Liver and intrahepatic bile ducts-nontumor

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Liver and intrahepatic bile ducts-nontumor

Metabolic diseases

Hemochromatosis

Reviewer: Komal Arora, M.D. (see Reviewers page)
Revised: 30 April 2012, last major update April 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
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● 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

General
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● Autosomal recessive disorder of excessive iron storage; may exceed 50g 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
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● 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%

Clinical features
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● 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 non-cirrhotic liver is strongly suggestive of hereditary hemochromatosis, although only 93% sensitive; Test is less specific in cirrhotic livers (some suggest raising cut-off to 4.2 in these patients); Sampling variation can occur

Diagrams
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Diagnostic testing algorithms

Treatment
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● 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
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● Dark brown liver

Micro description
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● 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

Gross images
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Liver, pancreas, lymph nodes

Micro images
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Various images

Iron overload in liver-cause not indicated

Prussian blue stain

Positive stains
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● Prussian blue (iron stain)

Additional references
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● Lancet 2003;361:669, Am J Hematol 2006;81:202, Hepatology 2011;54:328

Non-HFE hemochromatosis

General
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● 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

General
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● 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 thallasemia)
● Note: transfusions alone are usually not sufficient to cause systemic hemosiderosis
● Bantu siderosis: due to alcohol fermented in iron utensils in sub-Saharan Africa

Micro description
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● 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

General
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● 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: early antioxidant treatment and liver transplantation (Pediatrics 2006;118:2060)

Micro images
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Explanted liver shows iron deposition by iron staining

Differential diagnosis
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● Massive necrosis (also has excess hepatic iron)

End of Liver and intrahepatic bile ducts-nontumor > Metabolic diseases > Hemochromatosis

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