Liver & intrahepatic bile ducts

Metabolic diseases

Hemochromatosis



Topic Completed: 2 September 2021

Minor changes: 8 October 2021

Copyright: 2002-2021, PathologyOutlines.com, Inc.

PubMed Search: Hemochromatosis[title] liver pathology "last 5 years"[DP]


Nicole Leonard, M.D.
Kimberley J. Evason, M.D., Ph.D.
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Cite this page: Leonard N, Evason KJ. Hemochromatosis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/liverhemochromatosis.html. Accessed October 23rd, 2021.
Definition / general
  • Most common autosomal recessive disorder in Caucasians, caused by decreased hepcidin activity due to mutations in iron metabolism genes such as HFE (Nat Rev Dis Primers 2018;4:18016)
  • Characterized by increased iron absorption, toxic iron accumulation and end organ damage
Essential features
  • Caused by mutations in iron metabolism genes, such as HFE, resulting in hepcidin deficiency and increased iron absorption, toxic iron accumulation and end organ damage (Nat Rev Dis Primers 2018;4:18016)
  • Diagnosis can be confirmed with HFE genetic testing but liver biopsy may still be necessary to assess fibrosis
  • Excess iron accumulates predominantly in hepatocytes, in a periportal (early) to panlobular (advanced) distribution
  • Hemochromatosis patients with cirrhosis have up to 100 times the chance of developing hepatocellular carcinoma than the general population (J Hepatol 2010;53:3)
  • Distinct from secondary hemochromatosis (secondary iron overload), which occurs in the setting of inherited or acquired disorders of erythropoiesis or frequent blood transfusions (Dtsch Arztebl Int 2009;106:499)
Terminology
  • Type 1 hemochromatosis (specifically refers to HFE associated hemochromatosis)
  • Primary or inherited iron overload
  • Bronze diabetes
  • Hereditary hemochromatosis
ICD coding
  • ICD-10:
    • E83.11 - hemochromatosis
    • E83.110 - hereditary hemochromatosis
    • E83.119 - hemochromatosis, unspecified
Epidemiology
Sites
  • Liver, heart, pancreas, skin, gonads, joints
Pathophysiology
Etiology
Diagrams / tables

Images hosted on other servers:

Hemochromatosis diagnostic algorithm

Iron metabolism

Hepcidin regulation

Scheuer iron scoring system

Clinical features
  • Classic triad: liver cirrhosis, diabetes mellitus, bronzing of skin (Am J Hematol 2006;81:202)
  • May also have joint pain, fatigue, abdominal pain
Diagnosis
  • Laboratory testing (Nat Rev Dis Primers 2018;4:18016)
    • If iron overload is suspected, screen with transferrin saturation and serum ferritin
    • If transferrin saturation is ≥ 45% and ferritin is elevated, perform genetic testing
      • PCR testing targeted for C282Y variable H63D and S65C
    • Screening asymptomatic patients without family history of hemochromatosis with genetic testing is not recommended, due to high frequency of HFE mutations and variable penetrance (J Hepatol 2010;53:3)
    • First degree relatives of patients with hemochromatosis should undergo genetic testing
  • Liver biopsy:
    • Was the gold standard but is no longer required for diagnosis in the presence of genetic testing
    • Tissue can be used to determine hepatic iron concentration (HIC) via mass spectrometry
      • Useful to confirm diagnosis of hepatic iron overload when genetic testing for common HFE mutations is negative (Clin Liver Dis (Hoboken) 2021;17:232)
      • Hepatic iron index (HII) = hepatic iron concentration / patient’s age in years (Clin Liver Dis (Hoboken) 2021;17:232)
        • HII values < 1.0 are normal
        • HII values 1.0 to 1.9 indicate mild iron accumulation
          • Heterozygous for HFE or other hemochromatosis associated mutation
          • Alcoholic liver disease
        • HII values > 1.9 indicate iron overload
          • Homozygous HFE or other hemochromatosis associated mutation
          • Cirrhosis
    • Recommended to assess fibrosis when serum ferritin > 1,000 ug/L (J Hepatol 2010;53:3)
  • Imaging:
    • MRI can be used to quantify iron and determine distribution of iron in the liver
    • Transient elastography may help assess fibrosis and cirrhosis
Laboratory
  • Transferrin saturation ≥ 45% (J Hepatol 2010;53:3)
  • Elevated ferritin
  • May have elevated liver enzymes (AST, ALT) with disease progression
Radiology description
  • MRI can be used to determine distribution of iron deposition and quantify the iron (Insights Imaging 2012;3:173)
    • Increased iron leads to accelerated T2 relaxation and reduced signal intensity
  • Dual energy CT can also be used to quantitate iron (Radiology 2015;277:95)
Radiology images

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MRI findings in hemochromatosis

Iron quantification by MRI

Prognostic factors
  • Life expectancy is normal if diagnosed and managed before end organ damage develops
  • Prognosis is poor after development of cirrhosis, hepatocellular carcinoma, diabetes or cardiomyopathy
  • Patients with cirrhosis have up to a 100 times greater chance of developing hepatocellular carcinoma than the general population (J Hepatol 2010;53:3)
Case reports
Treatment
  • Therapeutic phlebotomy / venesection
  • Chelation therapy may be considered if therapeutic phlebotomy is not available or contraindicated or as an adjunct to phlebotomy in severe cases
Clinical images

Images hosted on other servers:

Skin
hyperpigmentation
(bronze diabetes)

Gross description
Gross images

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Dark brown discoloration of the liver

Dark brown discoloration of the myocardial muscle

Liver, pancreas, lymph nodes

Frozen section description
Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Kimberley J. Evason, M.D., Ph.D.

Liver with hepatocellular iron

Liver, iron stain

Periportal hepatocytes, iron stain


Canalicular pattern, iron stain

Bile duct epithelium iron

Trichrome

Pancreas, iron stain

Molecular / cytogenetics description
  • Type 1 (HFE hemochromatosis)
    • Hemochromatosis (HFE) mutation
    • Most common mutation is C282Y
    • Compound heterozygosity with H63D, S65C and mutations at other loci have been reported (J Hepatol 2010;53:3)
  • Non HFE hemochromatosis (StatPearls: Hemochromatosis [Accessed 16 July 2021])
    • Type 2 (juvenile hemochromatosis)
      • Hepcidin (HAMP) or hemojuvelin (HJV) mutation
      • Often have hypogonadism at presentation
      • Cardiac iron deposition typically results in heart failure, usually before the age of 30 (Am J Hematol 2006;81:202)
    • Type 3
      • Transferrin receptor 2 (TFR2) mutation
    • Type 4
      • Ferroportin 1 (FPN1, SLC40A1) mutation
      • Autosomal dominant
Molecular / cytogenetics images

Contributed by Pinar Bayrak-Toydemir, Ph.D.

Melting curve: wild type



Images hosted on other servers:

Compound heterozygote sequence analysis

Sample pathology report
  • Liver, biopsy:
    • Extensive hepatocellular siderosis consistent with hereditary hemochromatosis (see comment)
    • Comment: An iron stain shows extensive iron accumulation in hepatocytes with periportal accentuation. There is no evidence of fatty liver disease or chronic hepatitis, the other entities that can have siderosis. The pattern of intracellular iron deposition in hepatocytes in the clinical setting of homozygous HFE C282Y mutation is consistent with hereditary hemochromatosis.
Differential diagnosis
Board review style question #1

Which of the following genes is most commonly mutated in the heritable disease shown here in this liver biopsy stained with Prussian blue?

  1. FPN1 (encoding ferroportin)
  2. HAMP (encoding hepcidin)
  3. HFE
  4. HJV
  5. PTEN
Board review style answer #1
C. HFE

Comment Here

Reference: Hemochromatosis
Board review style question #2
Which of the following patterns of iron deposition is most consistent with hemochromatosis?

  1. Centrilobular, intracellular deposition within hepatocytes
  2. No specific pattern of deposition
  3. Panlobular, intracellular deposition within Kupffer cells
  4. Periportal, intracellular deposition within hepatocytes
  5. Periportal, intracellular deposition within Kupffer cells
Board review style answer #2
D. Periportal, intracellular deposition within hepatocytes

Comment Here

Reference: Hemochromatosis
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