Transcript Hemochromatosis - Children`s Liver Foundation

Hemochromatosis
– Diagnosis and Management
Pramod K. Mistry, MA, PhD, MD, FRCP
Professor of Pediatrics and Medicine
Chief, Pediatric Gastroenterology and Hepatology
Indian Association for the Study of the Liver
‘Metabolic Liver Disease’
Mumbai. January 13, 2012
SLIDE 1
What is the diagnosis?
Non-contrast CT
65 yr old male, ferritin 2660, AFP 6324
DDx GSD, thorotrast, amiodarone, cisplatin
Inherited Causes of Cirrhosis
Inherited Causes of Cirrhosis
Hemochromatosis
Familial intrahepatic
cholestasis
Wilson's
CF
Other
a1 – antitrypsin
deficiency
Newborn and infants
Adults
Clinical Manifestations
Hemochromatosis - Clinical Manifestations
Pituitary
Gonadotropin
deficiency
Skin bronzing
Cardiomyopathy
Conduction disorders
Cirrhosis
Hepatocellular
carcinoma
Diabetes mellitus
Bacteremia
Testicular atrophy
Arthropathy
Arthritis
Pseudogout
Clinical Manifestations of Hereditary Hemochromatosis
Hemochromatosis - Iron Balance Values
Serum
iron
TIBC
Transferrin
saturation
(mg/dL)
(mg/dL)
(%)
230-370
20-50
Normal 60-180
Quantitative
Ferritin hepatic iron
(mg/dL)
(mg/g dry wt)
20-200 300-1500
Hemochromatosis
>180
<300
>50
>300
>3000
Classification of Iron Overload Syndromes
Normal Iron Balance
Normal Iron Balance
Ingested
10-20 mg/day
Absorbed
1-2 mg/day
Lost
Gut, skin, urine - 1-2 mg/day
Menses - 30 mg/month
In HH daily absorption of iron is 2-4 mg
despite systemic iron overload
Iron Homeostasis in Health and Disease
HH –
sparing of Kuppfer cells
Pietrangelo, A. N Engl J Med 2004;350:2383-2397
Iron Transport and Storage
Iron Transport and Storage
Transport
Transferrin - two iron atoms
Intracellular storage
Ferritin - thousands of iron atoms
Total body iron - 4g
RBCs
Storage
iron
Other
Normal
Hfe Mutation
‘Mild’ Hemochromatosis
TfR2 hemochromatosis
Mild iron overload
HAMP hemochromatosis
Dramatic iron overload
HJV hemochromatosis
Massive iron overload
Ferroportin hemochromatosis –
Tissue iron overload with
Relative circulatory iron
deficiency
HFE Protein Structure
HFE Protein Structure
a Heavy chain
H63D Mutation
S65C
mutation
a1
a2
NH2
b2
microglobulin
COOH
COOH
Bacon BR, et al. Gastroenterology 1999; 116: 193
NH2
a3
C282Y Mutation
What about India?
Global Prevalence of HFE Mutations
Global Prevalence of HFE Mutations
Frequency
(%)
Population
United Kingdom
Norway
Denmark
Finland
Former USSR
Germany
Italy
Spain
Greece
Saudi Arabia
Africa
Indian subcontinent
Asia
Australasia
Americas
Bacon, et al., Gastroenterology 1999; 116:193
C282Y
allelic
6.4
6.4
9.5
0
1.0
3.9
0.5
3.2
1.3
0
0
0.2
0
0
0.7
H63D
allelic
12.8
11.2
12.2
11.8
10.4
14.8
12.6
26.3
13.5
8.5
2.6
8.4
1.9
0.2
2.6
Andrews, N. C. et al. N Engl J Med 2005;353:189-198
Pietrangelo, A. N Engl J Med 2004;350:2383-2397
Hemochromatosis
Natural History
Cirrhosis,
organ
failure
40
Tissue
injury
30
Total body
iron
20
(g)
10
Hepatic
iron
Serum
iron
Normal
0
10
20
30
Age (years)
40
50
Phenotype Expression
Phenotype Expression
 Men > women
 Increases with age
 Correlates with amount of iron in
the diet
 Chronic hemolysis, alcoholism,
steatohepatitis, hepatitis C
Prognosis
Risk of HCC 119 x N
Cirrhosis 10 xN
Cardiomyopathy 306 x N
Diabetes mellitus 10 x N
Reduced survival in cirrhotic HH. Non-cirrhotic
HH, normal survival
(Niederau, Gastro 1996 250 patients followed for 14 +/- 7 yrs – 69
patients died)
Iron Balance Values
Serum
iron
(mg/dL)
TIBC
(mg/dL)
60-180
230-370
Transferrin
saturation Ferritin
(%)
(mg/dL)
Quantitative
hepatic iron
(mg/g dry wt)
Normal
20-50 20-200
300-1500
Hemochromatosis
>180
<300
>50
>300
>3000
Diagnostic Testing
? Modified Diagnostic Algorithm for Use in India
Family history or suspicion of
hemochromatosis
Fe / TIBC -% saturation
Ferritin
% sat. >50%
Ferritin
>250 mg/L
>300 mg/L
Repeat iron panel high; Ferritin >1000
Elevated AST/ALT
Extrahepatic manifestations of iron overload;
Positive FH
Liver biopsy with iron stain
and quantitative iron
stainable Fe
Iron index >2
Equivocal results
Therapeutic Phlebotomy,
response confirms diagnosis
Interpretation of Ferritin Levels
Interpretation of Ferritin Levels
Hemochromatosis
iron
Acute liver injury
Ferritin and
iron
Acute phase
reactant
Normal ferritin and 
iron
Chronic disease
 Ferritin and  iron
Iron deficiency
Hepatic Iron Index
Hepatic Iron Index
Liver iron
(mmol/g)
Age
(yr)
15
10
5
Cirrhotic
4
Index
3
2
Precirrhotic
1
0
Normals
Alcoholic
Hemochromatosis
Heterozygotes
Homozygotes
Phlebotomy – Therapy for Iron Overload
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
Phlebotomy Improves Survival
Phlebotomy Improves Survival
Preventable: all clinical manifestations
Reversible:
skin
cardiac dysfunction, glucose
intolerance, hepatomegaly,
pigmentation
Irreversible: cirrhosis
risk of hepatocellular
carcinoma
arthropathy, hypogonadism
Niederau C, et al. N Engl J Med 1985; 313:1256
Iron Depletion Improves Survival
Iron Depletion Improves Survival
10
0
80
Cumulative
survival
(%)
Iron depleted
after 18 months
60
Untreated after
18 months
40
20
0
0
5
10
15
Time (years)
Niederau C, et al. N Engl J Med 1985; 313:1256
20
25
Response to Phlebotomy
Response to Phlebotomy
100
80
1500
Serum
ferritin
Transferri 60
n
%
2000
Transferrin
saturation
Hgb
drop
s
40
1000
500
20
Phlebotomy
0
0
4
8
12
16
Time
(months)
20
Edwards CQ, et al. Hospital Practice 1991; 26:30
24
28
32
Ferritin
ng/ml
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
Genetic Diseases - Liver
Inherited Causes of Cirrhosis
Hemochromatosis
Familial intrahepatic
cholestasis
Wilson's
CF
Other
a1 – antitrypsin
deficiency
Newborn and infants
Adults
Neonatal Hemochromatosis
• Late fetal or early neonatal loss
• Renal hypoplasia
• Often with oligohydramnios
Features
• Raised ferritin
• Hepatocellular synthetic failure
• Extensive cholestasis
• Low or absent AST/ALT
• AFP >200,000
• Systemic iron overload – Dx investigation: buccal
biopsy
Neonatal Hemochromatosis
Andrews, N. C. et al. N Engl J Med 2005;353:189-198
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 hepatitis
congental 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