Hereditary Hemochromatosis Bill Cayley MD MDiv UW Health Augusta Family Medicine

Objectives Participants will be able to: Describe hemochromatosis Discuss evaluation and management of hemochromatosis Discuss screening for hemochromatosis

Participants will be able to:

Describe hemochromatosis

Discuss evaluation and management of hemochromatosis

Discuss screening for hemochromatosis

Clinical Case 45 year old man 6 months of increasing fatigue & joint pains PMH, FH, SH unremarkable ROS Reveals additional complaints of vague abdominal discomfort, and difficulties maintaining erections

45 year old man

6 months of increasing fatigue & joint pains

PMH, FH, SH unremarkable

ROS

Reveals additional complaints of vague abdominal discomfort, and difficulties maintaining erections

Clinical Case 45 year old man Physical Examination Vitals normal HEENT normal Cardiac Regular w/ no murmur Lungs clear Abdomen soft with no masses Extremities unremarkable Skin normal color and normal turgor

45 year old man

Physical Examination

Vitals normal

HEENT normal

Cardiac Regular w/ no murmur

Lungs clear

Abdomen soft with no masses

Extremities unremarkable

Skin normal color and normal turgor

Clinical Case 45 year old man Labs: CBC, TSH, Chemistries normal Hepatic transaminase levels abnormally elevated

45 year old man

Labs:

CBC, TSH, Chemistries normal

Hepatic transaminase levels abnormally elevated

Clinical Case 45 year old man Test for Hereditary Hemochromatosis?

45 year old man

Test for Hereditary Hemochromatosis?

Hemochromatosis Overview History Classic triad described in the 1865 by Trousseau Diabetes, bronze skin, cirrhosis Named “Hemochromatosis” in 1889 by Von Recklinghaussen Iron storage and widespread tissue injury Inheritance described in 1935 HLA linkage to chromosome 6 identified 1976

History

Classic triad described in the 1865 by Trousseau

Diabetes, bronze skin, cirrhosis

Named “Hemochromatosis” in 1889 by Von Recklinghaussen

Iron storage and widespread tissue injury

Inheritance described in 1935

HLA linkage to chromosome 6 identified 1976

Hemochromatosis Overview Genetics HFE gene mutation – identified 1996 Autosomal recessive C282Y or H63D

Genetics

HFE gene mutation – identified 1996

Autosomal recessive

C282Y or H63D

Hemochromatosis Overview Onset ages 40-50 Fatigue Arthralgias Weight loss Abdominal pain Loss of libido

Onset ages 40-50

Fatigue

Arthralgias

Weight loss

Abdominal pain

Loss of libido

Iron Overload Primary Hereditary hemochromatosis (HH) Secondary Thalassemia Sideroblastic anemia Porphyria cutanea tarda Chronic liver disease Hepatitis C, hepatitis B, steatohepatitis (fatty liver), alcohol induced liver disease, previous porta-caval shunting Transfusions Chronic iron supplementation Uncertain classification??? Non-HFE hemochromatosis

Primary

Hereditary hemochromatosis (HH)

Secondary

Thalassemia

Sideroblastic anemia

Porphyria cutanea tarda

Chronic liver disease

Hepatitis C, hepatitis B, steatohepatitis (fatty liver), alcohol induced liver disease, previous porta-caval shunting

Transfusions

Chronic iron supplementation

Uncertain classification???

Non-HFE hemochromatosis

Epidemiology Origin Ancient Celt or Viking? Clinical distribution No good data

Origin

Ancient Celt or Viking?

Clinical distribution

No good data

Epidemiology Genetic distribution Most common single-gene mutation in US white population Heterozygous Hereditary Hemochromatosis White Northern Europeans 9.6% Homozygous Hereditary Hemochromatosis White Northern Europeans 0.4% Mexican-Americans 0.027% Non-hispanic blacks 0.014% Asians 0% Non-HFE Hemochromatosis – non-Caucasian populations?

Genetic distribution

Most common single-gene mutation in US white population

Heterozygous Hereditary Hemochromatosis

White Northern Europeans 9.6%

Homozygous Hereditary Hemochromatosis

White Northern Europeans 0.4%

Mexican-Americans 0.027%

Non-hispanic blacks 0.014%

Asians 0%

Non-HFE Hemochromatosis – non-Caucasian populations?

Pathophysiology Iron Aerobic metabolism, free radical creation Adults: 35 (F) to 45 (M) mg/kg total body iron Hemoglobin (60%) Myoglobin (10%) Enzymes & cytochromes (10%) Transferrin (<1%)

Iron

Aerobic metabolism, free radical creation

Adults: 35 (F) to 45 (M) mg/kg total body iron

Hemoglobin (60%)

Myoglobin (10%)

Enzymes & cytochromes (10%)

Transferrin (<1%)

Pathophysiology Iron Balance 1-2 mg of iron lost daily Sweat, sloughed cells Loss offset by regulated duodenal absorption Excess uptake cannot be offset, leads to overload

Iron Balance

1-2 mg of iron lost daily

Sweat, sloughed cells

Loss offset by regulated duodenal absorption

Excess uptake cannot be offset, leads to overload

Pathophysiology Hereditary Hemochromatosis Increased duodenal iron absorption DMT1 protein and ferroportin are inappropriately over-active Iron accumulates in excess of daily losses Clinical manifestations once total body iron = 15-40 grams C282Y mutation necessary but not sufficient for disease

Hereditary Hemochromatosis

Increased duodenal iron absorption

DMT1 protein and ferroportin are inappropriately over-active

Iron accumulates in excess of daily losses

Clinical manifestations once total body iron = 15-40 grams

C282Y mutation necessary but not sufficient for disease

Stages of Disease Genetic HH Abnormal Genotype Biochemical HH Iron Overload Clinical HH Symptomatic Disease

Genetic HH

Abnormal Genotype

Biochemical HH

Iron Overload

Clinical HH

Symptomatic Disease

Clinical HH Biochemical and Clinical Penetrance White Northern European ancestry 10% heterozygous for C282Y 0.4% homozygous for C282Y 60-75% will develop iron overload 2-5% may develop diabetes Up to 30% of men & up to 7% of women may develop liver disease

Biochemical and Clinical Penetrance

White Northern European ancestry

10% heterozygous for C282Y

0.4% homozygous for C282Y

60-75% will develop iron overload

2-5% may develop diabetes

Up to 30% of men & up to 7% of women may develop liver disease

Clinical HH Of patients with clinical HH Homozygous C282Y 85-100% Compound heterozygous C282Y & H63D 10% No increased risk of disease Heterozygous C282Y Homozygous for H63D

Of patients with clinical HH

Homozygous C282Y 85-100%

Compound heterozygous C282Y & H63D 10%

No increased risk of disease

Heterozygous C282Y

Homozygous for H63D

Clinical HH Gender Men Clinical disease rare before age 40 10-20 g iron by age 40 Women Clinical disease rare before menopause Menstrual blood losses offset iron accumulation

Gender

Men

Clinical disease rare before age 40

10-20 g iron by age 40

Women

Clinical disease rare before menopause

Menstrual blood losses offset iron accumulation

Clinical HH Clinical factors: Dietary iron Alcohol abuse Hepatitis C

Clinical factors:

Dietary iron

Alcohol abuse

Hepatitis C

HH: Signs & symptoms Reason for diagnosis Symptoms 35% Abnormal lab test 45% Family member with hemochromatosis 20% Source: Survey of 3562 patients with hemochromatosis Am J Med. 106:619

Reason for diagnosis

Symptoms 35%

Abnormal lab test 45%

Family member with hemochromatosis 20%

Source:

Survey of 3562 patients with hemochromatosis

Am J Med. 106:619

HH: Signs & symptoms Among patients with symptoms (58% of total) Symtoms Fatigue 46% Arthralgia 44% Loss of libido 26% Diagnoses Arthritis 65% Liver disease 52% Source: Survey of 3562 patients with hemochromatosis Am J Med. 106:619

Among patients with symptoms (58% of total)

Symtoms

Fatigue 46%

Arthralgia 44%

Loss of libido 26%

Diagnoses

Arthritis 65%

Liver disease 52%

Source:

Survey of 3562 patients with hemochromatosis

Am J Med. 106:619

Clinical manifestations Artwork is reproduced, with permission, from the Johns Hopkins Gastroenterology and Hepatology Resource Center, www.hopkins-gi.org, copyright 2006, Johns Hopkins University, all rights reserved.

Clinical manifestations Liver Abnormal liver enzymes, hepatomegaly, or cirrhosis Cirrhosis accounts for 89% of HH related deaths Hepatocellular carcinoma (30% of patients with cirrhosis) Cardiac Cardiomyopathy (dilated or dilated-restrictive) and heart failure Conduction disturbances, decrease in QRS amplitude, T-wave flattening Endocrine Diabetes (iron accumulation in β-cells, impaired insulin sensitivity) Hypogonadism (impotence, amenorrhea, loss of libido, or osteoporosis), due to iron accumulation in pituitary cells. Joints Non-inflammatory osteoarthritis (MCP and PIP joints) Skin “ Bronzing” due to melanin or iron deposition

Liver

Abnormal liver enzymes, hepatomegaly, or cirrhosis

Cirrhosis accounts for 89% of HH related deaths

Hepatocellular carcinoma (30% of patients with cirrhosis)

Cardiac

Cardiomyopathy (dilated or dilated-restrictive) and heart failure

Conduction disturbances, decrease in QRS amplitude, T-wave flattening

Endocrine

Diabetes (iron accumulation in β-cells, impaired insulin sensitivity)

Hypogonadism (impotence, amenorrhea, loss of libido, or osteoporosis), due to iron accumulation in pituitary cells.

Joints

Non-inflammatory osteoarthritis (MCP and PIP joints)

Skin

“ Bronzing” due to melanin or iron deposition

Diagnosis of HH Remember! Not all iron overload is hemochromatosis Not all patients with C282Y have clinical disease or shortened life expectancy Diagnosis requires: Clinical suspicion Biochemical testing Genetic confirmation

Remember!

Not all iron overload is hemochromatosis

Not all patients with C282Y have clinical disease or shortened life expectancy

Diagnosis requires:

Clinical suspicion

Biochemical testing

Genetic confirmation

Biochemical & genetic testing Iron overload & homozygous C282Y Transferrin saturation (TfS) > 45% 94% Sensitive, 94% Specific Ferritin ≥300μg/L 50% Sensitive, 88% Specific

Iron overload & homozygous C282Y

Transferrin saturation (TfS) > 45%

94% Sensitive, 94% Specific

Ferritin ≥300μg/L

50% Sensitive, 88% Specific

Biochemical & genetic testing Liver biopsy Hepatic iron load, other liver disease? Now mainly used if genetic testing unavailable or non-diagnostic

Liver biopsy

Hepatic iron load, other liver disease?

Now mainly used if genetic testing unavailable or non-diagnostic

Biochemical & genetic testing Imaging CT or MRI - investigational, not recommended as yet Genetic confirmation C282Y and H63D mutation testing for all patients suspected of iron overload

Imaging

CT or MRI - investigational, not recommended as yet

Genetic confirmation

C282Y and H63D mutation testing for all patients suspected of iron overload

Populations for evaluation Symptomatic patients Unexplained liver disease OR a presumably known cause of liver disease with abnormality of one or more iron markers Type 2 diabetes mellitus, esp. with hepatomegaly, elevated liver enzymes, atypical cardiac disease or early-onset sexual dysfunction Early-onset atypical arthropathy, cardiac disease, and male sexual dysfunction American Association for the Study of Liver Diseases. Hepatology. 33:1321

Symptomatic patients

Unexplained liver disease OR a presumably known cause of liver disease with abnormality of one or more iron markers

Type 2 diabetes mellitus, esp. with hepatomegaly, elevated liver enzymes, atypical cardiac disease or early-onset sexual dysfunction

Early-onset atypical arthropathy, cardiac disease, and male sexual dysfunction

American Association for the Study of Liver Diseases. Hepatology. 33:1321

Populations for evaluation Asymptomatic patients Priority groups First-degree relatives of a confirmed case of hemochromatosis Individuals with abnormal serum iron markers Individuals with unexplained elevation of liver enzymes or asymptomatic hepatomegaly General population??? American Association for the Study of Liver Diseases. Hepatology. 33:1321

Asymptomatic patients

Priority groups

First-degree relatives of a confirmed case of hemochromatosis

Individuals with abnormal serum iron markers

Individuals with unexplained elevation of liver enzymes or asymptomatic hepatomegaly

General population???

American Association for the Study of Liver Diseases. Hepatology. 33:1321

HH: Diagnostic algorithm Clinical suspicion Fasting TfS & Ferritin If Ferritin > 1000 OR ALT/AST elevated do liver bx Genotype if TfS AND Ferritin elevated If Heterozygous evaluate for other liver dz If Homozygous C282Y/C282Y: Phlebotomy If TfS OR Ferritin elevated evaluate for other liver dz No further eval if normal Adapted from Am J Med 119:391 & Hepatology 33:1321

Treatment Goals – iron depletion in order to: Prevent complications in patients with early iron overload Alleviate reversible consequences of HH if patients have clinical disease

Goals – iron depletion in order to:

Prevent complications in patients with early iron overload

Alleviate reversible consequences of HH if patients have clinical disease

Phlebotomy Artwork is reproduced, with permission, from the Johns Hopkins Gastroenterology and Hepatology Resource Center, www.hopkins-gi.org, copyright 2006, Johns Hopkins University, all rights reserved

Phlebotomy Initial treatment Remove ½ to 2 units (250 – 1000 cc) of blood/week Regimen depends on pt health and comorbidities Labs: Hb each time, Ferritin every 10-12 phlebotomies Endpoint: Ferritin < 50 mcg/L AND TfS < 50% Maintenance: Phlebotomy 3-4x/ year for men, 1-2x year for women Goal – maintain Ferritin 25-50 mcg/L

Initial treatment

Remove ½ to 2 units (250 – 1000 cc) of blood/week

Regimen depends on pt health and comorbidities

Labs: Hb each time, Ferritin every 10-12 phlebotomies

Endpoint: Ferritin < 50 mcg/L AND TfS < 50%

Maintenance:

Phlebotomy 3-4x/ year for men, 1-2x year for women

Goal – maintain Ferritin 25-50 mcg/L

Screening Pro: Common disorder Long presymptomatic phase Inexpensive screening test Effective treatment available Treatment improves survival

Pro:

Common disorder

Long presymptomatic phase

Inexpensive screening test

Effective treatment available

Treatment improves survival

Screening Con: Natural history unknown Significance of genetic mutation in absence of clinical manifestations unknown Future burden of clinical disease among currently asymptomatic heterozygous and homozygous individuals is unknown

Con:

Natural history unknown

Significance of genetic mutation in absence of clinical manifestations unknown

Future burden of clinical disease among currently asymptomatic heterozygous and homozygous individuals is unknown

Screening Recommendations AASLD Primary phenotypic screening of population with serum iron markers, secondary genetic evaluation if indicated.

AASLD

Primary phenotypic screening of population with serum iron markers, secondary genetic evaluation if indicated.

Screening Recommendations ACP Since only 2 persons per million screened by HFE screening and 3 per million screened by transferrin would be identified with cirrhosis, the benefit of early diagnosis is unclear.

ACP

Since only 2 persons per million screened by HFE screening and 3 per million screened by transferrin would be identified with cirrhosis, the benefit of early diagnosis is unclear.

Screening Recommendations USPSTF: Since screening could identify a large number of individuals with the high-risk genotype, who may never manifest clinical disease, “the USPSTF concludes that the potential harms of genetic screening for hereditary hemochromatosis outweigh the potential benefits.”

USPSTF:

Since screening could identify a large number of individuals with the high-risk genotype, who may never manifest clinical disease, “the USPSTF concludes that the potential harms of genetic screening for hereditary hemochromatosis outweigh the potential benefits.”

Summary Hereditary hemochromatosis is a disorder of iron overload due to absorption in excess of normal losses Mutation of HFE Gene (C282Y or H63D) necessary but not sufficient for clinical disease Diagnosis requires clinical suspicion, biochemical testing, and genetic confirmation Phlebotomy reduces sequellae of clinical disease Primary population screening for HH is controversial

Hereditary hemochromatosis is a disorder of iron overload due to absorption in excess of normal losses

Mutation of HFE Gene (C282Y or H63D) necessary but not sufficient for clinical disease

Diagnosis requires clinical suspicion, biochemical testing, and genetic confirmation

Phlebotomy reduces sequellae of clinical disease

Primary population screening for HH is controversial

Resources Brandhagen DJ, Fairbanks VF, Baldus W. Recognition and management of hereditary hemochromatosis. Am Fam Physician. 2002 Mar 1;65(5):853-60. PMID: 11898957 (http://www.aafp.org/afp/20020301/853.html, accessed 24 October 2006) Limdi JK, Crampton JR. Hereditary haemochromatosis. QJM. 2004 Jun;97(6):315-24. PMID: 15152104 (http://qjmed.oxfordjournals.org/cgi/content/full/97/6/315, accessed 26 October 2006) Qaseem A, Aronson M, Fitterman N, Snow V, Weiss KB, Owens DK; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2005 Oct 4;143(7):517-21. PMID: 16204164 (http://www.annals.org/cgi/content/full/143/7/517, accessed 26 October 2006)

Brandhagen DJ, Fairbanks VF, Baldus W. Recognition and management of hereditary hemochromatosis. Am Fam Physician. 2002 Mar 1;65(5):853-60. PMID: 11898957 (http://www.aafp.org/afp/20020301/853.html, accessed 24 October 2006)

Limdi JK, Crampton JR. Hereditary haemochromatosis. QJM. 2004 Jun;97(6):315-24. PMID: 15152104 (http://qjmed.oxfordjournals.org/cgi/content/full/97/6/315, accessed 26 October 2006)

Qaseem A, Aronson M, Fitterman N, Snow V, Weiss KB, Owens DK; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2005 Oct 4;143(7):517-21. PMID: 16204164 (http://www.annals.org/cgi/content/full/143/7/517, accessed 26 October 2006)

Resources Schmitt B, Golub RM, Green R. Screening primary care patients for hereditary hemochromatosis with transferring saturation and serum ferritin level: systematic review for the American College of Physicians. Ann Intern Med. 2005 Oct 4;143(7):522-36. PMID: 16204165 (http://www.annals.org/cgi/reprint/143/7/522.pdf, accessed 12 March 2007) Seamark CJ, Hutchinson M. Controversy in primary care: Should asymptomatic haemochromatosis be treated? BMJ. 2000 May 13;320(7245):1314-7. PMID: 10807626. (http://bmj.bmjjournals.com/cgi/content/full/320/7245/1314, accessed 12 March 2007) Tavill AS; American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association. Diagnosis and management of hemochromatosis. Hepatology. 2001 May;33(5):1321-8. PMID: 11343262 (http://www3.interscience.wiley.com/cgi-bin/abstract/106597263/ABSTRACT, accessed accessed 12 March 2007)

Schmitt B, Golub RM, Green R. Screening primary care patients for hereditary hemochromatosis with transferring saturation and serum ferritin level: systematic review for the American College of Physicians. Ann Intern Med. 2005 Oct 4;143(7):522-36. PMID: 16204165 (http://www.annals.org/cgi/reprint/143/7/522.pdf, accessed 12 March 2007)

Seamark CJ, Hutchinson M. Controversy in primary care: Should asymptomatic haemochromatosis be treated? BMJ. 2000 May 13;320(7245):1314-7. PMID: 10807626. (http://bmj.bmjjournals.com/cgi/content/full/320/7245/1314, accessed 12 March 2007)

Tavill AS; American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association. Diagnosis and management of hemochromatosis. Hepatology. 2001 May;33(5):1321-8. PMID: 11343262 (http://www3.interscience.wiley.com/cgi-bin/abstract/106597263/ABSTRACT, accessed accessed 12 March 2007)

Resources U.S. Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med. 2006 Aug 1;145(3):204-8. PMID: 16880462 (http://www.annals.org/cgi/content/abstract/145/3/204, accessed 12 March 2007) Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2006 Aug 1;145(3):209-23. PMID: 16880463 (http://www.annals.org/cgi/content/full/145/3/209, accessed 12 March 2007) Yen AW, Fancher TL, Bowlus CL. Revisiting hereditary hemochromatosis: current concepts and progress. Am J Med. 2006 May;119(5):391-9. PMID: 16651049

U.S. Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med. 2006 Aug 1;145(3):204-8. PMID: 16880462 (http://www.annals.org/cgi/content/abstract/145/3/204, accessed 12 March 2007)

Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2006 Aug 1;145(3):209-23. PMID: 16880463 (http://www.annals.org/cgi/content/full/145/3/209, accessed 12 March 2007)

Yen AW, Fancher TL, Bowlus CL. Revisiting hereditary hemochromatosis: current concepts and progress. Am J Med. 2006 May;119(5):391-9. PMID: 16651049

Resources Bacon BR, Powell LW, Adams PC, Kresina TF, Hoofnagle JH. Molecular medicine and haemochromatosis: at the crossroads. Gastroenterology 1999; 116:193–207. Adams P, Brissot P, Powell LW. EASL International Consensus Conference on Haemochromatosis. J Hepatol. 2000 Sep;33(3):485-504. Johns Hopkins Gastroenterology and Hepatology Resource Center. (http://hopkins-gi.nts.jhu.edu accessed 12 March 2007)

Bacon BR, Powell LW, Adams PC, Kresina TF, Hoofnagle JH. Molecular medicine and haemochromatosis: at the crossroads. Gastroenterology 1999; 116:193–207.

Adams P, Brissot P, Powell LW. EASL International Consensus Conference on Haemochromatosis. J Hepatol. 2000 Sep;33(3):485-504.

Johns Hopkins Gastroenterology and Hepatology Resource Center. (http://hopkins-gi.nts.jhu.edu accessed 12 March 2007)