Hemochromatosis: Presentations and Considerations in the Emergency Department

Authors: Aaron Deeds, MD (HO-1, University of Nebraska Medical Center) and Claudia Barthold, MD (EM Program Director, University of Nebraska Medical Center) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

Case

A 34-year-old man presents to the emergency department with chief complaint of chronic lethargy. He feels it’s more bothersome today and is “tired of feeling tired”.   He does not have a regular doctor and no known past medical history.  He has 3-4 alcoholic drinks 4-5 times a week.

Vital signs are within normal limits.  Lab results include: Glucose 247, AST 300, ALT 250, Hemoglobin 15.1, Hematocrit 49.1.

Physical examination is pertinent for diffuse brown/bronze pigmentation of the skin that has been progressive.  The patient reports his father had a similar pigmentation of the skin which is why he never paid attention to it.  Mild hepatomegaly is also noted.

What is in your differential for this patient’s presentation?  What tests should be ordered to definitively diagnose this condition?

Background

Hereditary hemochromatosis is a group of genetic iron-overload syndromes caused by increased iron accumulation or impaired iron recycling in the tissue leading to cellular damage.¹   Most commonly, a deficiency in the HFE gene causes the protein hepicidin to produce increased ferroportin expression on the cellular service and subsequent iron accumulation.¹ This iron is accumulated preferentially in cardiac, endocrine, hepatic, and pancreatic cells.  Cellular damage is mediated by reactive oxygen species produced by the excess iron.  The extent and timeline of cellular damage is poorly understood, but it is also mediated by genetic and environmental factors such as concurrent alcohol consumption.^1,2   The most common mutation causing the iron overload syndromes is present in about 10% of those of Northern European ancestry and about 1 in 200 of those will be homozygous for the mutation manifesting as disease.^3,4

Signs/Symptoms

Patients initially presenting with hemochromatosis have significantly changed with the advent of routine medical testing and visits, the variable penetrance of the disease, and the environmental factors affecting the timeline of manifestations of the disease.^1,3,4  The classic compilation of the disease manifests as diabetes, dilated/restrictive cardiomyopathy, hepatic cirrhosis, and skin pigmentation.¹  However, this is much rarer today than in the past.  Table 1 outlines the findings of a study investigating the clinical manifestations of hemochromatosis between 1997-2007.⁵  The penetrance of skin pigmentation was not included in the study.

The most common initial complaint is chronic lethargy.¹  Arthropathy and bone disease is another important clinical feature of hemochromatosis, and early osteoporosis may be an indicator for the disease.¹  Males develop symptoms usually in the 3^rd to 4^th decade of life, while females develop symptoms post-menopause, as monthly menses is a protective feature.  Environmental factors such as alcoholism, viral hepatitis infection, and diets heavy in red meat cause symptoms to develop earlier in life, however the timeline to developing symptoms is highly variable.

Table 1.  Manifestations of symptoms in classic HFE-Related Hemochromatosis

Testing

Diagnosis is made through clinical suspicion and abnormal lab tests.  Elevated transaminase levels, serum ferritin levels, and transferrin saturation in combination increase likelihood of hemochromatosis.⁵ Genetic testing is the gold standard for diagnosis.⁵  The penetrance of the disease is highly variable with environmental risk factors.  Increased alcohol consumption can increase the cellular damage and produce symptoms at a younger age, while others may be asymptomatic until much later in life.² 

Diagnosis is made through clinical suspicion and abnormal lab tests.  The most specific test for hemochromatosis is transferrin saturation levels elevated above 45%.¹  Serum ferritin and serum iron concentrations are also elevated in hemochromatosis, but with much less specificity and more false negative and false positive results.^1,5  Many acute and chronic conditions can elevate serum ferritin levels, and the test should be taken in consideration with the clinical picture.  Other lab results such as elevated liver function tests, elevated glucose/HbA1C, and abnormal EKG/echocardiogram findings suggest late manifestations of the disease.  The gold standard for diagnosing hemochromatosis is definitive genetic testing for the affected genes.¹

Prognosis

Hemochromatosis has a potentially excellent prognosis dependent with early diagnosis of the disease. With appropriate treatment, patients with hemochromatosis can expect normal life expectancy.¹  Patients with advanced features of the disease such as cirrhosis have a life expectancy of approximately 50 years.⁵  Patients must be counseled on the dangers of alcohol consumption with this disease.

Treatment

The goal in the emergency department should be suspicion of the diagnosis and establishment of appropriate follow-up for definitive diagnosis and treatment.  The gold standard of treatment is maintenance phlebotomy until serum ferritin levels are reduced to normal levels.  Alternative therapies include the use of iron chelators and erythrocytapharesis, which are more costly and non-superior to scheduled phlebotomy.¹

Key Points

1. Have higher suspicion in patients of northern European descent, men in their 3^rd-4^th decade, and postmenopausal women.
2. Presentations include chronic lethargy, arthropathies, diabetes, hepatitis, skin pigmentation, hypogonadism, cardiomyopathy.
3. Serum transferrin saturation greater than 45% is the most specific finding on testing.
4. Genetic testing is the gold standard for definitive diagnosis.
5. Suspecting diagnosis and ensuring adequate follow up are the goals of care in the emergency department.
6. Lifelong maintenance phlebotomy is the preferred treatment.

References/Further Reading: 

1. Powell, Lawrie W., Rebecca C. Seckington, and Yves Deugnier. “Haemochromatosis.” The Lancet 388.10045 (2016): 706-716.

2. Aragon, George, and Zobair M. Younossi. “When and how to evaluate mildly elevated liver enzymes in apparently healthy patients.” Cleve Clin J Med 77.3 (2010): 195-204.

3. Adams, Paul C., et al. “Hemochromatosis and iron-overload screening in a racially diverse population.” New England Journal of Medicine 352.17 (2005): 1769-1778.

4. Bacon, Bruce R., et al. “Molecular medicine and hemochromatosis: at the crossroads.” Gastroenterology 116.1 (1999): 193-207.

5. Fracanzani, Anna Ludovica, et al. “Hemochromatosis in Italy in the last 30 years: role of genetic and acquired factors.” Hepatology 51.2 (2010): 501-510.

6. Adams, P. C. “Epidemiology and diagnostic testing for hemochromatosis and iron overload.” International journal of laboratory hematology 37.S1 (2015): 25-30.