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Hemochromatosis1

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    • 1. Hereditary Hemochromatosis Bill Cayley MD MDiv UW Health Augusta Family Medicine
    • 2. Objectives
      • Participants will be able to:
      • Describe hemochromatosis
      • Discuss evaluation and management of hemochromatosis
      • Discuss screening for hemochromatosis
    • 3. 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
    • 4. 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
    • 5. Clinical Case
      • 45 year old man
        • Labs:
          • CBC, TSH, Chemistries normal
          • Hepatic transaminase levels abnormally elevated
    • 6. Clinical Case
      • 45 year old man
        • Test for Hereditary Hemochromatosis?
    • 7. 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
    • 8. Hemochromatosis Overview
      • Genetics
        • HFE gene mutation – identified 1996
        • Autosomal recessive
        • C282Y or H63D
    • 9. Hemochromatosis Overview
      • Onset ages 40-50
        • Fatigue
        • Arthralgias
        • Weight loss
        • Abdominal pain
        • Loss of libido
    • 10. 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
    • 11. Epidemiology
      • Origin
        • Ancient Celt or Viking?
      • Clinical distribution
        • No good data
    • 12. 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?
    • 13. 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%)
    • 14. 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
    • 15. 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
    • 16. Stages of Disease
      • Genetic HH
        • Abnormal Genotype
      • Biochemical HH
        • Iron Overload
      • Clinical HH
        • Symptomatic Disease
    • 17. 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
    • 18. 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
    • 19. 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
    • 20. Clinical HH
      • Clinical factors:
        • Dietary iron
        • Alcohol abuse
        • Hepatitis C
    • 21. 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
    • 22. 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
    • 23. 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.
    • 24. 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
    • 25. 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
    • 26. Biochemical & genetic testing
      • Iron overload & homozygous C282Y
        • Transferrin saturation (TfS) > 45%
          • 94% Sensitive, 94% Specific
        • Ferritin ≥300μg/L
          • 50% Sensitive, 88% Specific
    • 27. Biochemical & genetic testing
      • Liver biopsy
        • Hepatic iron load, other liver disease?
        • Now mainly used if genetic testing unavailable or non-diagnostic
    • 28. 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
    • 29. 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
    • 30. 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
    • 31. 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
    • 32. 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
    • 33. 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
    • 34. 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
    • 35. Screening
      • Pro:
        • Common disorder
        • Long presymptomatic phase
        • Inexpensive screening test
        • Effective treatment available
        • Treatment improves survival
    • 36. 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
    • 37. Screening Recommendations
      • AASLD
        • Primary phenotypic screening of population with serum iron markers, secondary genetic evaluation if indicated.
    • 38. 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.
    • 39. 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.”
    • 40. 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
    • 41. 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)
    • 42. 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)
    • 43. 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
    • 44. 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)

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