History

Fact Explanation
Age Hemochromatosis is a disorder of iron overload, with excess iron accumulation in tissues leading to organ toxicity. Hemochromatosis can be hereditary or can be secondary to iron loading anemias or rarely by excessive oral or parenteral iron loading.(Please refer section on differentials). In case of hereditary hemochromatosis middle aged men are more frequently and severely affected than women. Women develop symptoms several years later(usually after menopause). This is because pre-menopausal females lose iron through menstrual blood loss. Hereditary hemochromatosis is classified into types depending on age of onset, genetic cause and mode of inheritance. Type 1, also called Classic Hemochromatosis is the most common iron overload disease. Type 1 and type 4 (or ferroportin disease) are adult-onset disorders that typically occur in men between the ages of 40 and 60, and women usually develop symptoms after menopause. Type 2 hemochromatosis is a juvenile-onset disorder and symptoms may begin to appear in childhood. Type 3 hemochromatosis is an intermediate between types 1 and 2 and symptoms generally begin before age 30. Types 1, 2, and 3 are inherited in an autosomal recessive pattern and type 4 in autosomal dominant pattern. These patients absorb extra amounts of iron from the daily diet which get deposited in the body giving rise to an array of problems discussed below. Untreated hemochromatosis can be fatal. Rarely iron overload begins before birth, giving rise to neonatal hemochromatosis. [1][2][3][9]
Severe fatigue/tiredness This is the most common symptom found in these patients which may also be secondary to heart failure[3][6][8][9]
Abdominal pain, jaundice and liver failure (ascites or encephalopathy Due to progressive iron deposition in the liver parenchyma patient may eventually develop Cirrhosis. Cirrhosis may be complicated by hepato cellular carcinoma. Relative risk of developing HCC is 20-200 fold. HCC is the most common cause of death (45%) in patients with hereditary hemochromatosis. Mild to moderate iron overload is seen to be common in those with chronic hepatitis C infection[3][6][8][9]
Skin bronzing A combination of iron deposition and melanin causes the hyperpigmentation that is typical of this disease[3][6][8][9]
Polyuria, polydipsia, weight loss, lethargy etc. Diabetes mellitus is the most common endocrinopathy seen in these patients. They often require insulin therapy. Occurs as a result of excessive iron accumulation in the pancreas causing islet cell destruction. The classic triad consisting of cirrhosis, diabetes mellitus, and pigmentation of skin occurs late in the disease[3][6][8][9]
Joint pain, joint deformity Due to iron accumulation in joint tissues these patients develop arthropathy. The commonest joints involved are small joints of hands and feet, wrist, knees, back and neck [3][4][6][8][9]
Amenorrhea, loss of libido, impotence Hypogonadism due to pituitary iron deposition is a common endocrine abnormality associated with hemochromatosis. It causes decreased libido and impotence in men and absence of the menstrual cycle or early menopause in women. These may also be related to development of cirrhosis[3][6][8][9]
Shortness of breath, palpitations, chest pain, poor exercise tolerance, orthopnea, peripheral oedema etc These patients can develop dilated cardiomyopathy, associated with the development of heart failure and arrhythmias. Features of fluid overload are seen with development of congestive cardiac failure[3][8][9]
Bone pain, prone to bone fractures About 25% of patients with hemochromatosis have osteoporosis, while 41% are diagnosed with osteopenia.These are associated with hypogonadism and the severity of iron overload[5][8][9]
Loss of body hair Partial loss of body hair is evident in majority of patients. Most commonly affected is the pubic area, although total loss of body hair is seen in some patients[9]
Tiredness, lethargy, cold intolerance, constipation etc These are symptoms suggestive of hypothyroidism. Symptomatic patients should be tested for thyroid function[6][7]
Family history of iron overload disease Hereditary hemochromatosis(HH) is an inherited disease. HH types 1, 2, and 3 are inherited in an autosomal recessive pattern and type 4 in autosomal dominant pattern. Therefore the patient may have a positive family history[1][6]
References
  1. Hemochromatosis. Genetics home reference. U.S National Library of Medicine.[online] Reviewed October 2006. [viewed on 24 July 2014] Available from:http://ghr.nlm.nih.gov/condition/hemochromatosis
  2. GATTERMANN N. The Treatment of Secondary Hemochromatosis Dtsch Arztebl Int [online] 2009 Jul, 106(30):499-504 [viewed 24 July 2014] Available from: doi:10.3238/arztebl.2009.0499
  3. VUJIć M. Molecular basis of HFE-hemochromatosis Front Pharmacol [online] :42 [viewed 24 July 2014] Available from: doi:10.3389/fphar.2014.00042
  4. PASCART T, RICHETTE P, FLIPO RM. Treatment of nongout joint deposition diseases: an update. Arthritis [online] 2014:375202 [viewed 24 July 2014] Available from: doi:10.1155/2014/375202
  5. KEW MC. Hepatic iron overload and hepatocellular carcinoma. Liver Cancer [online] 2014 Mar, 3(1):31-40 [viewed 24 July 2014] Available from: doi:10.1159/000343856
  6. DEVER JB, MALLORY MA, MALLORY JE, WALLACE D, KOWDLEY KV. Phenotypic Characteristics and Diagnoses of Patients Referred to an Iron Overload Clinic Dig Dis Sci [online] 2010 Mar, 55(3):803-807 [viewed 27 July 2014] Available from: doi:10.1007/s10620-009-1080-1
  7. JEONG HK, AN JH, KIM HS, CHO EA, HAN MG, MOON JS, KIM HK, KANG HC. Hypoparathyroidism and Subclinical Hypothyroidism with Secondary Hemochromatosis Endocrinol Metab (Seoul) [online] 2014 Mar, 29(1):91-95 [viewed 27 July 2014] Available from: doi:10.3803/EnM.2014.29.1.91
  8. CROWNOVER BK, COVEY CJ. Hereditary hemochromatosis. Am Fam Physician [online] 2013 Feb 1, 87(3):183-90 [viewed 27 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23418762
  9. BACON BR, ADAMS PC, KOWDLEY KV, POWELL LW, TAVILL AS. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases Hepatology [online] 2011 Jul, 54(1):328-343 [viewed 27 July 2014] Available from: doi:10.1002/hep.24330

Examination

Fact Explanation
Pallor May indicate presence of anemia[1][2]
Skin bronzing or hyperpigmentation Is a typical sign in patients with hemochromatosis[1]
Tenderness in the right upper quadrant of abdomen, hepatomegaly, palmar erythema, spider angioma, jaundice, ascites, splenomegaly, encephalopathy Presence of these signs indicate advanced liver involvement[1]
Tachycardia, irregular pulse, hypotension, elevated jugular venous pressure, peripheral edema, displaced diffuse apex, S3 gallop, pan systolic murmur of mitral/tricuspid regurgitation, crackles in lung bases These signs are associated with dilated cardiomyopathy and cardiac failure[1]
Hair loss Most evident and commonly affected area of the body is the pubic area. Total loss of body hair is seen in some patients[1]
Joint swelling and tenderness Typically involves the first and second metacarpophalangeal joints. Other commonly involved joints include proximal interphalangeal joints, knees, feet, wrists, back and neck[1]
References
  1. BACON BR, ADAMS PC, KOWDLEY KV, POWELL LW, TAVILL AS. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases Hepatology [online] 2011 Jul, 54(1):328-343 [viewed 27 July 2014] Available from: doi:10.1002/hep.24330
  2. GATTERMANN N. The Treatment of Secondary Hemochromatosis Dtsch Arztebl Int [online] 2009 Jul, 106(30):499-504 [viewed 24 July 2014] Available from: doi:10.3238/arztebl.2009.0499

Differential Diagnoses

Fact Explanation
Hereditary hemochromatosis Is the main differential diagnosis in patients with hemochromatosis[3][4]
Alcoholic liver disease Can give rise to hemochromatosis[2][3][4]
Chronic hepatitis C infection Has shown to be associated with chronic iron overload[2][3][4]
Chronic hemolytic anemia Can cause secondary hemochromatosis. Patient with iron overload due to chronic anemias have increased duodenal iron absorption to a level that they may have clinically evident iron overload. Examples of such conditions include Hereditary spherocytosis, acquired sideroblastic anemia[1][3][4]
Multiple transfusions Patients with beta thalassemia major, sickle cell anemia, refractory aplastic anemia, and myelodysplastic syndrome etc. need multiple transfusions to maintain there hemoglobin levels. Each patient receive 200-250 mg of iron per each unit of packed red cells transfused. Normal daily loss of iron is only 1mg. All this excess iron accumulates in the body in the long term and cause hemochromatosis[1][3]
Ineffective erythropoiesis with marrow hyperplasia Patients with diseases such as beta thalassemia major, sickle cell anemia, refractory aplastic anemia, and myelodysplastic syndrome etc. fall under this category. These patients also have increased duodenal iron absorption[1][3][4]
Prolonged haemodialysis Dialysis patients receive intravenous iron supplements as treatment for anemia. This can also lead to chronic iron overload which can become evident clinically[3]
Porphyria cutanea tarda This is a subtype of porphyria with photosensitive skin manifestations associated with cirrhosis. skin hyperpigmentation and iron overload[3][4]
References
  1. GATTERMANN N. The Treatment of Secondary Hemochromatosis Dtsch Arztebl Int [online] 2009 Jul, 106(30):499-504 [viewed 24 July 2014] Available from: doi:10.3238/arztebl.2009.0499
  2. DEVER JB, MALLORY MA, MALLORY JE, WALLACE D, KOWDLEY KV. Phenotypic Characteristics and Diagnoses of Patients Referred to an Iron Overload Clinic Dig Dis Sci [online] 2010 Mar, 55(3):803-807 [viewed 27 July 2014] Available from: doi:10.1007/s10620-009-1080-1
  3. BACON BR, ADAMS PC, KOWDLEY KV, POWELL LW, TAVILL AS. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases Hepatology [online] 2011 Jul, 54(1):328-343 [viewed 27 July 2014] Available from: doi:10.1002/hep.24330
  4. BATTS KP. Iron overload syndromes and the liver. Mod Pathol [online] 2007 Feb:S31-9 [viewed 27 July 2014] Available from: doi:10.1038/modpathol.3800715

Investigations - for Diagnosis

Fact Explanation
Serum transferrin saturation This is the widely used screening test for hemochromatosis. The threshold for hemochromatosis is a fasting transferrin saturation greater than 45%[1][2][4][5]
Serum ferritin Ferritin levels are less sensitive than transferrin saturation as a screening tests for hemochromatosis because the levels may be elevated in a number of other diseases involving liver. But it is considered the best screening tool to assess iron overload related organ damage because levels greater than 1000 mcg/L are more associated with symptomatic disease and advanced state of liver fibrosis[1][2][4][5]
Serum iron Will be markedly elevated.[5]
Complete blood count(CBC) and blood picture May help in the diagnosis of hemochromatosis due to blood disorders. CBC should also be done before and after phlebotomy to determine hematocrit/ hemoglobin level[5][6][7]
Genetic testing About 85-90% of patients with inherited hemochromatosis are homozygous for C282Y mutation in HFE gene with a minority are heterozygotes for C282Y mutation and H63D or S65C mutation[1][2][3][5]
References
  1. KEW MC. Hepatic iron overload and hepatocellular carcinoma. Liver Cancer [online] 2014 Mar, 3(1):31-40 [viewed 25 July 2014] Available from: doi:10.1159/000343856
  2. BHAVNANI M, LLOYD D, MARPLES J, PENDRY K, WORWOOD M. Targeted screening for genetic haemochromatosis: a combined phenotype/genotype approach J Clin Pathol [online] 2006 May, 59(5):501-504 [viewed 25 July 2014] Available from: doi:10.1136/jcp.2005.031898
  3. BHAVNANI M, LLOYD D, BHATTACHARYYA A, MARPLES J, ELTON P, WORWOOD M. Screening for genetic haemochromatosis in blood samples with raised alanine aminotransferase Gut [online] 2000 May, 46(5):707-710 [viewed 25 July 2014] Available from: doi:10.1136/gut.46.5.707
  4. DEVER JB, MALLORY MA, MALLORY JE, WALLACE D, KOWDLEY KV. Phenotypic Characteristics and Diagnoses of Patients Referred to an Iron Overload Clinic Dig Dis Sci [online] 2010 Mar, 55(3):803-807 [viewed 27 July 2014] Available from: doi:10.1007/s10620-009-1080-1
  5. BACON BR, ADAMS PC, KOWDLEY KV, POWELL LW, TAVILL AS. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases Hepatology [online] 2011 Jul, 54(1):328-343 [viewed 27 July 2014] Available from: doi:10.1002/hep.24330
  6. JEONG HK, AN JH, KIM HS, CHO EA, HAN MG, MOON JS, KIM HK, KANG HC. Hypoparathyroidism and Subclinical Hypothyroidism with Secondary Hemochromatosis Endocrinol Metab (Seoul) [online] 2014 Mar, 29(1):91-95 [viewed 27 July 2014] Available from: doi:10.3803/EnM.2014.29.1.91
  7. GATTERMANN N. The Treatment of Secondary Hemochromatosis Dtsch Arztebl Int [online] 2009 Jul, 106(30):499-504 [viewed 24 July 2014] Available from: doi:10.3238/arztebl.2009.0499

Investigations - Fitness for Management

Fact Explanation
Liver function tests Elevated liver enzyme levels indicate involvement of liver[1][2][4]
Serum creatinine Done to determine baseline renal function[1][4]
Liver biopsy Done in patients with elevated liver enzymes or serum ferritin >1000 mcg/L to stage the degree of liver disease and determine degree of iron loading[1][2][4]
Thyroid stimulating hormone (TSH) / Free thyroxine (T4) Done to detect the presence of hypothyroidism in patients with hemochromatosis who have symptoms suggestive of hypothyroidism[2][3]
Echocardiogram Done in patients with clinical features suggestive of cardiomyopathy or heart failure[2]
Fasting plasma glucose/ HbA1c These tests are done in patients with symptoms of diabetes to confirm diagnosis and as a screening tool to detect presence of diabetes mellitus in patients with iron overload[5]
References
  1. PHATAK P, BRISSOT P, WURSTER M, ADAMS PC, BONKOVSKY HL, GROSS J, MALFERTHEINER P, MCLAREN GD, NIEDERAU C, PIPERNO A, POWELL LW, RUSSO MW, STOELZEL U, STREMMEL W, GRIFFEL L, LYNCH N, ZHANG Y, PIETRANGELO A. A Phase 1/2, Dose-Escalation Trial of Deferasirox for the Treatment of Iron Overload in HFE-Related Hereditary Hemochromatosis Hepatology [online] 2010 Nov, 52(5):1671-1679 [viewed 25 July 2014] Available from: doi:10.1002/hep.23879
  2. JEONG HK, AN JH, KIM HS, CHO EA, HAN MG, MOON JS, KIM HK, KANG HC. Hypoparathyroidism and Subclinical Hypothyroidism with Secondary Hemochromatosis Endocrinol Metab (Seoul) [online] 2014 Mar, 29(1):91-95 [viewed 27 July 2014] Available from: doi:10.3803/EnM.2014.29.1.91
  3. BARTON JC, LEIENDECKER-FOSTER C, REBOUSSIN DM, ADAMS PC, ACTON RT, ECKFELDT JH, HEMOCHROMATOSIS AND IRON OVERLOAD SCREENING STUDY RESEARCH INVESTIGATORS. Thyroid-stimulating hormone and free thyroxine levels in persons with HFE C282Y homozygosity, a common hemochromatosis genotype: the HEIRS study. Thyroid [online] 2008 Aug, 18(8):831-8 [viewed 27 July 2014] Available from: doi:10.1089/thy.2008.0091
  4. BACON BR, ADAMS PC, KOWDLEY KV, POWELL LW, TAVILL AS. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases Hepatology [online] 2011 Jul, 54(1):328-343 [viewed 27 July 2014] Available from: doi:10.1002/hep.24330
  5. SIMCOX JA, MCCLAIN DA. Iron and Diabetes Risk Cell Metab [online] 2013 Mar 5, 17(3):329-341 [viewed 28 July 2014] Available from: doi:10.1016/j.cmet.2013.02.007

Investigations - Followup

Fact Explanation
Serum alpha feto-protein (AFP) Is a tumor marker for hepatocellular carcinoma(HCC) which should be done during follow up of patients with cirrhosis. [1][2][3]
Ultrasound scan of abdomen This is also a test done for the follow up patients with cirrhosis. Both these tests help in early detection of HCC[1][2][3]
References
  1. VAN MEER S, DE MAN RA, SIERSEMA PD, VAN ERPECUM KJ. Surveillance for hepatocellular carcinoma in chronic liver disease: Evidence and controversies World J Gastroenterol [online] 2013 Oct 28, 19(40):6744-6756 [viewed 27 July 2014] Available from: doi:10.3748/wjg.v19.i40.6744
  2. FLORES A, MARRERO JA. Emerging Trends in Hepatocellular Carcinoma: Focus on Diagnosis and Therapeutics Clin Med Insights Oncol [online] :71-76 [viewed 27 July 2014] Available from: doi:10.4137/CMO.S9926
  3. BACON BR, ADAMS PC, KOWDLEY KV, POWELL LW, TAVILL AS. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases Hepatology [online] 2011 Jul, 54(1):328-343 [viewed 27 July 2014] Available from: doi:10.1002/hep.24330

Investigations - Screening/Staging

Fact Explanation
Serum ferritin(SF) and transferrin saturation(TS) Recommended to be done in all first degree relatives of an index patient with HFE related HH, for early diagnosis and prevention of complications[1]
Genetic testing This should be done together with SF and TS testing in first degree relatives of an affected person with HFE related HH[1]
References
  1. BACON BR, ADAMS PC, KOWDLEY KV, POWELL LW, TAVILL AS. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases Hepatology [online] 2011 Jul, 54(1):328-343 [viewed 27 July 2014] Available from: doi:10.1002/hep.24330

Management - General Measures

Fact Explanation
Dietary changes Dietary modification have not widely shown to change patient outcome in HH. However limiting foods that contain large concentrations of bioavailable iron ( e.g.red meats and organ meats) is beneficial for secondary hemochromatosis. All hemochromatosis patients should avoid iron supplements, including multivitamins with iron and vitamin C supplements. Tannates (in tea), phytates, oxalates, calcium, and phosphates, can inhibit iron absorption by binding.[1][2][3]
Abstain from alcohol consumption Alcohol abuse may accelerate disease progression by enhancing iron absorption and hepatotoxicity. Red wine, contains relatively high concentrations of iron. Alcohol also increases the relative risk for development of liver cancer in patients with cirrhosis. Heavy alcohol consumption has shown to be related with higher mortality in patients with HH[3]
References
  1. BACON BR, ADAMS PC, KOWDLEY KV, POWELL LW, TAVILL AS. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases Hepatology [online] 2011 Jul, 54(1):328-343 [viewed 27 July 2014] Available from: doi:10.1002/hep.24330
  2. HURRELL R, EGLI I. Iron bioavailability and dietary reference values. Am J Clin Nutr [online] 2010 May, 91(5):1461S-1467S [viewed 27 July 2014] Available from: doi:10.3945/ajcn.2010.28674F
  3. BORGAONKAR MR. Hemochromatosis; More common than you think. Canadian family physician[online] January 2003, (49)[viewed 27 July 2014] Available from; http://www.cfp.ca/content/49/1/36.full.pdf

Management - Specific Treatments

Fact Explanation
Phlebotomy Done to remove the excess iron from body and to maintain normal iron stores. This is the mainstay of treatment for HH. Initiation of phlebotomy before development of cirrhosis and/ or diabetes has shown to reduce morbidity and mortality. Feature such as skin pigmentation, abdominal pain, fatigue and progression of organ damage can be reversed with phlebotomy. But hypogonadism, advanced cirrhosis and arthropathy are less responsive. The target is to achieve a serum ferritin level of 50-100 mcg/L and avoid iatrogenic iron deficiency. Phlebotomy is contraindicated in patients with anemia, severe heart disease, poor venous access[1]
Deferisirox This is an oral iron chelator taken once daily. Given for treatment of secondary hemochromatosis due to recurrent transfusions or dyserythropoiesis or chronic hemolysis. Liver and renal function monitoring should be done[1][2][3][4]
Deferoxamine This is a parenteral iron chelator administered as continuous subcutaneous infusion by a battery operated infusion pump. Effective for the treatment of secondary hemochromatosis. Disadvantages of this therapy include cost, discomfort, inconvenience and neurotoxicity[1][2][3][4]
References
  1. PHATAK P, BRISSOT P, WURSTER M, ADAMS PC, BONKOVSKY HL, GROSS J, MALFERTHEINER P, MCLAREN GD, NIEDERAU C, PIPERNO A, POWELL LW, RUSSO MW, STOELZEL U, STREMMEL W, GRIFFEL L, LYNCH N, ZHANG Y, PIETRANGELO A. A Phase 1/2, Dose-Escalation Trial of Deferasirox for the Treatment of Iron Overload in HFE-Related Hereditary Hemochromatosis Hepatology [online] 2010 Nov, 52(5):1671-1679 [viewed 25 July 2014] Available from: doi:10.1002/hep.23879
  2. VICHINSKY E, ONYEKWERE O, PORTER J, SWERDLOW P, ECKMAN J, LANE P, FILES B, HASSELL K, KELLY P, WILSON F, BERNAUDIN F, FORNI GL, OKPALA I, RESSAYRE-DJAFFER C, ALBERTI D, HOLLAND J, MARKS P, FUNG E, FISCHER R, MUELLER BU, COATES T. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease Br J Haematol [online] 2007 Feb 1, 136(3):501-508 [viewed 25 July 2014] Available from: doi:10.1111/j.1365-2141.2006.06455.x
  3. BACON BR, ADAMS PC, KOWDLEY KV, POWELL LW, TAVILL AS. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases Hepatology [online] 2011 Jul, 54(1):328-343 [viewed 27 July 2014] Available from: doi:10.1002/hep.24330
  4. GATTERMANN N. The Treatment of Secondary Hemochromatosis Dtsch Arztebl Int [online] 2009 Jul, 106(30):499-504 [viewed 24 July 2014] Available from: doi:10.3238/arztebl.2009.0499