Hemochromatosis - Clinicals, Diagnosis, and Management

Gastroenterology

Clinicals - 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.
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.
Severe fatigue/tiredness This is the most common symptom found in these patients which may also be secondary to heart failure Severe fatigue/tiredness
This is the most common symptom found in these patients which may also be secondary to heart failure
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 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
Skin bronzing A combination of iron deposition and melanin causes the hyperpigmentation that is typical of this disease Skin bronzing
A combination of iron deposition and melanin causes the hyperpigmentation that is typical of this disease
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
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
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 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
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 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
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 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
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 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
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 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
Tiredness, lethargy, cold intolerance, constipation etc These are symptoms suggestive of hypothyroidism. Symptomatic patients should be tested for thyroid function Tiredness, lethargy, cold intolerance, constipation etc
These are symptoms suggestive of hypothyroidism. Symptomatic patients should be tested for thyroid function
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 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

Clinicals - Examination

Fact Explanation
Pallor May indicate presence of anemia Pallor
May indicate presence of anemia
Skin bronzing or hyperpigmentation Is a typical sign in patients with hemochromatosis Skin bronzing or hyperpigmentation
Is a typical sign in patients with hemochromatosis
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 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
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 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
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 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
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 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

Investigations - 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% Serum transferrin saturation
This is the widely used screening test for hemochromatosis. The threshold for hemochromatosis is a fasting transferrin saturation greater than 45%
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 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
Serum iron Will be markedly elevated. Serum iron
Will be markedly elevated.
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 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
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 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

Investigations - Management

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. Serum alpha feto-protein (AFP)
Is a tumor marker for hepatocellular carcinoma(HCC) which should be done during follow up of patients with cirrhosis.
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 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
Liver function tests Elevated liver enzyme levels indicate involvement of liver Liver function tests
Elevated liver enzyme levels indicate involvement of liver
Serum creatinine Done to determine baseline renal function Serum creatinine
Done to determine baseline renal function
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 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
Thyroid stimulating hormone (TSH) / Free thyroxine (T4) Done to detect the presence of hypothyroidism in patients with hemochromatosis who have symptoms suggestive of hypothyroidism Thyroid stimulating hormone (TSH) / Free thyroxine (T4)
Done to detect the presence of hypothyroidism in patients with hemochromatosis who have symptoms suggestive of hypothyroidism
Echocardiogram Done in patients with clinical features suggestive of cardiomyopathy or heart failure Echocardiogram
Done in patients with clinical features suggestive of cardiomyopathy or heart failure
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 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
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 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
Genetic testing This should be done together with SF and TS testing in first degree relatives of an affected person with HFE related HH Genetic testing
This should be done together with SF and TS testing in first degree relatives of an affected person with HFE related HH

Management - Supportive

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. 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.
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 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

Management - Specific

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 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
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 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
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 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

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  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. 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
  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. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. VUJIć M. Molecular basis of HFE-hemochromatosis Front Pharmacol [online] :42 [viewed 24 July 2014] Available from: doi:10.3389/fphar.2014.00042