Hemochromatosis

Definition

Autosomal recessive disorder of iron metabolism most common in Northern Europeans where there is increased iron deposition in liver, heart, pancreas and gonads. The most common mutation is missense (C282Y) of the HFE gene on chromosome 6p.

Clinical Features

Autosomal recessive:
- heterozygosity rarely associated with liver damage due to iron alone1
Most common inherited disorder in white Caucasians2
Risk of hepatocellular carcinoma:
- incidence ≈15%:
  - predominantly in males
- not prevented by removal of iron3

Pathogenesis

In Northern Europe:
- >90% of cases homozygous for missense mutation (C282Y) in HFE gene on short arm of chromosome 6:
- mutation leads to dysregulation of intracellular iron homeostasis in enterocytes:
  - results in inappropriately high iron absorption
- role of a second mutation (H63D) in HFE gene unclear:4
  - C282Y mutation alone leads to mild hepatic siderosis, with exception of H63D/C282Y compound heterozygotes5

Histopathology

Progressive iron accumulation in:
- liver
- heart
- pancreas
- other organs
Rate of accumulation varies:
- even within same family

If Young

Stainable iron in periportal hepatocytes:
- positivity in males generally greater than in females of same age
- first abnormality

With Advancing Age

Progressive deposition of hemosiderin toward centrilobular area:
- usually maintains decreasing portal–central gradient
Some Kupffer cells and occasional portal macrophage may become iron positive:
- overwhelmed by almost exclusive parenchymal storage
Hepatocellular iron appears as pericanalicular granules representing lysosomal storage (Fig. 1
Fig. 1: Parenchymal siderosis in genetic hemochromatosis. Detail of lobular parenchyma showing marked parenchymal siderosis in typical lysosomal (pericanalicular) localization. There was a decreasing portal–central gradient in lobular siderosis (not shown). (Perls' iron stain)
)

With Progressing Siderosis

Fibrosis with:
- expansion of portal tracts:
  - carry iron-laden macrophages
- small fibrous spurs conferring spiked contour to portal tracts
- some increase in ductular profiles:
  - usually without marked inflammation
- accumulation of granules of stainable iron by cholangiocytes of:
  - ductules
  - interlobular ducts
- some reports of foci of eosinophilic or lytic hepatocellular necrosis of iron-laden hepatocytes:
  - often close association with clusters of macrophages:
    - so-called sidero-necrosis6
- progressive increase in proportion of iron outside hepatocytes versus hepatocellular iron
Periportal fibrosis proceeds:
- slender periportal septa:
  - join portal tracts
  - progressively envelope lobules to produce pattern characteristic for hemochromatosis of combination of:7
    - discrete parenchymal nodules
    - partially preserved lobules
Further advancement:
- results in diffuse micronodular pattern with portal-based septal fibrosis:
  - resembles secondary biliary cirrhosis
Excessive alcohol consumption:
- induces shift of hemosiderin from parenchymal to:
  - Kupffer cells
  - macrophages in fibrous septa7
In later stages of heavy iron overload:
- occasional small areas:
  - without or with little parenchymal siderosis and only some Kupffer cell iron load
  - most often seen in established cirrhosis
  - represent preneoplastic lesion8

After Therapeutic Phlebotomies

Steady disappearance of stainable iron:
- pattern reverse of accumulation:
  - periportal hepatocytes remain Perls' positive longer:
    - iron removal unmasks brown lipofuscin-resembling pigment in hepatocytes and portal mesenchyme
- portal collagen most resistant to iron removal

Special Stains and Immunohistochemistry

Perls' Stain Using Acid Ferrocyanide

Best demonstrates siderosis
Gives Prussian blue reaction with ferric compounds:
- ferritin
- hemosiderin
Ferritin dispersed in hyaloplasm:
- gives diffuse bluish tint to the cell's cytoplasm
Intense blue granules:
- correspond to ferritin and hemosiderin packed together within siderosomes (iron-laden lysosomes)9
Evaluation requires attention to:
- extent (grade or amount) of stainable iron:
  - semiquantitative assessment of stored tissue iron achieved in different ways:
    - simplest system grades from 1 (minimal) to 4 (massive deposits)
    - grades 2 and 3 indicate intermediate amounts
- distribution in different cell types of portal tract and lobule

Diagnosis

Important:
- cirrhosis can be prevented by appropriate treatment of patient and homozygous relatives, with return of life expectancy to normal3
Usually based on clinical, biochemical, genetic, and histopathologic data
Genetic diagnosis a reality:16
- but phenotypic diagnosis remains important17
Unexplained small amounts of iron in hepatocytes should always raise suspicion of early stage:
- calculation of (H)HII and further serum biochemistry may help establish diagnosis

Other investigations

Chemical determination of tissue iron:
- performed on:
  - liver tissue separated from specimen taken for histology
  - block deparaffinized after histopathologic study:
    - ensures tissular composition of sample known10
Hepatic iron index (HII):11
- chemically measured hepatic iron concentration (μmol/g dry weight)/patient's age in years
- enables distinction of genetic hemochromatosis (HII ≥1.9) from heterozygous individuals and patients with siderosis from other causes
Chemically measured HII correlates well with histological hepatic iron index (HHII) (dividing by the age in years)12
Also grading system for estimation of iron in hepatocytes, mesenchymal cells, cholangiocytes, blood vessels, and connective tissue, generating a score between 0 and 60:13
- together with HHII14 helpful in assessment of genetic hemochromatosis
Microscopic evaluation:
- may allow blocked tissue to be preserved
- can be used to quantitate when chemical iron determination is not possible
Computerized image analysis:
- correlates well with classical assays
- additional technique15

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Hemochromatosis

Genetics

In Northern Europe:
- >90% of cases homozygous for missense mutation (C282Y) in HFE gene on short arm of chromosome 6:
- mutation leads to dysregulation of intracellular iron homeostasis in enterocytes:
  - results in inappropriately high iron absorption
- role of second mutation (H63D) in HFE gene unclear4
  - C282Y mutation alone leads to mild hepatic siderosis, with exception of H63D/C282Y compound heterozygotes5

Management

Therapeutic phlebotomies

References

1 Bulaj ZJ, Griffen LM, Jorde LB, Edwards CQ, Kushner JP. Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. N Engl J Med. 1996;335:1799–1805.

2 Bacon BR, Powell LW, Adams PC, Kresina TF, Hoofnagle JH. Molecular medicine and hemochromatosis: at the crossroad. Gastroenterology. 1999;116:193–207.

3 Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med. 1985;319:1256–1262.

4 Moirand R, Jouanolle AM, Brissot P, Le Gaill JY, David V, Deugnier Y. Phenotypic expression of HFE mutations: a French study of 1110 unrelated iron-overloaded patients and relatives. Gastroenterology. 1999;116:372–377.

5 Höhler T, Leininger S, Köhler HH, Schirmacher P, Galle PR. Heterozygosity for the hemochromatosis gene in liver diseases – prevalence and effects on liver histology. Liver. 2000;20:482–486.

6 Deugnier YM, Loréal O, Turlin B, Guyader D, Jouanolle H, Moirand R, et al. Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations. Gastroenterology. 1992;102:2050–2059.

7 Powell LW, Kerr JFR. The pathology of the liver in hemochromatosis. Pathobiol Annu. 1975;5:317–337.

8 Deugnier YM, Turlin B, Powell LW, Summers KM, Moirand R, Fletcher L, et al. Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: a study of 192 cases. Hepatology. 1993;17:30–34.

9 Richter GW. The iron-loaded cell – the cytopathology of iron storage. Am J Pathol. 1978;91:362–404.

10 Ludwig J, Batts KP, Moyer TP, Baldus WP, Fairbanks VF. Liver biopsy diagnosis of homozygous hemochromatosis: a diagnostic algorithm. Mayo Clin Proc. 1993;68:263–267.

11 Basset ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology. 1986;6:24–29.

12 Deugnier YM, Turlin B, Powell LW, Summers KM, Moirand R, Fletcher L, et al. Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: a study of 192 cases. Hepatology. 1993;17:30–34.

13 Deugnier YM, Loréal O, Turlin B, Guyader D, Jouanolle H, Moirand R, et al. Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations. Gastroenterology. 1992;102:2050–2059.

14 Deugnier YM, Turlin B, Powell LW, Summers KM, Moirand R, Fletcher L, et al. Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: a study of 192 cases. Hepatology. 1993;17:30–34.

15 Olynyk J, Hall P, Sallie R, Reed W, Shilkin K, Mackinnon M. Computerized measurement of iron in liver biopsies: a comparison with biochemical iron measurement. Hepatology. 1990;12:26–30.

16 EASL International Consensus Conference on Haemochromatosis. J Hepatol. 2000;33:485–504.

17 Camaschella C, Fargion S, Sampietro M, Roetto A, Bosio S, Garozzo G, et al. Inherited HFE-unrelated hemochromatosis in Italian families. Hepatology. 1999;29:1563–1564.

Last updated: 23 Nov 2006