Liver & intrahepatic bile ducts
Metabolic diseases
Hemochromatosis


Topic Completed: 1 April 2012

Minor changes: 22 September 2020

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PubMed Search: Hemochromatosis[TI] liver[TI] free full text[sb]


Komal Arora, M.D.
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Cite this page: Arora K. Hemochromatosis. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/liverhemochromatosis.html. Accessed September 28th, 2020.
Definition / general
  • Excessive accumulation of iron, usually deposited in liver, pancreas and heart
  • Either primary or secondary
  • Normal iron pool is 2 - 6 gm with 0.5 g in liver and 98% of that in hepatocytes
Primary hemochromatosis
Definition / general
  • Autosomal recessive disorder of excessive iron storage; may exceed 50 g in liver (normal 2 - 6 g)
  • Most common single gene disorder in whites
  • 80% males because menstruation and pregnancy delay iron accumulation in women
  • 1/220 of Northern European ancestry are homozygous for mutation; 1/11 are heterozygous; thus disease is very common


Pathophysiology
  • Due to mutation on transferrin receptor binding protein HFE (formerly called HLA-H) on 6p, close to HLA gene and in linkage disequilibrium with HLA-A3
  • Common mutation (83% of primary cases) is cysteine to tyrosine at amino acid 282 (C282Y), which inactivates the protein and causes excess iron absorption of 3 - 4 mg/day vs. 1 - 2 mg/day normal
  • Normal HFE downregulates transferrin; loss of HFE causes upregulation of transferrin; other mutations are H63D (3 - 7% of cases) and compound heterozygotes (1 - 4%)
  • Excessive iron cannot be eliminated and is directly toxic, due to lipid peroxidation, stimulation of collagen, interactions of iron with DNA
  • Mutation causes net iron accumulation of 0.5 to 1.0 g iron/year, although penetrance is less than 100%
Diagrams / tables

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Diagnostic testing algorithms

Clinical features
  • Symptoms: occur after accumulation of 20 g of iron; usually age 40+; primarily micronodular cirrhosis (100%), diabetes mellitus (deposition in pancreas) and skin pigmentation (65%)
  • Also hemosiderin deposition in myocardium, pituitary, adrenal, thyroid, parathyroid gland, joints, skin
  • Eventually cirrhosis and pancreatic fibrosis
  • High risk for hepatocellular carcinoma (200x, 20% risk)
  • Diagnosis: screen for % transferrin saturation (serum iron divided by total iron binding capacity)
  • If repeatedly elevated, check serum ferritin
  • If elevated, do DNA testing for C282Y mutation
  • Also screen family members of affected individuals
  • Hepatic iron index: micrograms iron per gram dry weight of liver/(55.846 x patient's age)
  • Interpretation: > 1.9 in noncirrhotic liver is strongly suggestive of hereditary hemochromatosis, although only 93% sensitive; test is less specific in cirrhotic livers (some suggest raising cutoff to 4.2 in these patients); sampling variation can occur
Treatment
  • Phlebotomy 1 - 2/week until serum ferritin is below 20 - 50 micrograms/L, then 3 - 6 times/year
  • With early treatment, life expectancy is normal
Gross description
  • Dark brown liver
Gross images

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Liver, pancreas, lymph nodes

Microscopic (histologic) description
  • Liver: iron within hepatocytes, initially heavy periportal parenchymal iron deposition with sparing of Kupffer cells
    • Iron distribution is pericanalicular, particularly in less involved areas
    • Hepatocytes otherwise normal
    • No inflammation, no fibrosis
  • Heart: enlarged with hemosiderin within myocardial fibers
  • Joints: acute synovitis, calcium pyrophosphate deposition (pseudogout)
  • Pancreas: intensely pigmented, diffuse interstitial fibrosis
  • Skin: hemosiderin in dermal macrophages and fibroblasts, also increased melanin production; causes slate gray skin
  • Testes: small, atrophic testis, due to hypothalamic pituitary derangement; minimal pigment deposition
Microscopic (histologic) images

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Iron overload in liver - cause not indicated

Prussian blue stain

Positive stains
  • Prussian blue (iron stain)
Non-HFE hemochromatosis
Definition / general
  • Four genes are responsible: hepcidin and hemojuvelin are the genes involved in type 2 or juvenile hemochromatosis, transferrin receptor 2 is involved in type 3 hemochromatosis and ferroportin 1 is mutated in type 4, the atypical dominant form of primary iron overload (Best Pract Res Clin Haematol 2005;18:235, Semin Liver Dis 2005;25:450)
Secondary hemochromatosis
Definition / general
  • Due to transfusions (secondary to aplastic anemia, hemodialysis, leukemia, myelodysplasia, sickle cell anemia), chronic liver disease (alcoholism, porphyria cutanea tarda), congenital atransferrinemia, increased oral intake of iron or iron dextran injections, ineffective erythropoiesis with increased erythroid activity (secondary to pyruvate kinase deficiency, sideroblastic anemia, beta thalassemia)
  • Note: transfusions alone are usually not sufficient to cause systemic hemosiderosis
  • Bantu siderosis: due to alcohol fermented in iron utensils in sub-Saharan Africa


Microscopic (histologic) description
  • Iron is mainly in Kupffer cells, not hepatocytes (at least initially) and is primarily centrilobular
  • Eventually iron is present in hepatocytes, which are otherwise normal
Neonatal hemochromatosis
Definition / general
  • Autosomal recessive but probably unrelated to adult type hemochromatosis, although similar histologic patterns
  • Liver failure soon after birth due to excess iron in liver
  • Also iron deposition in pancreas, thyroid, kidney, GI tract


Treatment

Microscopic (histologic) images

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Explanted liver shows iron deposition by iron staining



Differential diagnosis
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