S L I D E 1

Hemochromatosis – Diagnosis and Management 

Pramod K. Mistry, MA, PhD, MD, FRCPProfessor of Pediatrics and MedicineChief, Pediatric Gastroenterology and Hepatology

Indian Association for the Study of the Liver‘Metabolic Liver Disease’Mumbai. January 13, 2012

Non-contrast CT

65 yr old male, ferritin 2660, AFP 6324DDx GSD, thorotrast, amiodarone, cisplatin

What is the diagnosis?

Inherited Causes of Cirrhosis

a1 – antitrypsindeficiency

Other

CFWilson's

Familial intrahepatic cholestasis

Hemochromatosis

Newborn and infants Adults

Inherited Causes of Cirrhosis

PituitaryGonadotropin

deficiency

Skin bronzingCardiomyopathyConduction disordersCirrhosisHepatocellular carcinomaDiabetes mellitus

BacteremiaTesticular atrophy Arthropathy

ArthritisPseudogout

Hemochromatosis - Clinical ManifestationsClinical Manifestations

Clinical Manifestations of Hereditary Hemochromatosis

Serum TransferrinQuantitative

iron TIBC saturation Ferritinhepatic iron

(mg/dL) (mg/dL) (%) (mg/dL) (mg/g dry wt)

60-180 230-370 20-50 20-200 300-1500

>180 <300 >50 >300>3000

Hemochromatosis

Normal

Hemochromatosis - Iron Balance Values

Classification of Iron Overload Syndromes

Ingested10-20 mg/day

Absorbed1-2 mg/day

LostGut, skin, urine - 1-2 mg/dayMenses - 30 mg/month

Normal Iron BalanceNormal Iron Balance

In HH daily absorption of iron is 2-4 mg despite systemic iron overload

Pietrangelo, A. N Engl J Med 2004;350:2383-2397

Iron Homeostasis in Health and Disease

HH – sparing of Kuppfer cells

Iron Transport and StorageTransport

Transferrin - two iron atoms

Intracellular storageFerritin - thousands of iron atoms

Total body iron - 4g

Storageiron

Other

RBCs

Iron Transport and Storage

Normal Hfe Mutation ‘Mild’ Hemochromatosis

TfR2 hemochromatosisMild iron overload

HJV hemochromatosisMassive iron overload

HAMP hemochromatosisDramatic iron overload

Ferroportin hemochromatosis –Tissue iron overload withRelative circulatory iron deficiency

a Heavy chain

b2 microglobulin

a1 a2

a3

C282Y Mutation

H63D Mutation

NH2NH2

COOH

COOH

HFE Protein StructureHFE Protein Structure

Bacon BR, et al. Gastroenterology 1999; 116: 193

S65Cmutation

What about India?

Global Prevalence of HFE MutationsFrequency

(%)

C282Y H63D

Population allelic allelic

United Kingdom 6.412.8Norway 6.411.2Denmark 9.512.2Finland 011.8Former USSR 1.010.4Germany 3.914.8Italy 0.512.6Spain 3.226.3Greece 1.313.5Saudi Arabia 08.5Africa 02.6Indian subcontinent 0.28.4Asia 01.9Australasia 00.2Americas 0.72.6

Bacon, et al., Gastroenterology 1999; 116:193

Global Prevalence of HFE Mutations

Andrews, N. C. et al. N Engl J Med 2005;353:189-198

Pietrangelo, A. N Engl J Med 2004;350:2383-2397

Total body iron(g)

Age (years)

0

20

30

40

20 30 50

10

10 40

­ Serum

iron

Cirrhosis, organ failure

­ Hepatic

iron

Tissue injury

Normal

Natural HistoryHemochromatosis

Phenotype Expression·Men > women

· Increases with age

·Correlates with amount of iron in the diet

·Chronic hemolysis, alcoholism, steatohepatitis, hepatitis C

Phenotype Expression

Risk of HCC 119 x NCirrhosis 10 xNCardiomyopathy 306 x NDiabetes mellitus 10 x NReduced survival in cirrhotic HH. Non-cirrhotic HH, normal survival

(Niederau, Gastro 1996 250 patients followed for 14 +/- 7 yrs – 69 patients died)

Prognosis

Serum Transferrin Quantitativeiron TIBC saturation Ferritin hepatic iron

(mg/dL) (mg/dL) (%) (mg/dL) (mg/g dry wt)

60-180 230-370 20-50 20-200 300-1500

>180 <300 >50 >300 >3000Hemochromatosis

Normal

Iron Balance Values

Family history or suspicion of hemochromatosis

Repeat iron panel high; Ferritin >1000Elevated AST/ALTExtrahepatic manifestations of iron overload; Positive FH

Therapeutic Phlebotomy,response confirms diagnosis

% sat. >50%Ferritin

>250 mg/L >300 mg/L

­ stainable Fe Iron index >2

Fe / TIBC -% saturationFerritin

Liver biopsy with iron stain and quantitative iron

? Modified Diagnostic Algorithm for Use in IndiaDiagnostic Testing

Equivocal results

Interpretation of Ferritin Levels

­ Ferritin and

Normal ferritin and ¯ iron

¯ Ferritin and ¯ iron

­ iron

¯ iron

Hemochromatosis

Acute liver injury

Acute phase reactant

Chronic disease

Iron deficiency

Interpretation of Ferritin Levels

Index

Normals AlcoholicHeterozygotes

HemochromatosisHomozygotes

Precirrhotic

Cirrhotic

Liver iron Age

0

1

2

3

4

5

1015

(mmol/g) (yr)

Hepatic Iron Index

Hepatic Iron Index

PhlebotomyAcute

1 unit (250 mg Fe) weekly or biweekly until mildly anemic

Maintenance Once iron stores are depleted (ferritin <50ng/ml, transferrin sat <50%)

continue with phlebotomy every 2-3 months. Monitor hemoglobin, ferritin and transferrin saturation

Phlebotomy – Therapy for Iron Overload

Phlebotomy Improves Survival

Preventable: all clinical manifestations

Reversible: cardiac dysfunction, glucose intolerance, hepatomegaly,

skin pigmentation

Irreversible: cirrhosis risk of hepatocellular carcinomaarthropathy, hypogonadism

Phlebotomy Improves Survival

Niederau C, et al. N Engl J Med 1985; 313:1256

Iron Depletion Improves Survival

0

40

80

100

20

10 15 255 20

60

0

Cumulative survival

(%)

Time (years)

Iron depleted after 18 months

Untreated after 18 months

Iron Depletion Improves Survival

Niederau C, et al. N Engl J Med 1985; 313:1256

Response to Phlebotomy

0

40

60

80

100

4 12 20 24 32

500

1000

1500

20

80 16 28

2000

Transferrin%

Time (months)

Hgbdrop

s

Ferritinng/ml

Phlebotomy

Serum ferritin

Transferrin saturation

Response to Phlebotomy

Edwards CQ, et al. Hospital Practice 1991; 26:30

Quantitative Phlebotomy As A Diagnostic Test For HH

• Indication

liver biopsy cannot be performed but suspected iron overload• Determine the number of weekly 500 mL phlebotomies,

each of which removes 200 to 250 mg of elemental iron,

which are required to produce iron deficient erythropoiesis. • Normal men have approximately 1 g of iron stores. • Therefore, 4-5 phlebotomies during 4-8 weeks will produce

an iron deficiency anemia• In contrast, patients with significant iron loading usually

have at least 5 g (and often 20 g or more) of iron stores, requiring at least

20 units of phlebotomy to induce iron deficiency

Inherited Causes of Cirrhosis

a1 – antitrypsindeficiency

Other

CFWilson's

Familial intrahepatic cholestasis

Hemochromatosis

Newborn and infants Adults

Genetic Diseases - LiverInherited Causes of Cirrhosis

Neonatal Hemochromatosis

• Late fetal or early neonatal loss• Renal hypoplasia• Often with oligohydramniosFeatures• Raised ferritin• Hepatocellular synthetic failure• Extensive cholestasis• Low or absent AST/ALT• AFP >200,000• Systemic iron overload – Dx investigation: buccal

biopsy

Andrews, N. C. et al. N Engl J Med 2005;353:189-198

Neonatal Hemochromatosis

NH – pathogenetic mechanisms

• Non-specific consequence of any type of liver injury• Genetic: Recurrence rate 80% in children born to same

mothers*

• Infectious disease• Immune mediated disease

• Occurs in hemolysis with giant cell hepatitiscongental nephrotic syndrome, arthrogryphosis multiplex, all allo-immune mediated maternal diseases

• IgG from NH affected mother into pregnant mouse dams leads to liver failure in the newborn

NH – Treatments

• IVIG (Whitington, Lancet, 2001)• Chelation/antioxidant cocktail• NAC• Transplant