What's the Take Home?

A 55-Year-Old Man With Sore Hands, Ruddy Complexion

Ronald N. Rubin, MD
Volume 66 - Issue 4 - April 2026

  • Correct answer: E. JAK2 studies will confirm myeloproliferative polycythemia vera.

    Discussion. The clinical findings are consistent with hemochromatosis, a disease characterized by markedly increased iron accumulation in the body resulting in a lifetime of increased iron absorption from the gastrointestinal (GI) tract. Hemochromatosis is a genetic disease behaving as an autosomal recessive with homozygotes being responsible for essentially all clinical cases. There is a considerable degree of variable and incomplete penetrance of HFE gene homozygosity. Although biochemical iron overload, manifested by transferrin saturations above 50%, is seen in 75% of women and 94% of men, and elevated ferritin levels are present in 57% of women and 88% of men, clinically significant iron overload (e.g., arthritis and/or liver damage) occurs in only 40% and 13% of cases, respectively.1 Some of these variances can be explained by women being protected by the menstrual loss during their childbearing years and the important presence of comorbid liver insults of hepatitis C and/or excessive alcohol intake, which are synergistic to the iron overload in causing more numerous and severe liver disease in HFE positive hemochromatosis patients.1,2 A key epidemiological point is the finding by genetic anthropology that the HFE gene defect is believed to have developed in Nordic Viking populations and remains most frequent, with carrier rates as high as 1 in 7 people, in populations of northern European descent, e.g. Great Britain, Scandinavia and Australia.1 Although the increased iron absorption is ongoing from birth, clinical disease usually has onset in midlife. The present patient is thus a very good epidemiologic fit.

    The precise pathophysiology of hemochromatosis is somewhat complex.1,3 Iron is absorbed from the GI tract into the enterocytes through a ligand receptor site, the so-called ferroportin complex. This complex acts as a “gate”—when the ferroportin is open, the iron is absorbed, and when it is closed, it is not. Body iron is sensed by the liver, which controls this "gate" by synthesizing varying amounts of the 25 amino acid peptide hepcidin. When plasma and body storage iron are high, less hepcidin is produced, which “locks” the ferroportin mechanism and reduces iron absorption. When plasma/storage iron is low, more hepcidin is made, ferroportin gates are decreased, and thus functionally open, so more iron is absorbed. The HFE mutation in hemochromatosis results in loss of ability to upregulate hepcidin synthesis such that hepcidin is always low, ferroportin gates are always open regardless of iron levels or stores thus resulting is lifelong and ongoing overabsorption of iron. Eventually, serum iron is chronically overloading the plasma iron binding capacity, e.g. Fe/TIBC above 50%, and iron spills into and accumulates in tissues such as joints and the liver.1,3

    Interlocking the genetics and pathophysiology of HFE hemochromatosis, we find roughly 40% of men and 13% of women homozygotes manifesting disease during life. Again, this is due to (1) women protected by decades of menstrual life; (2) the variable penetrance of HFE genetics-not all homozygotes are phenotypically affected; and (3) the effects of second added liver insults, eg, alcohol, hepatitis C, and MASH (1).

    Clinically, the major actual symptoms typically reported are fatigue and hand arthritis usually involving the metacarpophalangeal joints and wrists symmetrically. Having said this, the usual, most involved and morbidity/mortality-related target organ in HFE hemochromatosis is the liver. Presentations will vary from AST elevations on biochemistry panels to the findings of unexplained hepatic fibrosis to frank clinical cirrhosis. An old clinical saw in years prior to the blood testing techniques and imaging available today was to evaluate for hemochromatosis for any patient with "unexplained cirrhosis of the liver" (ie, no alcohol or hepatitis history)

    In today's era of ubiquitous blood testing, many patients are now initially presenting biochemically so to speak when an incidental AST is elevated or and incidental iron panel records an iron/TIBC above 50 or ferritin above 300 µg/dL. Finally, less common presentations include the dreaded hepatocellular carcinoma (incidence 7.2%)2,4 the concordant finding of skin hype-pigmentation and new onset diabetes mellitus in the same patient ("bronze diabetes") and infection by the iron loving microbe Vibrio vulnificus.5

    Once entertained, definitive diagnosis and therapeutics are rather straight forward. If not already done, serum iron, total iron binding capacity (TIBC), and ferritin are measured. In men, Fe/TIBC above 45% is approximately 94% sensitive, and in women approximately 73% sensitive, and serum ferritin above 300 µg/mL has 88% sensitivity overall.1 These levels will also be useful in following therapy. Net is the genetic testing for the HFE gene, which is confirmatory or exclusionary. Once the diagnosis is confirmed, reasonable evaluation of extent of iron overload and risk for complications is performed. There was a period when liver biopsy and complicated tissue and MRI imaging techniques were performed to actually measure the total body iron burden.6 Today, a more streamlined, less invasive evaluation uses serum ferritin levels (above 1000 µg/mL is high risk for cirrhosis and liver cancer) and hepatic fibroelastogram measurements to evaluate levels of fibrosis present (F1-2 mild, moderate), F3-4 advanced, frank cirrhosis).1

    Treatment is also rather straight forward, involving the removal of iron by phlebotomy the only variable being the initial intensity level. When the ferritin is above 1000 µg/mL and/or fibrosis is F3 or F4 level or frank cirrhosis signs/symptoms are present, phlebotomy schedules of weekly are indicated and continued with target levels of ferritins less than 50-100 µg/mL and fibroelastogram scores of less than F2 are attained. Once there more liberal phlebotomy schedules of every several months will maintain satisfactory levels.7 Patients with iron overload can tolerate this as iron serves as an accelerator of erythropoiesis and patients usually manifest high hemoglobin and MCV levels which explain the generous complete blood count (CBC) and "ruddy complexion" manifested in the case presentation. Going forward, follow-up involves CBC and ferritin testing with maintenance phlebotomies as needed. Although most studies do not recommend population screening even in high-risk northern European lineage populations, e.g. Australia and British Isles,8 family screening of the index patient is recommended. Due to cancer risk in iron overload (more marked in F3 and F4 situations) hepatocellular carcinoma screening using ultrasound every 6 months is indicated.1,9 Finally, caution regarding exposure to iron-loving vibriosis organisms is warranted, e.g. eating raw oysters, bathing and crabbing in warm brackish waters, since vibrio infection in hemochromatosis is often very severe and life threatening.5

    To address the questions and offered answers related to the case presentation, answers B, C and D refer to the discussion of several management issues. As discussed, phlebotomy with targets for lowering body iron burden is the mainstay of therapy. Dietary iron restriction offers trivial, if any, benefit in HFE hemochromatosis as it is the hepcidin iron absorption regulation rather than the iron amounts in the body which is the key pathophysiology. Although significant morbid effects in hemochromatosis involve arthritis especially in the hands, cardiomyopathy and liver disease, the latter by far being the most frequent, are the dominant risks for serious/life threatening morbidity and mortality. Regarding screening, good studies1 have demonstrated that for now routine screening of the population is not recommended but when the screened population is concentrated down to the index case, there is efficacy and benefit. Part of this fact is due to the variable penetrance of the HFE gene-not everyone with it will develop hemochromatosis and iron overload in their lifetime and so-called "second insults" usually hepatitis C and/or alcohol abuse are acquired co-factors later in life that compound HFE effects. Finally, the interesting point involving Vibrio vulnificus, found more frequently now in warm, brackish waters, which are spreading ever northward in the United States from more limited prior locations, is an iron dependent organism essentially supercharged in humans when iron saturation is above 50% and the dreaded septicemia and necrotizing fasciitis soft tissue infections associated with this organism are significantly over represented in hemochromatosis cases such that avoidance of raw oyster eating and work/recreation in estuarial, warm, brackish waters is strongly recommended.5

    Patient follow-up. The clinical findings of hand arthritis, generous hemoglobin/hematocrit and Northern European lineage were suggestive of potential hemochromatosis and the iron saturation above 50% is highly suggestive of the diagnosis. Serum ferritin was obtained and measured at 800 µg/mL. Genetic studies confirmed homozygosity for the C282Y hemochromatosis gene. Other baseline studies included normal blood glucose and HbA1C, elevated transaminases and mild fibrosis liver fibroelastogram study. He was cautioned to limit his alcohol intake and avoid the eating of raw oysters and exposure to warm, brackish waters. An aggressive program of weekly phlebotomy was initiated with goals of lowering serum ferritin to less than 100 µg/mL in the initial phases with less frequent phlebotomy thereafter. He will have routine testing (e.g. alpha-fetoprotein and liver ultrasounds) for hepatocellular carcinoma. Family screening was performed and demonstrated HFE heterozygosity in both of his children.

    What’s the Take Home? Hemochromatosis is a relatively common genetic, inherited disease in which there is increased accumulation of iron in the body over time, which results in morbidity and the potential for mortality. Hemochromatosis is a disorder of iron absorption due to loss of hepcidin function. Hepcidin is a 25 amino acid peptide synthesized in the liver and is the keystone regulator of iron absorption in humans. Without hepcidin in appropriate amounts the ferroportin "gates" in the duodenum remain essentially wide open for ongoing iron absorption from the GI tract into the plasma regardless of the status of body iron stores. The hepcidin defect is related to a specific genetic lesion in the HFE iron regulator due to a single base change, guanine for adenine, on chromosome 6. The genetics behave as an autosomal recessive with an unusual degree of variable penetrance in homozygotes such that nor all are affected by the disease. Males are affected far more than females, who are protected by their menstrual blood loss in their younger years. Clinical onset generally occurs in midlife. The gene is overrepresented in people of Northern European lineage, where carrier rates as high as 1 in 7 and 1 in 150,200 will display clinical disease.

    Key target organs are liver (highest cause for morbidity and mortality), joints (especially hands), and in extreme cases, the heart. Key diagnostics are serum Fe/TIBC above 45% binding, ferritin greater than 1000 µg/mL being an alarm value. The definitive diagnostic is genetic testing study for the HFE mutation.

    Treatment involves simple phlebotomy as frequent as weekly until ferritins are in the 50-100 µg/mL range are obtained. As of this writing, genetic testing is recommended for family members but not for the general population.

    AUTHOR
    Ronald N. Rubin MD1,2

    AFFILIATIONS
    1Lewis Katz School of Medicine at Temple University, Philadelphia, PA
    2Department of Medicine, Temple University Hospital, Philadelphia, PA

    CITATION
    Rubin RN. A 55-year-old man with sore hands, ruddy complexion. Consultant. 2026;66(4):eXX. doi: 10.25270/con.2026.04.000003

    DISCLOSURES
    The author reports no relevant financial relationships.

    CORRESPONDENCE:
    Ronald N. Rubin, MD, Temple University Hospital, 3401 N. Broad Street, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)

    References

    1. Olynyk JK, Ramm GA. Hemochromatosis. N Engl J Med. 2022;387:2159-2170.
    2. Niederau C, Fischer R, Sonnenberg A, et al. Survival and causes of death in cirrhotic and noncirrhotic patients with primary hemochromatosis. N Engl J Med. 1985;313:1256-1262.
    3. Valenti L, Fracanzani AL, Rossi V, et al. The hand arthropathy of hereditary hemochromatosis is strongly associated with iron overload. J Rheumatol. 2008;35:153-158.
    4. Atkins JL, Pilling LC, Masoli JAH, et al. Association of hemochromatosis HFE homozygosity with hepatic carcinoma. JAMA. 2020;324:2048-2057.
    5. Rubin RN. A 70-year-old man with severe hand pain, part 2. Consultant. 2024;64(7):eXX. doi:10.25270/con.2024.07.000004
    6. Wang CY, Babitt JL. Liver iron sensing and body iron homeostasis. Blood. 2019;133:18-29.
    7. Allen KJ, Bertalli NA, Osborne NJ, et al. HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 µg/dL are at low risk for hemochromatosis. Hepatology. 2010;52:925-933.
    8. Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron screening in a racially diverse population. N Engl J Med. 2005;352:1767-1778.
    9. Girelli D, Busti F, Brissot P, et al. Hemochromatosis classification: update and recommendations by the BIOIRON Society. Blood. 2022;139:3018-3029.

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