochromatosis Society
Our current understanding of hereditary hemochromatosis (HHC) is that of a genetically-determined, slowly-progressive, accumulation of iron in non-physiological places with resulting organ failure. HHC has many definitions: a genetic one, a biochemical phenotypic one and a clinical phenotypic one. My deepest conviction as a rheumatologist is that patients have all the questions and all the answers. My job in a university-hospital is that of a clinician-scientist (physician, teacher and researcher) looking for insightful clues given by patients and for explanatory answers in the library or in the laboratory.
The rheumatology textbooks describe HHC arthritis as a slowly progressive degenerative type of arthritis i.e. osteoarthritis (OA) with typical but non-specific involvement of the 2nd and 3rd metacarpo-phalangeal joints (knuckles) and calcium pyrophosphate dihydrate (CPPD) crystals deposition in unusual places i.e. in joints other than the wrists, pubis and knees. The textbook further states that phlebotomies do not help HHC arthritis. Most doctors are not particularly aware of HHC when seeing new OA patients. In fact, I for one rarely if ever made a diagnosis of HHC based on EARLY, vague and non-specific rheumatic symptoms. On the other hand, I readily made the diagnosis of late HHC arthritis in patients referred to me with known HHC. That is not good medicine. Given what we now know, that part of the textbook on HHC OA needs to be rewritten not only textually but also conceptually. What brought about my change of mind?
I started changing about 10 years ago because of a HHC patient I had the privilege to care for. Like in many others, her HHC diagnosis was serendipitous. Her husband had to go to work in the USA and all his family had to undertake a general health assessment. To make a long story short, except for an “annoying ankle” problem, she was “apparently healthy”. Still, laboratory results showed high serum iron levels, high % transferrin saturation, high serum ferritin and HFE gene mutations. Although the liver function tests were normal, liver biopsy confirmed early liver involvement. She was given regular phlebotomies. She stopped those after a few years when ferritin had long become normal. Her % transferrin saturation remained elevated and she complained more and more of her “ankles”. That pain localized in the hind foot, more precisely her sub-talar joint – not the real ankle (See Figure A and B). She kept insisting that it was due to HHC. Since there were no CPPD crystals identified and since that localization was not mentioned in our textbook, I was reluctant to agree! Not anymore!
Figure A
Figure B. Hind foot complaint in two different patients due in A, to mildly/moderately severe sub-talar joint HCC arthritis (between the talus and calcaneus) and due in B to very advanced ankle joint HCC arthritis (between the tibia, fibula and talar bones).
At about the same time, Dr. Graeme Carroll in Australia stressed the frequent early localization to the hind foot of HHC arthritis even in patients having the so-called “silent” H63D HFE mutation and a normal iron profile. From that time on, I started to systematically test for HHC in all unexplained (“idiopathic” in medical jargon) hind foot complaints. I further became a strong believer, after I played golf with someone whom I never had much social interaction before. As we walked around the course, I noticed that he was limping, intermittently. When asked why, he answered “because of my ankle” but he or I could not find any reason why. That did not fall in a deaf ear and I invited him to drop by the office to sort this out, trying not to alarm him because he felt “generally fine, thank you”. Except for the subjective intermittent pain, his hind foot was clinically and radiologically normal. The hind foot clue was a long shot but to my great surprise, the lab results showed all the biochemical and genetic stigmata of HHC: high iron and ferritin, 99% fasting transferrin saturation and homozygous YY HFE mutations. Even if “apparently” healthy, he agreed (against the advice of his family doctor who did not see the point) to have weekly phlebotomies. After two years, he is on a Q. 1-2 month maintenance schedule at Héma-Québec. Six months after all his biochemical abnormalities were corrected his hind foot complaints disappeared and did not recur. Further, he “felt much healthier and energized, more than in a long time”. Enough to play golf and walk 9 of his daily 18 holes at 69 years of age! He, his wife, his family doctor and I, have all been impressed by his newly found vitality.
Like in Australia, the regular OA patients without the hind foot complaint rarely had HFE mutations. The big surprise was that also like in Australia, those selected Canadians often had the so-called “silent” H63D HFE mutation with normal iron profiles. Most had normal X-rays: no OA, no crystal deposits. Nevertheless, in some it was the earliest and only subjective complaint. It meant that we could use that clinical feature to predict the presence of HFE mutations before any serious “disease or damage” developed and that there may be a window of opportunity when phlebotomies, if indicated, could help prevent HHC disease. Further, it suggested that the effect on iron is not the only culprit in one with HFE mutations! We presented those findings at the 2011 American College of Rheumatology (ACR) meeting in Chicago and they were highlighted by the organizers.
We have since collected arguments to explain why the hind foot is targeted and have studied in vitro, how the human chondrocyte would react in the presence of both excess/normal iron and mutated/normal HFE. Chondrocytes are the cells that are sustaining cartilage, the tissue covering the bones in joints. HHC arthritis targets the cartilage. Dr John Dibattista’s research team at the McGill University Hospital Center Research Institute inserted the variously mutated HFE gene in normal chondrocytes in vitro and could reproduce the OA chondrocyte phenotype, even without excess iron in the medium. Those, well controlled experiments, were reproducible and suggested that although excess iron is important and treatable in vivo, there is more to HFE mutations than just excess iron. The H63D mutations may be silent from the iron perspective but they appear to be far from silent in cartilage physiology as well as emerging as co-morbidity factors in other diseases. Because of the potential impact of those findings in the general population – HFE mutations are present in 1/300 Caucasian Canadians, we have treaded very cautiously to confirm and re-confirm all those in vitro data. Our first application to get research support in 2012 was denied as is usual when the ideas are novel and/or against the grain. To perform and repeat the in vitro experiments, we had to divert funds obtained for other research projects. We feel it was a productive investment and we are planning to reapply for funds in 2015 with more preliminary supportive data. In fact, two formal detailed scientific papers are currently being submitted for publication. One describes our clinical observations in the hind foot selected patient cohort and discusses the reasons why the hind foot is targeted. The other describes the in vitro chondrocyte culture experiments that address the molecular mechanism(s) that we could explore within our limited means.
The hind foot clue was confirmed in a recent communication from England at the November 2014 ACR meeting in Boston. Dr Patrick Kiley sent a questionnaire to 1300 members of the UK Haemochromatosis Society and found that the hind foot area (ankle, sub-talar and midfoot taken together) was the most frequently involved area (more frequently than the textbook cited classic hand-wrist area), often years before the biochemical or genetic HHC diagnosis was made. Strikingly, few if any of the HHC diagnoses were primarily made by rheumatologists. The rheumatologists only recognized the arthritis of the known HHC patients, usually referred by the liver specialist i.e. the advanced cases where phlebotomies are indeed not very useful for the joint failure. Overall, it would appear that like me ten years ago, rheumatologists are not much more aware than general practitioners of the fact that often, HHC first presents as a (hind foot) rheumatologic condition significantly interfering with quality of life. If they would recognize that, an early or even pre-disease diagnosis could be made and appropriate treatment would make the known organ failures things of the past. It would also help identify those HFE carriers with a normal iron profile as candidate for further research into the other potential morbid or co-morbid roles of HFE mutations. I believe that silence is a misconception and definitively a misnomer for any HFE mutations.