S L I D E 1 Hemochromatosis – Diagnosis and Management Pramod K. Mistry, MA, PhD, MD, FRCP Professor of Pediatrics and Medicine Chief, Pediatric Gastroenterology.

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

a1 – antitrypsindeficiency

OtherOther

CFCF

Wilson'sWilson's

Familial intrahepatic cholestasis

Familial intrahepatic cholestasis

Hemochromatosis

Newborn and infantsNewborn and infants AdultsAdults

Inherited Causes of Cirrhosis

PituitaryGonadotropin

deficiency

Skin bronzing

CardiomyopathyConduction disordersCirrhosisHepatocellular carcinomaDiabetes mellitus

BacteremiaTesticular atrophy Arthropathy

ArthritisPseudogout

PituitaryGonadotropin

deficiency

Skin bronzing

CardiomyopathyConduction disordersCirrhosisHepatocellular carcinomaDiabetes mellitus

BacteremiaTesticular atrophy Arthropathy

ArthritisPseudogout

Hemochromatosis - Clinical ManifestationsHemochromatosis - Clinical Manifestations

Clinical 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

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

HemochromatosisHemochromatosis

NormalNormal

Hemochromatosis - Iron Balance ValuesHemochromatosis - Iron Balance Values

Classification of Iron Overload Syndromes

Ingested10-20 mg/day

Ingested10-20 mg/day

Absorbed1-2 mg/day

Absorbed1-2 mg/day

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

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

Normal Iron BalanceNormal Iron Balance

Normal 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 Storage

TransportTransferrin - two iron atoms

TransportTransferrin - two iron atoms

Intracellular storageFerritin - thousands of iron atoms

Intracellular storageFerritin - thousands of iron atoms

Total body iron - 4gTotal body iron - 4g

Storageiron

Storageiron

OtherOther

RBCsRBCs

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 chaina Heavy chain

b2

microglobulin

b2

microglobulin

a1a1 a2a2

a3a3

C282Y MutationC282Y Mutation

H63D MutationH63D Mutation

NH2NH2NH2NH2

COOHCOOH

COOHCOOH

HFE Protein StructureHFE Protein Structure

HFE Protein Structure

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

S65Cmutation

What about India?

Global Prevalence of HFE MutationsGlobal Prevalence of HFE MutationsFrequency

(%)

C282Y H63D

Population allelic allelic

Frequency (%)

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

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; 116:193Bacon, 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)

Total body iron(g)

Age (years)Age (years)

00

2020

3030

4040

2020 3030 5050

1010

1010 4040

­­Serum iron

­­Serum iron

Cirrhosis, organ failure

Cirrhosis, organ failure

­­Hepatic

iron

­­Hepatic

iron

Tissue injury

Tissue injury

NormalNormal

Natural HistoryNatural History

Hemochromatosis

Phenotype Expression

· Men > women

· Increases with age

· Correlates with amount of iron in the diet

· Chronic hemolysis, alcoholism, steatohepatitis, hepatitis C

· 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 Quantitative

iron 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 >3000

Serum Transferrin Quantitative

iron 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 >3000

HemochromatosisHemochromatosis

NormalNormal

Iron Balance Values

Family history or suspicion of hemochromatosis

Family history or suspicion of hemochromatosis

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

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

Therapeutic Phlebotomy,response confirms diagnosis

Therapeutic Phlebotomy,response confirms diagnosis

% sat. >50%Ferritin

>250 mg/L >300 mg/L

% sat. >50%Ferritin

>250 mg/L >300 mg/L

­­stainable Fe Iron index >2­­stainable Fe Iron index >2

Fe / TIBC -% saturationFerritin

Fe / TIBC -% saturationFerritin

Liver biopsy with iron stain and quantitative iron

Liver biopsy with iron stain and quantitative iron

? Modified Diagnostic Algorithm for Use in India? Modified Diagnostic Algorithm for Use in India

Diagnostic Testing

Equivocal results

Interpretation of Ferritin Levels

­­Ferritin and­­Ferritin and

Normal ferritin and ¯ ironNormal ferritin and ¯ iron

¯ Ferritin and ¯ iron¯ Ferritin and ¯ iron

­­iron­­iron

¯­iron¯­iron

HemochromatosisHemochromatosis

Acute liver injuryAcute liver injury

Acute phase reactantAcute phase reactant

Chronic diseaseChronic disease

Iron deficiencyIron deficiency

Interpretation of Ferritin Levels

IndexIndex

NormalsNormals AlcoholicAlcoholicHeterozygotesHeterozygotes

HemochromatosisHemochromatosisHomozygotesHomozygotes

PrecirrhoticPrecirrhotic

CirrhoticCirrhotic

Liver iron AgeLiver iron Age

00

11

22

33

44

55

10101515

(mmol/g) (yr)(mmol/g) (yr)

Hepatic Iron Index

Hepatic Iron Index

Phlebotomy

Acute

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

Acute

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 SurvivalPhlebotomy Improves Survival

Preventable: all clinical manifestations

Reversible: cardiac dysfunction, glucose intolerance, hepatomegaly,

skin pigmentation

Irreversible: cirrhosis risk of hepatocellular carcinomaarthropathy, hypogonadism

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

Iron Depletion Improves Survival

00

4040

8080

100100

2020

1010 1515 252555 2020

6060

00

Cumulative survival

(%)

Cumulative survival

(%)

Time (years)Time (years)

Iron depleted after 18 monthsIron depleted

after 18 months

Untreated after 18 months

Untreated after 18 months

Iron Depletion Improves Survival

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

Response to Phlebotomy

00

4040

6060

8080

100100

44 1212 2020 2424 3232

500500

10001000

15001500

2020

8800 1616 2828

20002000

Transferrin

%

Transferrin

%

Time (months)

Time (months)

Hgbdrop

s

Hgbdrop

s

Ferritinng/ml

Ferritinng/ml

PhlebotomyPhlebotomy

Serum ferritinSerum ferritin

Transferrin saturation

Transferrin saturation

Response to Phlebotomy

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

a1 – antitrypsindeficiency

OtherOther

CFCF

Wilson'sWilson's

Familial intrahepatic cholestasis

Familial intrahepatic cholestasis

Hemochromatosis

Newborn and infantsNewborn and infants AdultsAdults

Genetic Diseases - LiverGenetic Diseases - Liver

Inherited 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