Naima Cheema, MD Emory Family Medicine March 6, 2008

Agenda Case Presentation Case Presentation Introduction & Genetics Introduction & Genetics Pathophysiology Pathophysiology Clinical Features Clinical Features Diagnosis Diagnosis Treatment Treatment Prognosis Prognosis Screening Screening

Agenda Case Presentation Case Presentation Introduction & Genetics Introduction & Genetics Pathophysiology Pathophysiology Clinical Features Clinical Features Diagnosis Diagnosis Treatment Treatment Prognosis Prognosis Screening Screening

Case Presentation 58 yr old male came for followup visit for hypertension, hyperlipidemia and transaminitis 58 yr old male came for followup visit for hypertension, hyperlipidemia and transaminitis HPI : HPI : Pt. reports chest pains “once in a while” Pt. reports chest pains “once in a while” Occurs q 1-2 months. Most of the time he is fine. Occurs q 1-2 months. Most of the time he is fine. No exertional association of chest pain. No exertional association of chest pain. No pain today No pain today HTN poorly controlled. No home log available. HTN poorly controlled. No home log available. ROS : No CP/ No SOB/ No LE edema / No numbness / No weakness / No abdominal pain. ROS : No CP/ No SOB/ No LE edema / No numbness / No weakness / No abdominal pain. PMH : HTN / Hyperlipidemia / CVA PMH : HTN / Hyperlipidemia / CVA

Case Presentation PSH : Carotid endarterectomy (2002), Cardiac Catheterization (2002), Denies Angioplasty. PSH : Carotid endarterectomy (2002), Cardiac Catheterization (2002), Denies Angioplasty. Social : Social : Tobacco 2 ppd, ETOH : none, Rec Drugs: none Tobacco 2 ppd, ETOH : none, Rec Drugs: none Allergies : No known drug allergies Allergies : No known drug allergies Meds : Meds : Lisinopril 40 mg/day, Atenolol 100mg/day, Amlodipine 10 mg/day, Gemfibrozil 600mg/day, Aspirin 81mg/day Lisinopril 40 mg/day, Atenolol 100mg/day, Amlodipine 10 mg/day, Gemfibrozil 600mg/day, Aspirin 81mg/day Physical Exam : BP 149/88, Pulse 80, Temp 97.5, Resp 20, BMI 30.2 Physical Exam : BP 149/88, Pulse 80, Temp 97.5, Resp 20, BMI 30.2

Case Presentation Gen : NAD Gen : NAD Heent : Conj pink / sclera non-icteric Heent : Conj pink / sclera non-icteric Pulm : CTA Pulm : CTA CVS: Regular S1 S2, No murmurs CVS: Regular S1 S2, No murmurs Abd: BS+ soft NT ND No HSM Abd: BS+ soft NT ND No HSM Ext: No edema Ext: No edema Labs: Labs: Cr 1.2 / K 3.7, MDRD 66% Cr 1.2 / K 3.7, MDRD 66% Urine Protein negative Urine Protein negative AST 64/ ALT 36 / ALB 4.3 AST 64/ ALT 36 / ALB 4.3

Case Presentation Persistent Elevated Transaminitis Persistent Elevated Transaminitis Denies alcohol abuse (none in 12 yrs) Denies alcohol abuse (none in 12 yrs) Hep B and Hep C negative Hep B and Hep C negative RUQ U/S ordered RUQ U/S ordered Iron Studies : Iron Studies : Ferritin 968 ng/ml Ferritin 968 ng/ml Iron 321 Iron 321 TIBC 353 TIBC 353 Transferrin Saturation 318 (91%) Transferrin Saturation 318 (91%) Pt. with asymptomatic elevation of liver enzymes, elevated transferrin saturation and serum ferritin ……hemochromatosis Pt. with asymptomatic elevation of liver enzymes, elevated transferrin saturation and serum ferritin ……hemochromatosis

Agenda Case Presentation Case Presentation Introduction & Genetics Introduction & Genetics Pathophysiology Pathophysiology Clinical Features Clinical Features Diagnosis Diagnosis Treatment Treatment Prognosis Prognosis Screening Screening

Introduction Definition Most Common inherited single-gene disorder. Most Common inherited single-gene disorder. Increased intestinal absorption of iron. Increased intestinal absorption of iron. Deposition of iron in multiple organs like liver, pancreas, heart and skin. Deposition of iron in multiple organs like liver, pancreas, heart and skin.

Hemochromatosis Incidence Common in people of Northern European descent Common in people of Northern European descent Most Common single-gene disorder in the US white population Most Common single-gene disorder in the US white population One in white persons has homozygous genetic mutations of HH One in white persons has homozygous genetic mutations of HH One in 10 persons is a carrier for the mutation One in 10 persons is a carrier for the mutation Typical PCP encounters one patient with HH every two weeks Typical PCP encounters one patient with HH every two weeks

Genetics Autosomal recessive disorder Autosomal recessive disorder HFE gene located on short arm of chromosome 6 HFE gene located on short arm of chromosome 6 Two point mutations : C282Y and H63D Two point mutations : C282Y and H63D 60-93% of patients are homozygous for C282Y mutation 60-93% of patients are homozygous for C282Y mutation Minority of patients are heterozygotes, who have one copy of C282Y and one copy of H63D. Disease is of lesser severity in this case. Minority of patients are heterozygotes, who have one copy of C282Y and one copy of H63D. Disease is of lesser severity in this case.

Agenda Case Presentation Case Presentation Introduction & Genetics Introduction & Genetics Pathophysiology Pathophysiology Clinical Features Clinical Features Diagnosis Diagnosis Treatment Treatment Prognosis Prognosis Screening Screening

Pathophysiology HH develops as a result of imbalance between iron absorption and loss HH develops as a result of imbalance between iron absorption and loss Iron is normally lost in sweat, shed skin cells, and the GI tract at a rate of ~1mg/day Iron is normally lost in sweat, shed skin cells, and the GI tract at a rate of ~1mg/day Pre menopausal adult women lose an additional 0.5 to 1.0 mg/day because of menses Pre menopausal adult women lose an additional 0.5 to 1.0 mg/day because of menses These losses are balanced by the absorption of 10% of the 10–20 mg of iron in diet. These losses are balanced by the absorption of 10% of the 10–20 mg of iron in diet.

Pathophysiology A male patient with homozygous HH absorbs 4mg of iron per day rather than 1 mg/day needed to balance iron losses A male patient with homozygous HH absorbs 4mg of iron per day rather than 1 mg/day needed to balance iron losses Retention of 3mg of iron more per day than is needed to maintain iron balance will lead to net iron accumlation of approximately 1g per year Retention of 3mg of iron more per day than is needed to maintain iron balance will lead to net iron accumlation of approximately 1g per year Until age 40-50, the total iron accumulation will reach more than 20g of iron. At this level clinical features of HH start developing Until age 40-50, the total iron accumulation will reach more than 20g of iron. At this level clinical features of HH start developing

Agenda Case Presentation Case Presentation Introduction & Genetics Introduction & Genetics Pathophysiology Pathophysiology Clinical Features Clinical Features Diagnosis Diagnosis Treatment Treatment Prognosis Prognosis Screening Screening

Clinical Features Clinical manifestations occur after the age of 40 years, when body iron stores have reached 15 to 40 g. Clinical manifestations occur after the age of 40 years, when body iron stores have reached 15 to 40 g.

Clinical Features Women manifest disease less frequently than men. Women manifest disease less frequently than men. Alcohol abuse and hepatitis C may accelerate disease expression. Alcohol abuse and hepatitis C may accelerate disease expression. Fatigue 74%,arthralgias 44% and impotence 45% are the most common symptoms of this disorder. Fatigue 74%,arthralgias 44% and impotence 45% are the most common symptoms of this disorder. “Bronze Diabetes” i.e., cutaneous hyperpigmentation,DM and cirrhosis are presentations of advanced disease. “Bronze Diabetes” i.e., cutaneous hyperpigmentation,DM and cirrhosis are presentations of advanced disease. If HH is diagnosed early and treated appropriately, most clinical manifestations are easily preventable. If HH is diagnosed early and treated appropriately, most clinical manifestations are easily preventable.

Changing Clinical Features of HH

Agenda Case Presentation Case Presentation Introduction & Genetics Introduction & Genetics Pathophysiology Pathophysiology Clinical Features Clinical Features Diagnosis Diagnosis Treatment Treatment Prognosis Prognosis Screening Screening

Diagnosis HH is diagnosed by combination of clinical, laboratory and pathologic criteria. HH is diagnosed by combination of clinical, laboratory and pathologic criteria. Elevated transferrin saturation Elevated transferrin saturation TS=serum iron concentration/total iron-binding capacity X100 TS=serum iron concentration/total iron-binding capacity X100 Initial test of choice – 94% specificity Initial test of choice – 94% specificity An elevated transferrin saturation should be repeated as a fasting early morning test. An elevated transferrin saturation should be repeated as a fasting early morning test. A value greater than 60% in men and greater than 50 % in women is highly specific. A value greater than 60% in men and greater than 50 % in women is highly specific.

Diagnosis Serum transferrin saturation may be normal early in the course of disease. Serum transferrin saturation may be normal early in the course of disease. Serum ferritin levels elevated greater than 200 mcg/l in premenopausal women and 300 mcg/l in post menopausal women and men indicate iron overload due to HH, especially when associated with elevated transferrin saturation and evidence of liver disease. Serum ferritin levels elevated greater than 200 mcg/l in premenopausal women and 300 mcg/l in post menopausal women and men indicate iron overload due to HH, especially when associated with elevated transferrin saturation and evidence of liver disease.

Diagnosis Ferritin is acute phase reactant and it’s concentration can be high in infection, inflammation and liver disease. Ferritin is acute phase reactant and it’s concentration can be high in infection, inflammation and liver disease. Ferritin concentration higher than 1000mcg/l suggests liver damage with fibrosis or cirrhosis. Ferritin concentration higher than 1000mcg/l suggests liver damage with fibrosis or cirrhosis. Ferritin levels are less sensitive than transferrin saturation as a screening test for HH. Ferritin levels are less sensitive than transferrin saturation as a screening test for HH.

Iron Studies in Pt. with HH

Diagnosis Pt. with elevated ferritin and serum transferrin saturation should undergo HFE gene testing to confirm the diagnosis of HH. Pt. with elevated ferritin and serum transferrin saturation should undergo HFE gene testing to confirm the diagnosis of HH. HFE gene testing has replaced liver biopsy to confirm the diagnosis of HH. HFE gene testing has replaced liver biopsy to confirm the diagnosis of HH. Liver biopsy is the gold standard for assessing the degree of fibrosis. Liver biopsy is the gold standard for assessing the degree of fibrosis. Definite exclusion of cirrhosis is important because the risk of hepatocellular carcinoma is 200 times higher in pt. with HH and cirrhosis. Definite exclusion of cirrhosis is important because the risk of hepatocellular carcinoma is 200 times higher in pt. with HH and cirrhosis.

Diagnosis The risk of cancer persists even after excess iron stores have been depleted. The risk of cancer persists even after excess iron stores have been depleted. Pt. with cirrhosis should be screened every 6 months with abdominal ultrasound and alfa- fetoprotein test for HCC. Pt. with cirrhosis should be screened every 6 months with abdominal ultrasound and alfa- fetoprotein test for HCC. Every pt. with cirrhosis should undergo screening EGD to look for varices. Every pt. with cirrhosis should undergo screening EGD to look for varices. If varices are present, pt. should be started on propranolol or nadolol as primary prevention. If varices are present, pt. should be started on propranolol or nadolol as primary prevention. Phlebotomy also help reverse varices. Phlebotomy also help reverse varices.

Diagnosis Some pt. with HH are at low risk for cirrhosis and therefore may not require liver biopsy. Non- invasive predictors are helpful in excluding cirrhosis in these pt. Some pt. with HH are at low risk for cirrhosis and therefore may not require liver biopsy. Non- invasive predictors are helpful in excluding cirrhosis in these pt. Non-invasive predictors: Non-invasive predictors: Serum ferritin concentration below 1000ng/ml Serum ferritin concentration below 1000ng/ml Normal AST values and Normal AST values and No hepatomegaly No hepatomegaly

Agenda Case Presentation Case Presentation Introduction & Genetics Introduction & Genetics Pathophysiology Pathophysiology Clinical Features Clinical Features Diagnosis Diagnosis Treatment Treatment Prognosis Prognosis Screening Screening

Treatment Treatment for HH is reserved for pt. with eveidence of iron overload based on an elevated serum ferritin concentration. Treatment for HH is reserved for pt. with eveidence of iron overload based on an elevated serum ferritin concentration. Phlebotomy is the preferred treatment as it is simple,effective and inexpensive. Phlebotomy is the preferred treatment as it is simple,effective and inexpensive. Initial treatment: Removal of 500 ml of blood on a weekly basis until the hemoglobin concentration is below the reference range (less than g/dl). Initial treatment: Removal of 500 ml of blood on a weekly basis until the hemoglobin concentration is below the reference range (less than g/dl). Removal of every 500 ml of blood removes mg of iron. Removal of every 500 ml of blood removes mg of iron.

Treatment Iron depletion is confirmed by serum ferritin concentration less than 50 ng/ml and serum transferritin saturation less than 50 %. Iron depletion is confirmed by serum ferritin concentration less than 50 ng/ml and serum transferritin saturation less than 50 %. Usually, pt. require weekly phlebotomies for 50 weeks before they start maintenance therapy. Usually, pt. require weekly phlebotomies for 50 weeks before they start maintenance therapy. Maintenance treatment: Once iron depletion has accomplished, most pt. require four to eight phlebotomies per year.Goal is to maintain serum ferritin concentration less than 50 ng/ml. Maintenance treatment: Once iron depletion has accomplished, most pt. require four to eight phlebotomies per year.Goal is to maintain serum ferritin concentration less than 50 ng/ml.

Treatment Phlebotomies help reverse several clinical features including cardiomyopathy, conduction abnormalities, hepatomegaly, varices, skin pigmentation and infections. Phlebotomies help reverse several clinical features including cardiomyopathy, conduction abnormalities, hepatomegaly, varices, skin pigmentation and infections. Cirrhosis, diabetes mellitus, primary and secondary hypogonadism and arthralgias are irreversible features of the disease. Cirrhosis, diabetes mellitus, primary and secondary hypogonadism and arthralgias are irreversible features of the disease.

Treatment The blood withdrawn from a patient with HH can be used for direct transfusion. The blood withdrawn from a patient with HH can be used for direct transfusion. FDA regulations require that containers should be labeled conspicuously that the donor had Hemochromatosis. FDA regulations require that containers should be labeled conspicuously that the donor had Hemochromatosis. CHELATION THERAPY : Chelation therapy for HH with deferoxamine can lead to clinical improvement. It is reserved only for those patients who cannot tolerate phlebotomy. CHELATION THERAPY : Chelation therapy for HH with deferoxamine can lead to clinical improvement. It is reserved only for those patients who cannot tolerate phlebotomy.

Treatment

Agenda Case Presentation Case Presentation Introduction & Genetics Introduction & Genetics Pathophysiology Pathophysiology Clinical Features Clinical Features Diagnosis Diagnosis Treatment Treatment Prognosis Prognosis Screening Screening

Prognosis The presence or absence of cirrhosis is a major determinant of prognosis in HH. The presence or absence of cirrhosis is a major determinant of prognosis in HH. In one study, survival was shortened in patient with cirrhosis and diabetes but was normal in those without cirrhosis In one study, survival was shortened in patient with cirrhosis and diabetes but was normal in those without cirrhosis HCC – 119 times more common HCC – 119 times more common Cirrhosis – 10 times more common Cirrhosis – 10 times more common Cardiomyopathy – 306 times more common Cardiomyopathy – 306 times more common Diabetes Mellitus – 14 times more common Diabetes Mellitus – 14 times more common Liver cancers were associated with cirrhosis and not with the presence of hepatitis B or C markers. Liver cancers were associated with cirrhosis and not with the presence of hepatitis B or C markers.

Agenda Case Presentation Case Presentation Introduction & Genetics Introduction & Genetics Pathophysiology Pathophysiology Clinical Features Clinical Features Diagnosis Diagnosis Treatment Treatment Prognosis Prognosis Screening Screening

Screening There is general agreement to screen family members of pt. with HH. There is general agreement to screen family members of pt. with HH. Screening for family members is critical because 25 % of siblings and 5% of the children of a proband have HH. Screening for family members is critical because 25 % of siblings and 5% of the children of a proband have HH. HFE gene testing is the most useful screening test. HFE gene testing is the most useful screening test. Pt. with otherwise unexplained CLD, arthritis, impotence, late onset DM (Type 1) should be screened for hemochromatosis. Pt. with otherwise unexplained CLD, arthritis, impotence, late onset DM (Type 1) should be screened for hemochromatosis.

Screening HFE gene testing is also useful in ambiguous situations,such as iron overload associated with hepatitis C, alcoholic liver disease, and other causes of ESLD. HFE gene testing is also useful in ambiguous situations,such as iron overload associated with hepatitis C, alcoholic liver disease, and other causes of ESLD. HFE gene test is a PCR test that is performed on whole blood sample. It cost $200. HFE gene test is a PCR test that is performed on whole blood sample. It cost $200. USPSTF and CDC do not recommend routine screening of general population for HH USPSTF and CDC do not recommend routine screening of general population for HH

Screening

Screening

Summary

References 1)Brandhagen DJ, Fairbanks VF, Baldus W, Recognition and management of hereditary hemochromatosis,American Family Physician,March1,2002 2)Who should be screened for hemochromatosis, American Family Physician, Jan 1, )Sfeir HE, Hemochromatosis, Nov 8,

References 4)Stanley SL, Bruce BR, Clinical features of heriditary hemochromatosis, 6)Stanley SL, Bruce BR,Screening of hereditary hemochromatosis, 7)Stanley SL, Bruce BR, Genetics of hereditary hemochromatosis, 8)Stanley SL, Bruce BR,Diagnosis of hereditary hemochromatosis,