eMedicine Specialties > Radiology > Gastrointestinal

Hemochromatosis

Sandor Joffe, MD, Section Chief of Abdominal Imaging, Department of Radiology, Beth Israel Medical Center

Updated: May 8, 2009

Introduction

Background

Hemochromatosis is characterized by a progressive increase in total body iron stores with abnormal iron deposition in multiple organs.¹ Primary hemochromatosis is a genetic disorder, whereas secondary hemochromatosis can be the result of a variety of disorders, most commonly chronic hemolytic anemias.²

Pathophysiology

Primary hemochromatosis (also termed hereditary hemochromatosis or idiopathic hemochromatosis) is an autosomal recessive disorder.^3,4 This disease is the result of an abnormality, usually a single site mutation, in the HFE gene, which is located near the HLA complex and produces a glycoprotein. In such cases, affected patients have lower levels of hepcidin, a hepatic peptide hormone that negatively regulates iron efflux from the intestines into the blood. The normal HFE glycoprotein interacts with the transferrin receptor and decreases the affinity of this receptor for iron-bound transferrin.⁵ The mutated HFE glycoprotein does not have this interaction and allows cellular uptake of iron-based transferrin. In addition, these patients have an increase in intestinal iron absorption. Patients with primary hemochromatosis have increased total body iron stores of up to 20-40 g, whereas normal patients have iron stores of 1-3 g.^6,7

T2-weighted gradient echo axial image in a patient with hemochromatosis demonstrates diffuse abnormal low signal intensity of the liver. The pancreas and spleen appear normal.

Noncontrast CT scan in a 47-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse increased attenuation of the liver, representing abnormal iron deposition. The spleen is small and calcified from autosplenectomy.

Patients who receive multiple blood transfusions also develop iron overload, occasionally termed hemosiderosis or secondary hemochromatosis.^{1,8,9,10,11,12,13} Iron from the transfused erythrocytes is deposited in the reticuloendothelial system in the liver, spleen, and bone marrow. Abnormal iron accumulation in the reticuloendothelial system does not damage the affected organs and, thus, is of little clinical significance.

In patients who have received more than 40 units of blood, the reticuloendothelial system is typically saturated with iron (10 g), and additional iron deposits are seen in the parenchymal cells of the liver, pancreas, and heart. The abnormal parenchymal iron deposition can cause organ dysfunction, similar to that seen in primary hemochromatosis. Iron chelation therapy is used in patients who receive large numbers of transfusions to remove excess iron and prevent organ damage.^{1,8,9,10,11,12}

Patients with thalassemia have increased demand for iron in the bone marrow because of ineffective erythropoiesis. This results in increased absorption of iron. In patients without transfusions, the excess iron is deposited in hepatocytes, not in Kupffer cells. If patients are transfusion-dependent, they also may have abnormal iron deposition in the reticuloendothelial system.

Bantu siderosis, a condition found in parts of Africa, causes abnormal iron deposition in the liver. The disorder occurs in patients who drink a large amount of locally brewed beer, which is iron-laden. In addition, these patients have a genetic predisposition for increased iron absorption. These patients have abnormal iron deposition in both parenchymal cells (hepatocytes) and the reticuloendothelial system (Kupffer cells).

Frequency

International

Homozygous hemochromatosis occurs in 0.4-1% of persons of Northern European origin and is much less common in other populations.

Mortality/Morbidity

Patients with primary hemochromatosis who do not have cirrhosis have the same life expectancy as normal persons. Patients with cirrhosis and primary hemochromatosis have a poor prognosis. One third of deaths from hemochromatosis are the result of hepatocellular carcinoma. Other complications of cirrhosis, such as decreased liver function and varices, also account for a significant number of deaths from hemochromatosis. Cardiomyopathy and diabetes are uncommon causes of death in patients with hemochromatosis; however, patients with hemochromatosis and diabetes have a worse prognosis than other patients with hemochromatosis. The presence of arthropathy does not affect the prognosis in patients with hemochromatosis.

Race

Hemochromatosis occurs predominantly in white populations of Northern European origin.

Sex

Male-to-female ratio is 1.8:1.

Presentation

In primary hemochromatosis, the liver is the main organ for abnormal iron deposition and, if left untreated, may lead to cirrhosis. In addition to liver dysfunction in patients with cirrhosis from primary hemochromatosis, approximately 30% develop hepatocellular carcinoma. Hepatocellular carcinoma is not commonly seen in patients with hemochromatosis without cirrhosis.

The pancreas also is commonly involved by primary hemochromatosis. Patients with early hemochromatosis (noncirrhotic) frequently have insulin resistance, while patients with cirrhosis and hemochromatosis often have type 1 diabetes mellitus.

Patients with primary hemochromatosis often have hyperpigmentation of the skin.

Arthropathy occurs in 25-50% of patients with primary hemochromatosis and classically occurs in the second and third metacarpophalangeal joints. Arthropathy may occur early in the course of the disease.

Later in the course of the disease, approximately 40% of males develop pituitary hypogonadism with subsequent sexual impotence and loss of libido.

Cardiac involvement includes cardiomyopathy and arrhythmias and is a common cause of death in patients with primary hemochromatosis. Cardiac transplantation may be necessary in patients with severe cardiomyopathy.

Treatment involves frequent phlebotomy, particularly during the period after initial diagnosis. Symptoms such as hepatomegaly, skin pigmentation, lethargy, and abdominal pain are significantly improved with phlebotomy, but arthritis is not affected by therapy. Mild abnormalities of glucose metabolism improve with therapy, but type 1 diabetes mellitus is not affected by therapy. Hepatic fibrosis and cardiac dysfunction also improve after therapy.⁸

Screening for hemochromatosis can be performed with measurement of serum ferritin and transferring saturation. Definitive diagnosis of primary hemochromatosis can be made with genetic testing³ or liver biopsy with quantitative determination of liver iron concentration.^{14,15,16,17,18}

Preferred Examination

MRI is the best imaging examination to evaluate abnormal iron deposition in the liver. CT is less sensitive than MRI but can demonstrate increased iron if it is severe.

Limitations of Techniques

Although quantification of iron deposition in the liver is possible with MRI, calibration of each MR scanner is necessary. Therefore, quantitative MRI for iron deposition is not available at many institutions.

Differential Diagnoses

Hemochromatosis
Thalassemia

Computed Tomography

Noncontrast CT scan in a 47-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse increased attenuation of the liver, representing abnormal iron deposition. The spleen is small and calcified from autosplenectomy.

Findings

Patients with increased hepatic iron demonstrate diffuse increased attenuation of the liver, usually greater than 75 Hounsfield units on noncontrast examination. The liver vasculature appears particularly prominent because of the increased contrast between the vessels and the high-attenuation liver. Hepatomegaly also may be seen on CT scan.¹⁹ Dual-phase (arterial and venous) CT can help detect hepatocellular carcinoma in patients with cirrhosis.

Degree of Confidence

MRI is more sensitive and specific than CT for detection of abnormal hepatic iron deposition.

False Positives/Negatives

Other abnormalities that can cause increased attenuation of the liver on CT include amiodarone toxicity, Thorotrast, glycogen storage disease, gold therapy, and Wilson disease.

Magnetic Resonance Imaging

T2-weighted gradient echo axial image in a patient with hemochromatosis demonstrates diffuse abnormal low signal intensity of the liver. The pancreas and spleen appear normal.

T2-weighted spin echo axial image in a 4-year-old boy with thalassemia demonstrates abnormal low signal intensity of the liver, spleen, and pancreas.

T2-weighted gradient echo axial image in a 24-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse abnormal low signal intensity of the liver and spleen.

T2-weighted spin echo axial image in a 40-year-old man with alpha-thalassemia demonstrates diffuse abnormal low signal intensity of the liver, spleen, and pancreas.

Findings

Increased iron in the liver can be detected and quantified by MRI. Iron causes magnetic susceptibility artifact, which leads to spin dephasing (T2*-related signal loss). This dephasing results in decreased signal intensity on MRI images.^{11,19,20,21,22,23,24}

• T2-weighted gradient echo images are most sensitive to magnetic susceptibility artifact, thus are the best sequences to detect increased iron in the liver. T2-weighted gradient echo images can be performed as breath-hold images on most scanners. On a 1.5-T scanner, an echo time (TE) of at least 10 milliseconds and a flip angle of less than 30° should be used. The recovery time (TR) is less important and should be chosen based on the number of slices to be obtained and duration of the breath-hold.
• Although less sensitive than T2-weighted gradient echo sequences, spin echo sequences also may demonstrate decreased signal intensity of the liver in patients with increased hepatic iron concentration. Spin echo pulse sequences with a long TE (T2-weighted sequences) are more sensitive than those with a short TE.
• In determining whether the signal intensity of the liver is abnormally low, skeletal muscle can be used as a control. If the liver demonstrates signal intensity equal to or lower than that of skeletal muscle, such as the paraspinal muscles, on either T2-weighted gradient echo, or T2-weighted spin echo images, increased iron accumulation in the liver can be diagnosed.
• Most patients with primary hemochromatosis do not have involvement of the spleen; iron deposition in primary hemochromatosis occurs in the parenchymal cells of the liver (hepatocytes) and not in the reticuloendothelial system (Kupffer cells and spleen). Therefore, splenic signal intensity usually is normal in these patients.
• In patients with primary hemochromatosis, iron deposition can occur in the pancreas. Pancreatic involvement is uncommon in patients without cirrhosis. Most cirrhotic patients with primary hemochromatosis have pancreatic involvement and may have type 1 diabetes mellitus. These patients with pancreatic involvement usually demonstrate low signal intensity of the pancreas, regardless of whether they have diabetes.
• Many types of anemia require multiple blood transfusions, resulting in abnormal iron deposition in the reticuloendothelial system. These patients demonstrate MR evidence of iron overload in the liver and spleen with low signal of both organs, particularly on T2-weighted gradient echo images. If the reticuloendothelial system becomes saturated with iron from too many transfusions, iron may deposit in the parenchymal cells of the liver, pancreas, and heart. Therefore, these patients may demonstrate low signal in the liver, spleen, and pancreas.^{1,8,9,10,11,12}
• Patients with thalassemia who have not undergone transfusions may have increased iron in the liver with a similar appearance to that in patients with primary hemochromatosis. If these patients are transfusion-dependent, they may demonstrate low signal in the liver and spleen and possibly the pancreas. Bantu siderosis also may cause decreased signal intensity of the liver and spleen from abnormal iron deposition in these organs.
• Quantitative measurement of hepatic iron content can be performed with MR. Gandon et al evaluated T2 relaxation time and signal intensity ratios of liver to other tissues as a means of quantifying hepatic iron content. T2 relaxation time did not correlate with hepatic iron content as well as the liver-to-tissue signal-intensity ratios. They found the best correlation using a T2-weighted gradient echo sequence and calculating a ratio of the signal intensity of liver to that of fat.
• Bonkovsky et al found the best results using a gradient echo sequence with a repetition time of 18 milliseconds, a TE of 5 milliseconds, and a flip angle of 10°.²¹ They found the best results with a correlation between the iron concentration in the liver and the natural logarithm of the ratio of signal intensity of the liver to the standard deviation of the background noise. However, to accurately perform quantitative MR, each MR scanner needs to be properly calibrated with patients who have undergone liver biopsy to measure iron content.
• Alustiza et al found that at least 2 different pulse sequences are required to adequately quantify hemochromatosis, and they used T2- and intermediate-weighted gradient echo sequences.²⁰
• In order to accurately perform quantitative MR, each MR scanner must be properly calibrated with patients who have undergone liver biopsy to measure iron content. In the future, if phantoms are developed, it may be possible to calibrate each MR scanner against phantoms. High field-strength magnets are likely to be more accurate at quantifying hepatic iron concentration than mid or low field-strength units.

Degree of Confidence

Quantitative measurement of hepatic iron content by MRI has the advantage of sampling the entire liver, whereas liver biopsy only samples a small area of liver parenchyma. In addition, quantitative measurement of hepatic iron by MRI avoids the risks inherent in percutaneous liver biopsy.

False Positives/Negatives

Although MR is sensitive at detecting abnormal hepatic iron, particularly if performed with optimized technique for this purpose, it may not always determine the etiology of the abnormal iron deposition based on its distribution. However, this is typically not a difficult problem clinically, as the patient's history usually confirms the etiology.

Ultrasonography

Findings

Iron deposits in the liver usually do not alter liver echogenicity. If sonographic liver abnormalities are present, they are usually secondary to cirrhosis. An echogenic pancreas has been described with iron deposition.

Intervention

Measurement of hepatic iron concentration is most accurately performed by liver biopsy.²⁵ This is frequently performed with ultrasound or CT guidance. However, errors in this measurement can occur, often caused by inadequate sample size, sampling error, contamination, or laboratory error. In addition, hepatic biopsy samples only a small area of liver, while MR images the entire liver.^{14,15,16,17,18}

Multimedia

Media file 1: T2-weighted gradient echo axial image in a patient with hemochromatosis demonstrates diffuse abnormal low signal intensity of the liver. The pancreas and spleen appear normal.

Media file 2: T2-weighted spin echo axial image in a 4-year-old boy with thalassemia demonstrates abnormal low signal intensity of the liver, spleen, and pancreas.

Media file 3: T2-weighted gradient echo axial image in a 24-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse abnormal low signal intensity of the liver and spleen.

Media file 4: T2-weighted spin echo axial image in the same patient as Picture 3 demonstrates diffuse abnormal low signal intensity of the liver and spleen. Signal abnormality is less apparent on this spin echo image, and the liver is only slightly lower in signal intensity than the paraspinal muscles.

Media file 5: T1-weighted spin echo axial image in the same patient as Pictures 3 and 4 fails to demonstrate abnormal low signal intensity of the liver and spleen.

Media file 6: T2-weighted spin echo axial image in a 40-year-old man with alpha-thalassemia demonstrates diffuse abnormal low signal intensity of the liver, spleen, and pancreas.

Media file 7: T1-weighted spin echo axial image in the same patient as Picture 6 demonstrates diffuse abnormal low signal intensity of the liver, spleen, and pancreas. Although T1-weighted images are less sensitive than many other pulse sequences at detecting abnormal iron deposition, they still may demonstrate this abnormality.

Media file 8: Noncontrast CT scan in a 47-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse increased attenuation of the liver, representing abnormal iron deposition. The spleen is small and calcified from autosplenectomy.

Media file 9: T1-weighted spin echo image in the same patient as Picture 8 demonstrates diffuse abnormal low signal intensity of the liver.

Media file 10: T2-weighted spin echo image in the same patient as Pictures 8 and 9 demonstrates diffuse abnormal low signal intensity of the liver.

Media file 11: T2-weighted gradient echo image in the same patient as Pictures 8-10 demonstrates diffuse abnormal low signal intensity of the liver. Magnetic susceptibility artifact obscures the upper pole of the left kidney because of dense splenic calcification.

Media file 12: MRI demonstrates abnormal low signal intensity of the liver on this T2-weighted gradient echo image in a 37-year-old male. The spleen and pancreas are normal. These findings indicate abnormal iron deposition in the liver with sparing of the spleen and pancreas. This distribution is typical of hemochromatosis before the onset of cirrhosis.

References

1. Schranz M, Talasz H, Graziadei I, Winder T, Sergi C, Bogner K, et al. Diagnosis of hepatic iron overload: a family study illustrating pitfalls in diagnosing hemochromatosis. Diagn Mol Pathol. Mar 2009;18(1):53-60. [Medline].

2. Pietrangelo A. Inherited metabolic disease of the liver. Curr Opin Gastroenterol. Apr 1 2009;[Medline].

3. Picot J, Bryant J, Cooper K, Clegg A, Roderick P, Rosenberg W, et al. Psychosocial aspects of DNA testing for hereditary hemochromatosis in at-risk individuals: a systematic review. Genet Test Mol Biomarkers. Feb 2009;13(1):7-14. [Medline].

4. Phatak PD, Sham RL, Raubertas RF. Prevalence of hereditary hemochromatosis in 16031 primary care patients. Ann Intern Med. Dec 1 1998;129(11):954-61. [Medline].

5. Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab. Mar 2009;9(3):217-27. [Medline].

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7. Bartolo C, McAndrew PE, Sosolik RC. Differential diagnosis of hereditary hemochromatosis from other liver disorders by genetic analysis: gene mutation analysis of patients previously diagnosed with hemochromatosis by liver biopsy. Arch Pathol Lab Med. Jul 1998;122(7):633-7. [Medline].

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13. Flyer MA, Haller JO, Sundaram R. Transfusional hemosiderosis in sickle cell anemia: another cause of an echogenic pancreas. Pediatric Radiology. 1993;23(2):140-2.

14. Wang X, Leiendecker-Foster C, Acton RT, Barton JC, McLaren CE, McLaren GD, et al. Heme carrier protein 1 (HCP1) genetic variants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study participants. Blood Cells Mol Dis. Mar-Apr 2009;42(2):150-4. [Medline].

15. Pedersen P, Milman N. Genetic screening for HFE hemochromatosis in 6,020 Danish men: penetrance of C282Y, H63D, and S65C variants. Ann Hematol. Jan 22 2009;[Medline].

16. Phatak PD, Bonkovsky HL, Kowdley KV. Hereditary hemochromatosis: time for targeted screening. Ann Intern Med. Aug 19 2008;149(4):270-2. [Medline].

17. Adams PC, Reboussin DM, Barton JC, Acton RT, Speechley M, Leiendecker-Foster C, et al. Serial serum ferritin measurements in untreated HFE C282Y homozygotes in the Hemochromatosis and Iron Overload Screening Study. Int J Lab Hematol. Aug 2008;30(4):300-5. [Medline].

18. Acton RT, Barton JC, Passmore LV, Adams PC, McLaren GD, Leiendecker-Foster C, et al. Accuracy of family history of hemochromatosis or iron overload: the hemochromatosis and iron overload screening study. Clin Gastroenterol Hepatol. Aug 2008;6(8):934-8. [Medline].

19. Kawamoto S, Soyer PA, Fishman EK. Nonneoplastic liver disease: evaluation with CT and MR imaging. Radiographics. Jul-Aug 1998;18(4):827-48. [Medline].

20. Alustiza JM, Artetxe J, Castiella A, et al. MR quantification of hepatic iron concentration. Radiology. Feb 2004;230(2):479-84. [Medline].

21. Bonkovsky HL, Rubin RB, Cable EE. Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques. Radiology. Jul 1999;212(1):227-34. [Medline].

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Keywords

hemochromatosis, haemochromatosis, hereditary hemochromatosis, primary hemochromatosis, secondary hemochromatosis, idiopathic hemochromatosis, hemosiderosis, iron overload, iron toxicity

Contributor Information and Disclosures

Author

Sandor Joffe, MD, Section Chief of Abdominal Imaging, Department of Radiology, Beth Israel Medical Center
Sandor Joffe, MD is a member of the following medical societies: American College of Radiology, American Roentgen Ray Society, and Radiological Society of North America
Disclosure: Nothing to disclose.

Medical Editor

Neela Lamki, MD, Professor, Department of Radiology, Sultan Qaboos University, Oman; Adjunct Professor, Department of Radiology, Baylor College of Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand
Disclosure: Nothing to disclose.

Managing Editor

Udo P Schmiedl, MD, PhD, Clinical Professor, Department of Radiology, University of Washington; Consulting Staff, Swedish Medical Center, University of Washington Medical Center, Seattle Radiologists
Udo P Schmiedl, MD, PhD is a member of the following medical societies: American College of Radiology and Radiological Society of North America
Disclosure: Nothing to disclose.

CME Editor

Robert M Krasny, MD, Consulting Staff, Department of Radiology, Resolution Imaging Medical Corporation
Robert M Krasny, MD is a member of the following medical societies: American Roentgen Ray Society and Radiological Society of North America
Disclosure: Nothing to disclose.

Chief Editor

John Karani, MBBS, FRCR, Clinical Director of Radiology and Consultant Radiologist, Department of Radiology, King's College Hospital, London
John Karani, MBBS, FRCR is a member of the following medical societies: British Institute of Radiology, British Society of Interventional Radiology, Cardiovascular and Interventional Radiological Society of Europe, European Society of Gastrointestinal and Abdominal Radiology, European Society of Radiology, Radiological Society of North America, and Royal College of Radiologists
Disclosure: Nothing to disclose.

Clinical guidelines

Screening for hemochromatosis: recommendation statement.
United States Preventive Services Task Force - Independent Expert Panel.  2006.  5 pages.  NGC:004959

Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians.
American College of Physicians - Medical Specialty Society.  2005 Oct 4.  5 pages.  NGC:004540

AASLD practice guidelines: evaluation of the patient for liver transplantation.
American Association for the Study of Liver Diseases - Private Nonprofit Research Organization.  2000 Jan (revised 2005 Jun).  26 pages.  NGC:004333


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Treatment of Hemochromatosis

Erythrocyte Apheresis Versus Phlebotomy in Hemochromatosis

Oral Nifedipine to Treat Iron Overload


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