Does this patient have hemochromatosis?

Hemochromatosis refers to the presence of excess iron storage and the deposition of hemosiderin which causes tissue damage and organ dysfunction. The increased iron absorption is due to either primary or secondary causes.

Hereditary hemochromatosis, the primary form, affects males more than females, often with symptoms beginning in their 30-50’s as iron storage accumulates to 20-30 grams. Historically, diagnosis often proceeds symptoms by 10 years.

Early symptoms include arthralgias typically at the second and third MCPs, extreme fatigue, apathy, lethargy, weight loss, loss of libido, impotence, and right upper quadrant abdominal pain.

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Diagnosis is often made in asymptomatic patients after screening tests reveal elevated liver enzymes. Late findings can include progressive arthritis, cirrhosis, hepatocellular carcinoma, diabetes, skin hyperpigmentation, arrhythmia and heart failure. The disease can be fatal if not treated.

Joint manifestations

Arthritis is a common symptom, often late in the course, affecting 50-80%, with a significant impact on quality of life. Arthralgias and fatigue are often the first presenting features of joint disease. Involvement of the second and third MCPs is common and described as the “iron salute” sign, which includes mild tenderness (especially after use), impaired flexion and bony hypertrophy.

Joint inflammation is often minimal but acute presentations can occur. Other commonly affected joints include wrists, knees, hips, shoulders and the intervertebral disks of the cervical and lumbar spine.

Infrequently the distribution can be polyarticular, symmetrical, and severe, mimicking rheumatoid arthritis. Hydroxyapatite and calcium pyrophosphate crystal deposition are commonly associated with hemochromatosis and often happen concomitantly. This likely accounts for the acute flares. Over time joint deformity often occurs. Osteoporosis is found in 25-50% with an iron overload state, likely due to hypogonadism from gonadotropin deficiencies.

Nonarticular manifestations

Physical exam findings include hepatomegaly, extrahepatic manifestations of chronic liver disease, testicular atrophy, gynecomastia, loss of body hair, skin pigmentation, congestive heart failure, or arthritis.

Differential diagnosis

The rheumatologic differential diagnosis includes:

  • Osteoarthritis with bony hypertrophy.

  • Rheumatoid arthritis, although hemochromatosis lacks ulnar deviation.

  • Crystalline arthritis, specifically calcium pyrophosphate deposition.

What tests to perform?

Iron testing


  • All symptomatic patients.

  • Asymptomatic patients with AST/ALT elevations.

  • Adult first degree relatives of patients with hereditary hemochromatosis.

The panel for testing includes: serum transferrin saturation (Serum iron x 100/TIBC) and ferritin. A cutoff of >45% for the transferrin saturation and ferritin > 200 µg/L should be set. It is advisable to confirm an elevated transferrin saturation with a fasting specimen. In patients with normal ferritin and transferrin saturation < 45%, no further evaluation is necessary. Ferritin level elevation coincides with risk for hepatic fibrosis and cirrhosis.

HFE genetic testing


  • All first degree relatives of homozygotes irregardless of their iron studies.

  • All patients (symptomatic or asymptomatic) with elevations in their transferrin saturation (> 45%) and/or ferritin (>200 µg/L), should be sent for HFE genotyping.

The genetic testing includes screening for C282y and H63D mutations. Genetic positivity for C282Y mutation or compound heterozygosity for C282Y/H63D confirms the diagnosis.

For symptomatic patients with elevated ferritin and transferrin saturations and negative C282y and H63D mutations, genetic testing for HAMP, HJV, HFE and TfR2 mutations is recommended.

For compound heterozygotes or non C282Y mutations who have elevated transferrin saturation or ferritin, workup to exclude other liver or hematologic disease which may include liver biopsy. Recommendations based on the AASLD guidelines (Association for the Study of Liver Diseases).

Children of a patient with hereditary hemochromatosis are only at risk if the other parent carries gene mutations. In this scenario, HFE testing of the other parent is recommended.

For C282Y homozygotes with no clinical evidence of disease, yearly ferritin, transferrin saturation, and liver enzymes should be performed. HFE heterozygotes should be reassured that they are at very low risk for iron overload. All positive genotypes (including heterozygotes without phenotypic expression) should be informed that it can be synergistic in development of liver disease if other hepatotoxic insults occur such as hepatitis infection, alcohol and non-alcohol related liver disease.

In patients diagnosed with hemochromatosis, regular monitoring for organ involvement is warranted including glucose, electrocardiograms (EKGs), thyroid stimulating hormone (TSH), gonadotropic hormones, and liver enzymes.

Osteoporotic patients should be tested for hypogonadism and thyroid disease.


Radiological examination should first include x-rays of the affected joints. The findings may resemble osteoarthritis with irregular joint space narrowing, subchondral bone sclerosis, bone cysts, and osteophytosis. Findings may also resemble calcium pyrophosphate disease, with involvement of joints often spared by osteoarthritis (including metacarpal-phalangeal joints, wrists and shoulders), large subchondral cysts, uniform loss of joint space and chondrocalcinosis.

Distinguishing x-ray features that may help differentiate hemochromatosis from calcium pyrophosphate disease include:

  • Second and third MCP involvement with joint space loss.

  • “Hook-like” osteophytes at the radial sides of the distal metacarpals.

  • Diffuse involvement of the wrist with less scapholunate dissociation and radiocarpal involvement compared to calcium pyrophosphate disease.

  • Hips may exhibit a radiolucent zone in the subchondral area of the femoral head.

MRI is generally not necessary for diagnosis. MRI will show similar findings including degenerative changes, bone cysts and synovial thickening. MRI can also be used to estimate iron overload on abdominal T2 weighted series examining hepatic parenchyma.

Bone mineral density testing should be performed on all homozygotes with significant iron overload and repeated periodically.


Biopsy is generally not needed for diagnosis for arthritis related to iron overload. In atypical cases, biopsy findings consistent with iron overload include: brown discoloration of the synovium due to iron deposition, calcium pyrophosphate crystals, iron deposits, degenerative changes in the articular cartilage, synovial lining with proliferation of neutrophils.

Eroded cartilage is commonly coated with calcium pyrophosphate dihydrate and hydroxyapatite crystals.

Liver biopsy may be used for prognostic purposes evaluating hepatic iron concentration, fibrosis, and cirrhosis. If cirrhosis is found, screening for hepatocellular carcinoma at regular intervals is recommended with alpha fetoprotein levels. Ferritin levels can be used to identify the at risk patients for hepatocellular carcinoma and biopsy is recommended in C282Y homozygotes with ferritin > 1000 µg/L.

Overall interpretation of test results

Clinical diagnosis of hemochromatosis is based on evidence of elevated iron storage (transferrin saturation and/or ferritin). This is further characterized by genotyping to distinguish primary (hereditary) from secondary causes.

Controversies in diagnostic testing

Ferritin level elevation is nonspecific and leads to significant false positive rates for hemochromatosis. Some favor the use of transferrin saturation as the marker for iron overload.

Other selected etiologies of elevated ferritin include: chronic inflammatory connective tissue diseases (such as rheumatoid arthritis and adult onset Stills disease), lymphoma, hepatitis B, C, alcoholic and non-alcoholic liver disease. The combination of normal ferritin and transferrin saturation is reassuring, and has a high negative predictive value when screening for disease. .

Iron overload may be present in patients with elevated ferritin and normal transferrin saturation, seen in non-HFE related iron overload and in the C282Y/C63D heterozygote.

How should patients with hemochromatosis be managed?


For arthritis, phlebotomy has not been proven to have a beneficial effect on the clinical, radiological or histological progression. Management is mostly symptomatic with the cornerstone of treatment being non-steroidal anti-inflammatory drugs (NSAIDS) and steroid injections. Colchicine therapy may be helpful, especially when there is an episodic nature to the presentation, as concomitant calcium pyrophosphate deposition could be a factor.

Joint replacement surgery should be considered for severe symptoms.


Patients with osteoporosis should be evaluated for testosterone deficiency and thyroid disease and treated appropriately with replacement therapy if present.

Organ related disease

Management of organ related disease includes lifelong phlebotomy to remove excess iron to prevent and improve organ damage. Initiation of phlebotomy before the development of organ disease will reduce mortality and morbidity. Phlebotomy has been shown to improve cardiac function, energy level, diabetic glycemic control, abdominal pain, skin pigmentation, normalization of liver enzymes, and reverse some cases of hepatic fibrosis.

The risk of hepatocellular carcinoma is eliminated if iron removal is achieved before the development of cirrhosis.

Phlebotomy does not improve arthritis, hypogonadism or cirrhosis.

C282Y homozygotes

For C282Y homozygotes, a recommended strategy is to measure ferritin levels and if they are >1000 µg/L, recommend a liver biopsy to evaluate for cirrhosis and initiate phlebotomy. Initially phlebotomy of 500 cc is performed 1-2 times per week. Check hematocrit and hemoglobin prior to each phlebotomy and allow this to decrease by no more than 20% of the previous level.

Check serum ferritin levels after every 10-12 phlebotomies. Stop frequent phlebotomy when serum ferritin is 50-100 µg/L. In patients with total body iron stores >30 grams, this may take 2-3 years.

Lifelong maintenance

Once stable, lifelong maintenance therapy can be initiated at 2-6 month intervals based on yearly ferritin levels with the goal ferritin level between 50-100 µg/L.

Dietary restrictions

Dietary restrictions include: alcohol avoidance as it can act synergistically with iron to induce cirrhosis; raw shellfish avoidance due to potential contamination with
Vibrio vulnificus, a siderophilic bacteria, also gastroenteritis caused by Yersinia enterocolitica is more common; vitamin c supplementation should be avoided as it may facilitate iron release and free radical activity. It is controversial whether dietary restriction of high iron containing foods such as red meat and organ meat is necessary.

Hepatocellular carcinoma

In cases of hepatocellular carcinoma, liver transplant is an option.

What happens to patients with hemochromatosis?

Primary hemochromatosis
Epidemiology and Pathophysiology

Primary hereditary hemochromatosis is the most common identified genetic disorder in Caucasians. This includes four well described subtypes: HFE related HHC (Type 1), Juvenile type HHC (Types 2a and 2b), TfR2 Related (Type 3), and Ferroportin-related (Type 4).

All but Type 4 are autosomal recessive. The most common mutation is at the HFE gene on chromosome 6, accounting for 90% of hereditary disease. The disease commonly presents in the fourth to sixth decade of life, with the juvenile form presenting in the second or third decade.

Genotypic expression is roughly equal between the sexes. Phenotypic expression, defined as increased iron stores and measured by increased ferritin/transferrin saturation levels, occurs in 70% of HFE mutated homozygotes. Of this 70%, cohort studies estimate that 28% of men and 1.2% of women will develop severe iron overload with clinical manifestations and organ damage.

The proportion of men with iron overload related disease is estimated to be 10 times more common than females, and hypothesized to be due to menstruation. Additionally, homozygous and heterozygous genotypes correlate with major or minor disease expression, respectively.

C282Y HFE mutation

Approximately 0.45% of individuals from Northern European descent are homozygous for the C282Y HFE mutation, with the prevalence in other populations ranging from 0.11% in Native Americans to 0.0004% in Asians. There is varied phenotypic expression relative to each mutation suggests other factors are contributors to expression.

Secondary hemochromatosis

Secondary hemochromatosis refers to iron overload which could be due to:

  • Increased iron availability: includes iron-loading anemias such as thalassemia major, sideroblastic anemia, chronic hemolytic anemia, aplastic anemia, pyruvate kinase deficiency, pyridoxine responsive anemia.

  • Parenteral iron overload states: red blood cell transfusions, iron dextran injections and long term hemodialysis.

  • Chronic liver disease: Hepatitis B, Hepatitis C, alcoholic liver disease, porphyria cutanea tarda, non-alcoholic fatty liver disease, portocaval shunting, dysmetabolic iron overload syndrome.

If the disorder occurs without tissue deposition damage it is called hemosiderosis, and with damage, secondary hemochromatosis. The severity of tissue damage is less when due to secondary causes.

Physiologic and/or pathophysiologic implications

Humans absorb 10-20% of elemental iron by duodenal enterocytes daily, typically 1-2 mg. The average total body iron content is 3-4 grams, mostly contained within hemoglobin. Other cells such as myoglobin, ferritin, cytochromes and hemosiderin contain iron.

Regulation of absorption is complex and controlled by intake of iron, iron stores, and erythropoetic factors. Iron hemostasis is regulated in the intestine. When stores are adequate, to facilitate storage, the transferrin receptor is downregulated.

With increased iron stores, circulating transferrin becomes saturated and iron is offloaded to tissues with high levels of transferrin receptors such as the heart, liver, thyroid, gonads and pancreatic islet cells.

Humans do not have a mechanism to increase iron excretion which allows for iron overload to occur.


The pathogenesis of arthropathy in hereditary hemochromatosis is not known and iron depletion therapy has not proven to hasten its development. Iron deposition in the joints is associated with promotion of calcium pyrophosphate crystals and inhibition of crystal removal. This is supported by pathological evidence of both iron deposition and calcium pyrophosphate deposition in synovium of affected individuals. There is no correlation between the extent of iron deposits and radiological or pathological findings within joints.

Factors other than iron deposition are hypothesized to play a role in arthropathy. Interestingly, juvenile hemochromatosis does not present with arthropathy, supporting this hypothesis.

The proposed mechanisms include:

  • Increased levels of a fragment of parathyroid hormone (PTH 44-68) seen in this population may lead to arthropathy.

  • Alternate genes that modify the clinical expression of the mutated HFE genes that are yet to be identified.

  • Several immunological abnormalities are present including low numbers of CD8 T lymphocytes with elevations in CD4:CD8 ratios that may modulate expression.

Extra-articular manifestations

Extra-articular manifestations include glucose intolerance, often a late finding with beta cells producing low levels of c-peptide and low insulin levels, resulting in diabetes. Heart involvement can result in conduction abnormalities and heart failure. Pituitary involvement is due to iron deposition at the hypophysis resulting in reduced gonadotropins.

Hypothyroidism is due to both a direct toxic effect of iron on thyroid cells. Skin discoloration is a late finding and is a result of extra melanin and iron in the epidermis. Infection rates are increased, as high serum iron may increase bacterial virulence and excess iron in macrophages may hamper phagocytosis.

Porphyria cutanea tarda is associated with HFE mutations, although overt hemochromatosis is rare. Hepatocellular carcinoma is estimated to affect 30% with cirrhosis.

The main causes of mortality in the absence of treatment include heart failure, liver cirrhosis, and hepatocellular carcinoma. With treatment, liver, heart, and pancreatic iron deposition can improve.

How to utilize team care?

Specialty consultations

Orthopedic surgery for severe arthropathy. Gastroenterology if patient has evidence of elevated iron storage. Endocrinology for hypogonadism and hypothyroidism. Cardiology for arrhythmia and heart failure. Rheumatology or endocrinology for osteoporosis.




Occupational and physical therapy for joint related illness for muscle strengthening, range of motion exercises and functionality.

Are there clinical practice guidelines to inform decision making?

America Association of Liver Disease Practice Guideline for diagnosis, biopsy and phlebotomy for non- joint related organ involvement.

What is the evidence?

Axford, JS. ” Rheumatic manifestations of hereditary hemochromatosis”.

Cunnane, G. “Hemochromatosis”. Kelley's Textbook of Rheumatology. vol. Volume II. 2009. pp. 1809-1811.

Gordon, DA. ” Storage and Deposition Diseases Primer on the Rheumatic Diseases”. 2012. pp. 523-525.

Mcdonnell, SM, Preston, BL, Jewell, SA, Edwards, CQ, Adams, PC, Yip, R. “A Survey of 2,851 Patients with Hemochromatosis: Symptoms and response to treatment”. Am J Med.. vol. 106. 1999. pp. 619-624. (A large questionnaire based study of patients with hemochromatosis evaluating frequency of symptoms, quality of life, treatment received and response to treatment.)

Ines, LS, da Silva, J, Malcata, AB, Porto, AL. “Arthropathy of Genetic Hemochromatosis: A Major and Distinctive Manifestation of the Disease”. Clin Exp Rheumatol.. vol. 19. 2001 Jan-Feb. pp. 98-102. (Review on the genetics, presentation and hypothesized pathogenesis of arthropathy.)

Pietrangelo, A. “Hereditary Hemochromatosis- A New Look at an Old Disease”. N Engl J Med. vol. 350. 2004. pp. 2383-2397. (A complete review on iron absorption, genetics, proposed pathophysiology leading to iron overload, diagnosis, and management.)

Allen, KJ, Gurrin, LC, Constantine, CC, Osborne, NJ, Delatycki, MB, Nicoll, AJ. “Iron Overload-Related Disease in HFE Hereditary Hemochromatosis”. N Engl J Med. vol. 358. 2008. pp. 221-230. (Prospective study following 208 patients with C282Y homozygous mutations for an average of 12 years evaluating gender, genetic and laboratory variables with penetrance of disease (symptoms and organ involvement.))

Dymock, W, Hamilton, EBD, Laws, JW, Williams, R. “Arthropathy of Haemochromatosis”. Ann. rheum. Dis. vol. 29. 1970. pp. 469-476.

Greenspan, A. ” Miscellaneous Arthritides and Arthropathies”. Orthopedic Imaging. 2004. pp. 517-519.

Romas, E. “The 'Iron Salute" in haemochromatosis”. Aust Fam Physician. vol. 38. 2009 Mar. pp. 113-4. (Case study explaining the initial arthritic symptoms and findings.)

Schmid, H, Struppler, C, Braun, GS, Kellner, W, Kellner, H. “Ankle and Hindfoot Arthropathy in Hereditary Hemochromatosis”. J Rheumatol. vol. 30. 2003. pp. 196-9. (Review of atypical presentations, MRI imaging and proposed pathophysiology related to disease.)

Diamond, T, Stiel, D, Posen, S. “Osteoporosis in Hemochromatosis: Iron Excess, Gonadal Deficiency, or Other Factors”. Annals of Internal Medicine. vol. 110. 1989. pp. 430-436. (Prospective study evaluating 22 males with hemochromatosis showing significant lower bone density in hemochromatosis with hypogonadism present.)

Bacon, B, Adams, P, Kowdley, K, Powell, L, Tavill, A. “Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases”. Hepatology. vol. 6. 2011. pp. 328-43. (The latest treatment guidelines and testing algorithm for organ related disease.)

Schumacher, RH, Straka, PC, Krikker, MA, Dudley, AT. “The Arthropathy of Hemochromatosis”. Ann N Y acad Sci.. vol. 526. 1988. pp. 224-33. (Pathology findings in cartilage samples.)