1. Hereditary Hemochromatosis Bill Cayley MD MDiv UW Health Augusta Family Medicine

2. Objectives Participants will be able to: 1. Describe hemochromatosis 2. Discuss evaluation and management of hemochromatosis 3. 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 Europeans9.6%  Homozygous Hereditary Hemochromatosis White Northern Europeans0.4% Mexican-Americans0.027% Non-hispanic blacks0.014% Asians0%  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 C282Y85-100%  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  Symptoms35%  Abnormal lab test45%  Family member with hemochromatosis20%  Source: Survey of 3562 patients with hemochromatosis Am J Med. 106:619

22. HH: Signs & symptoms Among patients with symptoms (58% of total)  Symtoms Fatigue46% Arthralgia44% Loss of libido26%  Diagnoses Arthritis65% Liver disease52%  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)