This document discusses hemochromatosis, an iron overload disorder. It begins by providing background on the diagnosis of a 65-year-old male patient. It then covers the inherited causes of cirrhosis, with a focus on hemochromatosis. The clinical manifestations of hemochromatosis are described, including effects on the pituitary gland, skin, heart, liver and other organs. Normal iron balance is contrasted with the imbalance that occurs in hemochromatosis. The document discusses the HFE gene mutation most commonly associated with hemochromatosis and other genetic causes of iron overload. Global prevalence of the HFE mutations is reviewed. The natural history and factors influencing the phenotype expression of he

1. 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

2. What is the diagnosis?
Non-contrast CT
65 yr old male, ferritin 2660, AFP 6324
DDx GSD, thorotrast, amiodarone, cisplatin

3. Inherited Causes of Cirrhosis
Inherited Causes of Cirrhosis
Hemochromatosis
Familial intrahepatic
cholestasis
Wilson's
CF
Other
a1 – antitrypsin
deficiency
Newborn and infants Adults

4. Clinical Manifestations
Hemochromatosis - Clinical Manifestations
Pituitary
Gonadotropin
deficiency
Skin bronzing
Cardiomyopathy
Conduction disorders
Cirrhosis
Hepatocellular
carcinoma
Diabetes mellitus
Bacteremia
Testicular atrophy
Arthropathy
Arthritis
Pseudogout

5. Clinical Manifestations of Hereditary Hemochromatosis

6. Hemochromatosis - Iron Balance Values
Serum Transferrin Quantitative
iron TIBC saturation Ferritin hepatic iron
(mg/dL) (mg/dL) (%) (mg/dL) (mg/g dry wt)
Normal 60-180 230-370 20-50 20-200 300-1500
Hemochromatosis
>180 <300 >50 >300 >3000

8. Classification of Iron Overload Syndromes

9. 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

10. Iron Homeostasis in Health and Disease
HH –
sparing of Kuppfer cells
Pietrangelo, A. N Engl J Med 2004;350:2383-2397

11. 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 Other
iron

12. Hfe Mutation
Normal
‘Mild’ Hemochromatosis

13. TfR2 hemochromatosis HJV hemochromatosis
Mild iron overload Massive iron overload
Ferroportin hemochromatosis –
Tissue iron overload with
Relative circulatory iron
HAMP hemochromatosis deficiency
Dramatic iron overload

14. HFE Protein Structure
HFE Protein Structure
S65C H63D Mutation
mutation
a Heavy chain
a1
a2
NH2
NH2
b2
a3
microglobulin
COOH C282Y Mutation
COOH
Bacon BR, et al. Gastroenterology 1999; 116: 193

15. What about India?

16. Global Prevalence of HFE Mutations
Global Prevalence of HFE Mutations
Frequency
(%)
C282Y H63D
Population allelic allelic
United Kingdom 6.4 12.8
Norway 6.4 11.2
Denmark 9.5 12.2
Finland 0 11.8
Former USSR 1.0 10.4
Germany 3.9 14.8
Italy 0.5 12.6
Spain 3.2 26.3
Greece 1.3 13.5
Saudi Arabia 0 8.5
Africa 0 2.6
Indian subcontinent 0.2 8.4
Asia 0 1.9
Australasia 0 0.2
Americas 0.7 2.6
Bacon, et al., Gastroenterology 1999; 116:193

17. Andrews, N. C. et al. N Engl J Med 2005;353:189-198
Pietrangelo, A. N Engl J Med 2004;350:2383-2397

18. Hemochromatosis
Natural History
Cirrhosis,
40 organ
failure
30 Tissue
injury
Total body
iron 20
(g)

Hepatic
10  iron
Serum
iron
Normal
0
10 20 30 40 50
Age (years)

19. Phenotype Expression
Phenotype Expression
 Men > women
 Increases with age
 Correlates with amount of iron in
the diet
 Chronic hemolysis, alcoholism,
steatohepatitis, hepatitis C

20. 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)

21. Iron Balance Values
Serum Transferrin Quantitative
iron TIBC saturation Ferritin hepatic iron
(mg/dL) (mg/dL) (%) (mg/dL) (mg/g dry wt)
Normal
60-180 230-370 20-50 20-200 300-1500
Hemochromatosis
>180 <300 >50 >300 >3000

22. 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 Liver biopsy with iron stain
Extrahepatic manifestations of iron overload; and quantitative iron
Positive FH
stainable Fe
Iron index >2
Therapeutic Phlebotomy,
Equivocal results response confirms diagnosis

23. Interpretation of Ferritin Levels
Interpretation of Ferritin Levels
Hemochromatosis
iron
Ferritin Acute liver injury
and
iron Acute phase
reactant
Normal ferritin and  Chronic disease
iron
 Ferritin and  iron Iron deficiency

24. Hepatic Iron Index
Hepatic Iron Index
Liver iron Age
(mmol/g) (yr)
15
10
5
Cirrhotic
4
Index
3
2 Precirrhotic
1
0
Normals Alcoholic Hemochromatosis
Heterozygotes Homozygotes

25. 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

26. Phlebotomy Improves Survival
Phlebotomy Improves Survival
Preventable: all clinical manifestations
Reversible: cardiac dysfunction, glucose
intolerance, hepatomegaly,
skin pigmentation
Irreversible: cirrhosis
risk of hepatocellular
carcinoma
arthropathy, hypogonadism
Niederau C, et al. N Engl J Med 1985; 313:1256

27. Iron Depletion Improves Survival
Iron Depletion Improves Survival
10
0
80
Iron depleted
after 18 months
60
Cumulative
survival
(%) Untreated after
40
18 months
20
0
0 5 10 15 20 25
Time (years)
Niederau C, et al. N Engl J Med 1985; 313:1256

28. Response to Phlebotomy
Response to Phlebotomy
100
Transferrin 2000
saturation
80
1500
Serum
Transferri 60 ferritin
Ferritin
n Hgb 1000 ng/ml
drop
% 40 s
20 500
Phlebotomy
0
0 4 8 12 16 20 24 28 32
Time
(months)
Edwards CQ, et al. Hospital Practice 1991; 26:30

29. 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

30. 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

31. 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

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

33. 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

34. NH – Treatments
• IVIG (Whitington, Lancet, 2001)
• Chelation/antioxidant cocktail
• NAC
• Transplant