Hereditary Hemochromatosis

Bill Cayley MD MDiv

UW Health Augusta Family Medicine

Objectives

Participants will be able to:

1. Describe hemochromatosis

2. Discuss evaluation and management of hemochromatosis

3. 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

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

Clinical Case

45 year old man Labs:

CBC, TSH, Chemistries normal Hepatic transaminase levels abnormally elevated

Clinical Case

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

Hemochromatosis Overview

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

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

Epidemiology

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?

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%)

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

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

Stages of 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

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

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

Clinical HH

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

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

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

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

Biochemical & genetic testing 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

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

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

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

HH: Diagnostic algorithm

Clinical suspicion

Fasting TfS & Ferritin

If Ferritin > 1000OR ALT/ASTelevated do

liver bx

Genotype if TfS AND Ferritin elevated

If Heterozygousevaluate

for other liver dz

If HomozygousC282Y/C282Y:

Phlebotomy

If TfS OR Ferritinelevated evaluatefor other liver dz

No further evalif 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

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

Screening

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

Screening Recommendations

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.

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.”

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

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)

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)

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

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)