Naima Cheema, MD Emory Family Medicine March 6, 2008.

Naima Cheema, MDNaima Cheema, MD

Emory Family MedicineEmory Family Medicine

March 6, 2008March 6, 2008

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Case PresentationCase Presentation Introduction & GeneticsIntroduction & Genetics PathophysiologyPathophysiology Clinical FeaturesClinical Features DiagnosisDiagnosis TreatmentTreatment PrognosisPrognosis ScreeningScreening

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Case PresentationCase Presentation 58 yr old male came for followup visit for 58 yr old male came for followup visit for

hypertension, hyperlipidemia and hypertension, hyperlipidemia and transaminitistransaminitis

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 Occurs q 1-2 months. Most of the time he is

fine. fine. No exertional association of chest pain. No exertional association of chest pain. No pain todayNo pain today

HTN poorly controlled. No home log HTN poorly controlled. No home log available.available.

ROS : No CP/ No SOB/ No LE edema / No ROS : No CP/ No SOB/ No LE edema / No numbness / No weakness / No abdominal numbness / No weakness / No abdominal pain.pain.

PMH : HTN / Hyperlipidemia / CVAPMH : HTN / Hyperlipidemia / CVA

Case PresentationCase Presentation PSH : Carotid endarterectomy (2002), PSH : Carotid endarterectomy (2002),

Cardiac Catheterization (2002), Denies Cardiac Catheterization (2002), Denies Angioplasty. Angioplasty.

Social : Social : Tobacco 2 ppd, ETOH : none, Rec Drugs: noneTobacco 2 ppd, ETOH : none, Rec Drugs: none

Allergies : No known drug allergiesAllergies : No known drug allergies Meds : Meds :

Lisinopril 40 mg/day , Atenolol 100mg/day, Lisinopril 40 mg/day , Atenolol 100mg/day, Amlodipine 10 mg/day, Gemfibrozil Amlodipine 10 mg/day, Gemfibrozil 600mg/day, Aspirin 81mg/day600mg/day, Aspirin 81mg/day

Physical Exam : BP 149/88, Pulse 80, Temp Physical Exam : BP 149/88, Pulse 80, Temp 97.5, Resp 20, BMI 30.297.5, Resp 20, BMI 30.2

Case PresentationCase Presentation Gen : NADGen : NAD Heent : Conj pink / sclera non-ictericHeent : Conj pink / sclera non-icteric Pulm : CTAPulm : CTA CVS: Regular S1 S2, No murmursCVS: Regular S1 S2, No murmurs Abd: BS+ soft NT ND No HSMAbd: BS+ soft NT ND No HSM Ext: No edemaExt: No edema Labs: Labs:

Cr 1.2 / K 3.7, MDRD 66%Cr 1.2 / K 3.7, MDRD 66% Urine Protein negativeUrine Protein negative AST 64/ ALT 36 / ALB 4.3AST 64/ ALT 36 / ALB 4.3

Case PresentationCase Presentation Persistent Elevated TransaminitisPersistent Elevated Transaminitis Denies alcohol abuse (none in 12 yrs)Denies alcohol abuse (none in 12 yrs) Hep B and Hep C negativeHep B and Hep C negative RUQ U/S orderedRUQ U/S ordered Iron Studies :Iron Studies :

Ferritin 968 ng/mlFerritin 968 ng/ml Iron 321Iron 321 TIBC 353TIBC 353 Transferrin Saturation 318 (91%)Transferrin Saturation 318 (91%)

Pt. with asymptomatic elevation of liver Pt. with asymptomatic elevation of liver enzymes, elevated transferrin saturation enzymes, elevated transferrin saturation and serum ferritin ……hemochromatosisand serum ferritin ……hemochromatosis

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IntroductionIntroduction

DefinitionDefinition Most Common inherited single-gene Most Common inherited single-gene

disorder.disorder. Increased intestinal absorption of iron.Increased intestinal absorption of iron. Deposition of iron in multiple organs like Deposition of iron in multiple organs like

liver, pancreas, heart and skin.liver, pancreas, heart and skin.

HemochromatosisHemochromatosis

IncidenceIncidence

Common in people of Northern European descentCommon in people of Northern European descent Most Common single-gene disorder in the US Most Common single-gene disorder in the US

white populationwhite population One in 250-300 white persons has homozygous One in 250-300 white persons has homozygous

genetic mutations of HHgenetic mutations of HH One in 10 persons is a carrier for the mutationOne in 10 persons is a carrier for the mutation Typical PCP encounters one patient with HH every Typical PCP encounters one patient with HH every

two weekstwo weeks

GeneticsGenetics Autosomal recessive disorder Autosomal recessive disorder HFE gene located on short arm of HFE gene located on short arm of

chromosome 6chromosome 6 Two point mutations : C282Y and H63DTwo point mutations : C282Y and H63D 60-93% of patients are homozygous for 60-93% of patients are homozygous for

C282Y mutationC282Y mutation Minority of patients are heterozygotes, Minority of patients are heterozygotes,

who have one copy of C282Y and one copy who have one copy of C282Y and one copy of H63D. Disease is of lesser severity in of H63D. Disease is of lesser severity in this case.this case.

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PathophysiologyPathophysiology HH develops as a result of imbalance HH develops as a result of imbalance

between iron absorption and lossbetween iron absorption and loss Iron is normally lost in sweat, shed skin Iron is normally lost in sweat, shed skin

cells, and the GI tract at a rate of cells, and the GI tract at a rate of ~1mg/day~1mg/day

Pre menopausal adult women lose an Pre menopausal adult women lose an additional 0.5 to 1.0 mg/day because of additional 0.5 to 1.0 mg/day because of mensesmenses

These losses are balanced by the These losses are balanced by the absorption of 10% of the 10–20 mg of iron absorption of 10% of the 10–20 mg of iron in diet.in diet.

PathophysiologyPathophysiology A male patient with homozygous HH A male patient with homozygous HH

absorbs 4mg of iron per day rather than 1 absorbs 4mg of iron per day rather than 1 mg/day needed to balance iron lossesmg/day needed to balance iron losses

Retention of 3mg of iron more per day Retention of 3mg of iron more per day than is needed to maintain iron balance than is needed to maintain iron balance will lead to net iron accumlation of will lead to net iron accumlation of approximately 1g per yearapproximately 1g per year

Until age 40-50, the total iron Until age 40-50, the total iron accumulation will reach more than 20g of accumulation will reach more than 20g of iron. At this level clinical features of HH iron. At this level clinical features of HH start developingstart developing

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Clinical FeaturesClinical Features Clinical manifestations occur after the age Clinical manifestations occur after the age

of 40 years, when body iron stores have of 40 years, when body iron stores have reached 15 to 40 g.reached 15 to 40 g.

Clinical FeaturesClinical Features Women manifest disease less frequently Women manifest disease less frequently

than men.than men. Alcohol abuse and hepatitis C may Alcohol abuse and hepatitis C may

accelerate disease expression.accelerate disease expression. Fatigue 74%,arthralgias 44% and impotence Fatigue 74%,arthralgias 44% and impotence

45% are the most common symptoms of 45% are the most common symptoms of this disorder.this disorder.

““Bronze Diabetes” i.e., cutaneous Bronze Diabetes” i.e., cutaneous hyperpigmentation,DM and cirrhosis are hyperpigmentation,DM and cirrhosis are presentations of advanced disease.presentations of advanced disease.

If HH is diagnosed early and treated If HH is diagnosed early and treated appropriately, most clinical manifestations appropriately, most clinical manifestations are easily preventable.are easily preventable.

Changing Clinical Features of Changing Clinical Features of HHHH

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DiagnosisDiagnosis HH is diagnosed by combination of HH is diagnosed by combination of

clinical , laboratory and pathologic criteria.clinical , laboratory and pathologic criteria. Elevated transferrin saturationElevated transferrin saturation TS=serum iron concentration/total iron-TS=serum iron concentration/total iron-

binding capacity X100binding capacity X100 Initial test of choice – 94% specificityInitial test of choice – 94% specificity An elevated transferrin saturation should An elevated transferrin saturation should

be repeated as a fasting early morning be repeated as a fasting early morning test.test.

A value greater than 60% in men and A value greater than 60% in men and greater than 50 % in women is highly greater than 50 % in women is highly specific. specific.

DiagnosisDiagnosis Serum transferrin saturation may be Serum transferrin saturation may be

normal early in the course of disease.normal early in the course of disease. Serum ferritin levels elevated greater than Serum ferritin levels elevated greater than

200 mcg/l in premenopausal women and 200 mcg/l in premenopausal women and 300 mcg/l in post menopausal women and 300 mcg/l in post menopausal women and men indicate iron overload due to HH, men indicate iron overload due to HH, especially when associated with elevated especially when associated with elevated transferrin saturation and evidence of liver transferrin saturation and evidence of liver disease. disease.

DiagnosisDiagnosis Ferritin is acute phase reactant and it’s Ferritin is acute phase reactant and it’s

concentration can be high in infection, concentration can be high in infection, inflammation and liver disease.inflammation and liver disease.

Ferritin concentration higher than Ferritin concentration higher than 1000mcg/l suggests liver damage with 1000mcg/l suggests liver damage with fibrosis or cirrhosis.fibrosis or cirrhosis.

Ferritin levels are less sensitive than Ferritin levels are less sensitive than transferrin saturation as a screening test transferrin saturation as a screening test for HH.for HH.

Iron Studies in Pt. with HHIron Studies in Pt. with HH

DiagnosisDiagnosis Pt. with elevated ferritin and serum Pt. with elevated ferritin and serum

transferrin saturation should undergo HFE transferrin saturation should undergo HFE gene testing to confirm the diagnosis of gene testing to confirm the diagnosis of HH.HH.

HFE gene testing has replaced liver biopsy HFE gene testing has replaced liver biopsy to confirm the diagnosis of HH.to confirm the diagnosis of HH.

Liver biopsy is the gold standard for Liver biopsy is the gold standard for assessing the degree of fibrosis. assessing the degree of fibrosis.

Definite exclusion of cirrhosis is important Definite exclusion of cirrhosis is important because the risk of hepatocellular because the risk of hepatocellular carcinoma is 200 times higher in pt. with carcinoma is 200 times higher in pt. with HH and cirrhosis. HH and cirrhosis.

DiagnosisDiagnosis The risk of cancer persists even after The risk of cancer persists even after

excess iron stores have been depleted. excess iron stores have been depleted. Pt. with cirrhosis should be screened every Pt. with cirrhosis should be screened every

6 months with abdominal ultrasound and 6 months with abdominal ultrasound and alfa-fetoprotein test for HCC. alfa-fetoprotein test for HCC.

Every pt. with cirrhosis should undergo Every pt. with cirrhosis should undergo screening EGD to look for varices. screening EGD to look for varices.

If varices are present , pt. should be If varices are present , pt. should be started on propranolol or nadolol as started on propranolol or nadolol as primary prevention.primary prevention.

Phlebotomy also help reverse varices.Phlebotomy also help reverse varices.

DiagnosisDiagnosis Some pt. with HH are at low risk for Some pt. with HH are at low risk for

cirrhosis and therefore may not require cirrhosis and therefore may not require liver biopsy. Non-invasive predictors are liver biopsy. Non-invasive predictors are helpful in excluding cirrhosis in these pt. helpful in excluding cirrhosis in these pt.

Non-invasive predictors: Non-invasive predictors: Serum ferritin concentration below 1000ng/mlSerum ferritin concentration below 1000ng/ml Normal AST values and Normal AST values and No hepatomegalyNo hepatomegaly

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TreatmentTreatment Treatment for HH is reserved for pt. with Treatment for HH is reserved for pt. with

eveidence of iron overload based on an eveidence of iron overload based on an elevated serum ferritin concentration.elevated serum ferritin concentration.

Phlebotomy is the preferred treatment as Phlebotomy is the preferred treatment as it is simple,effective and inexpensive.it is simple,effective and inexpensive.

Initial treatment: Removal of 500 ml of Initial treatment: Removal of 500 ml of blood on a weekly basis until the blood on a weekly basis until the hemoglobin concentration is below the hemoglobin concentration is below the reference range (less than 12-13 g/dl).reference range (less than 12-13 g/dl).

Removal of every 500 ml of blood removes Removal of every 500 ml of blood removes 200-250 mg of iron.200-250 mg of iron.

TreatmentTreatment Iron depletion is confirmed by serum Iron depletion is confirmed by serum

ferritin concentration less than 50 ng/ml ferritin concentration less than 50 ng/ml and serum transferritin saturation less and serum transferritin saturation less than 50 %.than 50 %.

Usually, pt. require weekly phlebotomies Usually, pt. require weekly phlebotomies for 50 weeks before they start for 50 weeks before they start maintenance therapy. maintenance therapy.

Maintenance treatment: Once iron Maintenance treatment: Once iron depletion has accomplished, most pt. depletion has accomplished, most pt. require four to eight phlebotomies per require four to eight phlebotomies per year .Goal is to maintain serum ferritin year .Goal is to maintain serum ferritin concentration less than 50 ng/ml.concentration less than 50 ng/ml.

TreatmentTreatment Phlebotomies help reverse several clinical Phlebotomies help reverse several clinical

features including cardiomyopathy, features including cardiomyopathy, conduction abnormalities, hepatomegaly, conduction abnormalities, hepatomegaly, varices, skin pigmentation and infections. varices, skin pigmentation and infections.

Cirrhosis, diabetes mellitus , primary and Cirrhosis, diabetes mellitus , primary and secondary hypogonadism and arthralgias secondary hypogonadism and arthralgias are irreversible features of the disease. are irreversible features of the disease.

TreatmentTreatment The blood withdrawn from a patient with The blood withdrawn from a patient with

HH can be used for direct transfusion. HH can be used for direct transfusion. FDA regulations require that containers FDA regulations require that containers

should be labeled conspicuously that the should be labeled conspicuously that the donor had Hemochromatosis.donor had Hemochromatosis.

CHELATION THERAPY : Chelation therapy CHELATION THERAPY : Chelation therapy for HH with deferoxamine can lead to for HH with deferoxamine can lead to clinical improvement. It is reserved only clinical improvement. It is reserved only for those patients who cannot tolerate for those patients who cannot tolerate phlebotomy.phlebotomy.

TreatmentTreatment

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PrognosisPrognosis The presence or absence of cirrhosis is a The presence or absence of cirrhosis is a

major determinant of prognosis in HH.major determinant of prognosis in HH. In one study, survival was shortened in In one study, survival was shortened in

patient with cirrhosis and diabetes but was patient with cirrhosis and diabetes but was normal in those without cirrhosisnormal in those without cirrhosis

HCC – 119 times more commonHCC – 119 times more common Cirrhosis – 10 times more commonCirrhosis – 10 times more common Cardiomyopathy – 306 times more commonCardiomyopathy – 306 times more common Diabetes Mellitus – 14 times more commonDiabetes Mellitus – 14 times more common Liver cancers were associated with cirrhosis Liver cancers were associated with cirrhosis

and not with the presence of hepatitis B or and not with the presence of hepatitis B or C markers.C markers.

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ScreeningScreening There is general agreement to screen There is general agreement to screen

family members of pt. with HH.family members of pt. with HH. Screening for family members is critical Screening for family members is critical

because 25 % of siblings and 5% of the because 25 % of siblings and 5% of the children of a proband have HH. children of a proband have HH.

HFE gene testing is the most useful HFE gene testing is the most useful screening test. screening test.

Pt. with otherwise unexplained CLD, Pt. with otherwise unexplained CLD, arthritis, impotence, late onset DM (Type arthritis, impotence, late onset DM (Type 1) should be screened for 1) should be screened for hemochromatosis.hemochromatosis.

ScreeningScreening HFE gene testing is also useful in HFE gene testing is also useful in

ambiguous situations,such as iron ambiguous situations,such as iron overload associated with hepatitis C , overload associated with hepatitis C , alcoholic liver disease, and other causes of alcoholic liver disease, and other causes of ESLD.ESLD.

HFE gene test is a PCR test that is HFE gene test is a PCR test that is performed on whole blood sample. It cost performed on whole blood sample. It cost $200.$200.

USPSTF and CDC do not recommend USPSTF and CDC do not recommend routine screening of general population for routine screening of general population for HHHH

ScreeningScreening

ScreeningScreening

SummarySummary

ReferencesReferences1)Brandhagen DJ, Fairbanks VF, Baldus W, 1)Brandhagen DJ, Fairbanks VF, Baldus W,

Recognition and management of Recognition and management of hereditary hemochromatosis,American hereditary hemochromatosis,American Family Physician,March1,2002Family Physician,March1,2002

2)Who should be screened for 2)Who should be screened for hemochromatosis, American Family hemochromatosis, American Family Physician, Jan 1 ,2003.Physician, Jan 1 ,2003.

3)Sfeir HE, Hemochromatosis, 3)Sfeir HE, Hemochromatosis, www.emedicine.com/med/topic975.htm, , Nov 8, 2006.Nov 8, 2006.

http://www.emedicine.com/med/topic975.htm

ReferencesReferences4)Stanley SL, Bruce BR, Clinical features of 4)Stanley SL, Bruce BR, Clinical features of

heriditary hemochromatosis, heriditary hemochromatosis, www.uptodate.com

6)Stanley SL, Bruce BR,Screening of 6)Stanley SL, Bruce BR,Screening of hereditary hemochromatosis, hereditary hemochromatosis, www.uptodate.com

7)Stanley SL , Bruce BR, Genetics of 7)Stanley SL , Bruce BR, Genetics of hereditary hemochromatosis, hereditary hemochromatosis, www.uptodate.com

8)Stanley SL, Bruce BR ,Diagnosis of 8)Stanley SL, Bruce BR ,Diagnosis of hereditary hemochromatosis, hereditary hemochromatosis, www.uptodate.com

http://www.uptodate.com/




Naima Cheema, MD Emory Family Medicine March 6, 2008.

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