eMedicine Specialties > Dermatology > Metabolic Diseases

Hemochromatosis: Differential Diagnoses & Workup

Author: Jacek Drobnik, MD, PhD, Assistant Professor of Physiology and Medicine, Department of Pathophysiology, Medical University of Lodz, Poland
Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Oct 14, 2009

Differential Diagnoses

Addison Disease
Postinflammatory Hyperpigmentation
Argyria
Riehl Melanosis
Phytophotodermatitis
Poikiloderma of Civatte
Polymorphous Light Eruption

Other Problems to Be Considered

The cutaneous hyperpigmentation in patients with hereditary hemochromatosis (HH) should be differentiated from drug-induced hyperpigmentation and actinic reticuloid.

The discovery of the HFE gene allows easy differentiation of hereditary hemochromatosis from other forms of hepatic iron overload, including a new syndrome termed dysmetabolic hepatosiderosis.

Serum abnormalities of iron metabolism could be seen in 50% of patients with alcoholic liver disease, nonalcoholic steatohepatitis (NASH), or chronic viral hepatitis.28 These abnormalities comprise an increased ferritin level, which is sometimes accompanied with elevated transferrin saturation. Hepatic iron concentration (HIC) could be slightly elevated, but the level of HIC in patients with hereditary hemochromatosis is much higher. Patients with chronic hepatitis C virus infection (HCV) who do not respond to interferon therapy usually have higher HIC than responders. Examination of HFE mutations is pivotal for diagnosis of hemochromatosis.

The prevalence of the C282Y and H63D mutations in patients with alcoholic liver disease and in those with chronic HCV is the same as in the control population, whereas, in patients with NASH, the prevalence of HFE mutations is higher. Moreover, 40% of patients with porphyria cutanea tarda are homozygous or heterozygous for the C282Y mutation. This finding was shown in patients from the United States, the United Kingdom, and Australia but not in Italian patients. Some studies show that HFE mutations in patients with HCV are associated with higher frequencies of fibrosis and cirrhosis.29,30 Increased fibrosis was also found in patients with NASH who had the C282Y mutation.31,32

Heart diseases are associated with hereditary hemochromatosis in one third of patients. Cardiac disease is mainly manifested by congestive heart failure accompanied by supraventricular arrhythmias. On radiographs, cardiomegaly with increased pulmonary vascular markings are seen. Echocardiography reveals the features of the restrictive type of cardiomyopathy. Cardiac manifestations of hereditary hemochromatosis could have sudden onset and could be poorly responsive to therapy. The hemochromatic etiology of the cardiomyopathy should be identified to ensure appropriate treatment. The diagnosis of hemochromatosis is based on clinical features of the disease; these features include diffuse hyperpigmentation, hepatomegaly, and diabetes mellitus accompanied with biochemical abnormalities of iron metabolism and genotypic investigation.33

Distinguishing hemochromatosis arthropathy from rheumatoid arthritis is important for several reasons. For example, patients with hereditary hemochromatosis do not require corticosteroid treatment. In addition, if a diagnosis of rheumatoid arthritis is made incorrectly, treatment with phlebotomy is not started early and familial genetic counseling is not considered.34

Workup

Laboratory Studies

  • Serum iron concentration in patients with hereditary hemochromatosis is greater than 150 mcg/dL.
  • Serum ferritin level is greater than 500 ng/mL.
  • Transferrin saturation is usually more than 45%; however, transferrin saturation greater than 62% identifies hereditary hemochromatosis in 92% of patients. If transferrin saturation is greater than 45%, the presence of the C282Y or H63D mutation may be evaluated to confirm the diagnosis of hemochromatosis.

Imaging Studies

  • Radiographs demonstrate cardiomegaly and increased pulmonary vascular markings.
  • Features of restrictive cardiomyopathy are visible on echocardiograms.

Other Tests

  • Genetic tests for the C282Y and H63D mutations are widely available. Detection of hemochromatosis-associated mutations is conducted to confirm the diagnosis or to discover asymptomatic patients. Detection of homozygosity for the C282Y mutation or compound heterozygosity for the C282Y/H63D mutation definitely confirms the diagnosis of hereditary hemochromatosis.
  • Supraventricular arrhythmias are often revealed on electrocardiograms.

Procedures

  • A skin biopsy specimen may confirm the diagnosis of hereditary hemochromatosis. Any cutaneous site, hyperpigmented or not, may be selected for biopsy, but avoid performing cutaneous skin biopsies on the legs because iron deposition in that area may be due to stasis. In healthy people, iron deposition may be evident only around apocrine glands and not around eccrine glands.
  • Liver biopsy is no longer obligatory to establish the diagnosis, but it may be helpful in patients with cirrhosis, which is the primary risk factor for hepatocellular carcinoma.

Histologic Findings

Microscopically, cutaneous hyperpigmentation appears as increased melanin within the epidermal basal layers.12 An iron stain, such as Perls Prussian blue stain, should be used to detect azure granules around the blood vessels and within the basement membrane zone of sweat glands and the connective tissue cells surrounding them. Siderosis around eccrine glands may be specific for idiopathic hemochromatosis.

Primary liver cancer in patients with hemochromatosis may have a wide histologic spectrum.35 Some tumors show frequent biliary differentiation. Others arise on a nonfibrotic or cirrhotic liver and are often associated with von Meyenburg complexes and, to a lesser extent, with bile duct adenomas.

More on Hemochromatosis

Overview: Hemochromatosis
Differential Diagnoses & Workup: Hemochromatosis
Treatment & Medication: Hemochromatosis
Follow-up: Hemochromatosis
References
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Further Reading

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Keywords

hemochromatosis, hereditary hemochromatosis, HH, bronze diabetes, iron deposition disease, cirrhosis, diabetes mellitus, hyperpigmentation, cardiac failure, iron overload, hepatic iron overload, iron homeostasis, iron metabolism, excess iron absorption, neonatal iron overload, neonatal hemochromatosis

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Contributor Information and Disclosures

Author

Jacek Drobnik, MD, PhD, Assistant Professor of Physiology and Medicine, Department of Pathophysiology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Peter Fritsch, MD, Chair, Department of Dermatology and Venereology, University of Innsbruck, Austria
Peter Fritsch, MD is a member of the following medical societies: American Dermatological Association, International Society of Pediatric Dermatology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine
Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology
Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Honoraria Consulting; Centocor Honoraria Consulting; Medicis Honoraria Consulting; Celgene Honoraria Consulting

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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