Iron Overload

Iron deposition in Kupffer cells and spilling into parenchymal cells in late stages of hemosiderosis

Definition

Deposition of iron in the liver secondary to chronic anemia, blood transfusion, chronic renal failure and porphyria cutanea tarda.

Clinical Features

Demonstrable iron in tissues
Causes:
- genetic hemochromatosis
- chronic anemia including thalassemia:
  - often termed secondary hemochromatosis
- neonatal iron overload:
  - rare
- blood transfusion
- hemolysis
- chronic renal failure
- porphyria cutanea tarda
- ingestion of excessive amounts of iron e.g. due to:1
  - self-medication with iron compounds
  - use of iron containers by South African blacks for brewing traditional beers

Pathogenesis

Neonatal iron overload:
- etiology unknown
- no relationship with genetic hemochromatosis
- putative environmental agents suspected to interact with one or more factors intrinsic to developing fetal liver2

Histopathology

Iron Distribution

Varies according to cause
Exogenous siderosis loads Kupffer cells first (Fig. 1
Fig. 1: Secondary siderosis. Hemosiderin (blue) is located exclusively in Kupffer cells, sparing the hepatocytes. (Perls' iron stain)
)
Always most pronounced in periportal hepatocytes
Predominantly parenchymal in:
- hemochromatosis
- neonatal iron overload:
  - marked hepatocellular necrosis
  - parenchymal giant cell transformation
  - siderosis
  - fibrosis
  - parenchymal nodule development3
In thalassemia and other forms of chronic anemia:
- both hepatocytes and Kupffer cells store iron:
  - Kupffer cell and macrophage siderosis is present from early stages
- associated fibrosis and cirrhosis
- in contrast with genetic hemochromatosis, often more portal and lobular lymphocytic infiltration, due to transfusion-related viral hepatitis C4
Dense Perls-positive granules in endothelial cells in various liver diseases, including:
- acute hepatitis
- alcoholic liver disease:
  - some hepatic siderosis common in cirrhosis
  - most alcoholics with marked hepatic iron overload also have genetic hemochromatosis5
Porphyria cutanea tarda:
- often siderosis in periportal hepatocytes:
  - usually mild6
Ingestion of excessive amounts of iron:1
- combined reticuloendothelial and hepatocellular siderosis

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)7
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

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 known8
Hepatic iron index (HII):9
- 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)10
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 technique11

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Iron Overload

Genetic hemochromatosis

References

1 Bothwell TH, Abrahams C, Bradlow BA, Charlton RW. Idiopathic and Bantu hemochromatosis. Arch Pathol. 1965;79:163–168.

2 Silver MM, Valberg LS, Cutz E, Lines LD, Phillips MJ. Hepatic morphology and iron quantitation in perinatal hemochromatosis. Am J Pathol. 1993;143:1312–1325.

3 Moerman P, Pauwels P, Vandenberghe K, Devlieger H, Fryns JP, Verresen H, et al. Neonatal haemochromatosis. Histopathology. 1990;17:345–351.

4 Wonke B, Hoffbrand AV, Brown D, Dusheiko G. Antibody to hepatitis C virus in multiply transfused patients with thalassaemia major. J Clin Pathol. 1990;43:638–640.

5 Bassett ML, Halliday JW, Powell LW. Genetic hemochromatosis. Semin Liver Dis. 1984;4:217–227.

6 Cortes JM, Oliva H, Paradinas FJ, Hernandez-Guio C. The pathology of the liver in porphyria cutanea tarda. Histopathology. 1980;4:471–485.

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

8 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.

9 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.

10 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.

11 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.

Last updated: 23 Nov 2006