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Hemochromatosis is a devastating disease with a relentless clinical course. It is characterized by progressive accumulation of iron within various tissues. The most severe form of the disease is hereditary hemochromatosis, also known as genetic hemochromatosis. This genetic mutation is one of the most common inborn errors of metabolism. Patients usually present with hepatomegaly, abdominal pain, and darkened skin pigmentation. As the iron deposits continue in other tissues leading to progressive damage and dysfunction, additional complications may ensue (see disease associations). The pathologist can play a very important role in the laboratory screening for the disease both by chemical analysis and liver biopsy.


Disease Associations  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Electron Microscopy
Differential Diagnosis  
Commonly Used Terms  
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AGE RANGE-MEDIAN Onset usually by 40 years
M 5-7:1
Physiologic iron loss in women helps to delay iron accumulation
White populations of northern European extraction Gene frequency estimated at 6%
Frequency for homozygosity is 0.45% (1/220) and heterozygosity 11% (1/9)


Hemolytic anemias with ineffective dyserythropoiesis
Alcoholic cirrhosis
Bantu siderosis
Sub-Saharan African tribespeople drink alcoholic beverages fermented in iron utensils

Diabetes mellitus secondary to progressive pancreatic fibrosis

Classic triad of hepatomegaly, skin pigmentation, and diabetes mellitus

HEART Dysrrhythmias, cardiomyopathy
Association of porphyria cutanea tarda with hereditary hemochromatosis.

Mehrany K, Drage LA, Brandhagen DJ, Pittelkow MR.

Department of Dermatology, Mayo Clinic, Rochester, MN 55905, USA.

J Am Acad Dermatol. 2004 Aug;51(2):205-11. Abstact quote

BACKGROUND: An increased frequency of hereditary hemochromatosis gene mutations occurs in patients with porphyria cutanea tarda. Polymerase chain reaction analysis of peripheral blood for hemochromatosis gene (HFE) mutations is available for clinical use. Early detection and treatment of hereditary hemochromatosis limit disease progression and improve life expectancy.

OBJECTIVE: We present 8 patients with porphyria cutanea tarda subsequently found to have hereditary hemochromatosis or mutations in the HFE gene.

METHODS: Retrospective review of patients in whom both porphyria cutanea tarda and hereditary hemochromatosis or HFE gene mutations were diagnosed between 1976 and 2000.

RESULTS: Eight patients with porphyria cutanea tarda (6 males, 2 females; age range, 4-60 years; mean age at diagnosis of porphyria cutanea tarda, 42 years) were subsequently found to have hepatic iron overload or HFE gene mutations. Two patients had liver biopsy findings compatible with homozygous hereditary hemochromatosis. In the other 6 patients, HFE gene analysis revealed 3 homozygous C282Y, 1 compound heterozygous C282Y/H63D, and 2 heterozygous C282Y mutations. Seven patients (88%) had no specific signs or symptoms of hereditary hemochromatosis at diagnosis. In 5 patients (63%), the diagnosis of hereditary hemochromatosis or HFE gene mutation was initially suspected by the dermatologist.

CONCLUSION: Porphyria cutanea tarda can be an important cutaneous marker for patients with mutations of the HFE gene. HFE gene analysis should be done in patients who present with porphyria cutanea tarda. The dermatologist may play a key role in the early diagnosis of subclinical hereditary hemochromatosis in patients who present with porphyria cutanea tarda.


Hereditary hemochromatosis

Autosomal dominant
HLA-H Gene located on 6p, close to HLA gene locus

Encodes for HLA-class I-like molecule that influences iron absorption
Commonly a point mutation such as cysteine to tyrosine substitution at AA 282

In linkage disequilibrium with HLA-A3

Iron metabolism Primary defect in intestinal absorption of iron leads to net accumulation of 0.5-1 gm iron per year

Iron has high toxicity to tissue leading to injury via:

Lipid peroxidation through free radicals
Stimulation of collagen production
Direct interactions of iron with DNA



Laboratory Markers  
Biochemical quantification of hepatic iron in unfixed tissue

This is the current gold standard for quantitating hepatic iron content

Normal liver has <1000 ug/gram dry weight of liver
Adult patients with hemochromatosis >10,000 ug/gram liver
>22,000 ug/gram liver weight associated with fibrosis and cirrhosis


Serum iron and ferritin are effective and sensitive screens

One should also screen family members


The role of transferrin saturation as a screening test for hereditary haemochromatosis in an Irish population seeking medical care.

O'Hara R, Cavanagh N, Cassidy M, Cullina M.

Biochemistry Laboratory, Portiuncula Hospital Ballinasloe, Co. Galway, Ireland.


Ann Clin Biochem 2003 Mar;40(Pt 2):169-74 Related Articles, Links

The role of transferrin saturation as a screening test for hereditary haemochromatosis in an Irish population seeking medical care.

O'Hara R, Cavanagh N, Cassidy M, Cullina M.

Biochemistry Laboratory, Portiuncula Hospital Ballinasloe, Co. Galway, Ireland.

BACKGROUND: Genetic studies have indicated a high prevalence of mutations for hereditary haemochromatosis (HH) in Irish populations. Given the high cost of genetic screening and the ethical implications thereof, we assessed the role of transferrin saturation (TS) as a primary screening test for HH in an Irish population seeking medical care. METHODS: TS and ferritin were measured on 330 consecutive blood specimens received in the laboratory for routine screening. Patients with TS > 45% were genetically screened for the C282Y and H63D mutations. RESULTS: Twenty-six patients had TS values > 45%. Of these, specimens were available for genetic screening on 20 patients. Three previously undiagnosed patients were found to be C282Y homozygotes and one a compound heterozygote (C282Y/H63D). The prevalence of C282Y homozygotes was 0.93%, which is similar to the reported prevalence found in Irish populations by genetic screening. CONCLUSION: Given the number of positive findings in this study, we conclude that, in the absence of a national programme, TS could be used as part of a health-screening panel in the Irish setting. Patients expressing iron overload would be detected before organ damage occurred, leading to less severe clinical disease and better patient prognosis.


General Prussian blue stain for iron easily highlights the deposits


Hemosiderin deposition
Pancreatic fibrosis
Role of Liver Biopsy in the Diagnosis of Hepatic Iron Overload in the Era of Genetic Testing

Shirin Nash, MD, etal.

Am J Clin Pathol 2002;118:73-81 Abstract quote

We studied hepatic iron overload (HIOL) patterns in 32 patients who underwent liver biopsies and testing for HFE mutations (C282Y, H63D). Iron-stained biopsy specimens were examined for patterns of iron deposits: hereditary hemochromatosis (HH) pattern or non-HH pattern. Visual iron grade based on amount of cellular and lobular iron was evaluated.

We found the HH pattern in 17 biopsy specimens (53%) and the non-HH pattern in 6 specimens (19%). HH with superimposed non-HH was noted in 9 cases (28%). In 25 patients with HFE mutations, HH alone and combined with non-HH patterns was noted in 22 specimens (88%). Visual iron grade correlated approximately with the hepatic iron index. Heavy HIOL was noted in C282Y homozygotes and 1 patient with cirrhosis without either HFE mutation. Mild steatohepatitis was found in 21 specimens (66%); it was associated with the non-HH pattern in 80% (12/15) and the HH pattern in 62% (16/26) of cases.

Liver biopsy can identify pattern and grade of HIOL and associated pathology for diagnosis and management of patients with abnormal iron studies and elevated liver function test results. Genetic tests for HFE mutations and liver biopsies are complementary in the workup of these patients.

Gastric Siderosis: Patterns and Significance.

Marginean EC, Bennick M, Cyczk J, Robert ME, Jain D.

*Department of Anatomic Pathology, Program in Gastrointestinal Pathology daggerDepartment of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.

Am J Surg Pathol. 2006 Apr;30(4):514-520. Abstract quote  

Recently, we encountered 2 cases of diffuse iron deposition in gastric antral and fundic glandular epithelium, which in 1 patient eventually led to the diagnosis of hemochromatosis.

Gastric mucosal siderosis (GS) has previously been described in hemochromatosis patients, alcoholics, and in association with iron medications. However, the prevalence of various patterns of iron deposition in the gastric mucosa and their clinical significance have not been studied in detail. The 2 index cases mentioned above and 500 additional consecutive gastric biopsies examined over a period of 8 months at our institution were stained for iron by the Prussian blue method. In addition, all patients with genetic hemochromatosis diagnosed by liver biopsy in our department between 1998 and 2003 who also had gastric biopsies were identified from the surgical pathology files and included in the study (n=3). The location of iron deposition {stromal cells (endothelium, fibroblasts, macrophages), glandular epithelium, or extracellular} was recorded and subjectively graded as 1+ to 3+ according to the severity of deposition within the mucosa. Relevant histologic changes (inflammation, presence of H. pylori, ulceration) and clinical features were reviewed.

Three patterns of GS were identified: A) "nonspecific GS" with predominant iron deposition in the stromal cells including macrophages, and focally in epithelium; B) "iron-pill gastritis" with often mild gastritis and reactive gastropathy type changes, and mostly extracellular deposition with focal stromal cells and epithelial deposition; and C) predominant deposition in antral and fundic glandular epithelium. Of the 500 cases studied, a total of 18 (3.6%) cases were found to have GS. Of these 18 cases, 11 (2.2%) showed pattern A, 4 (0.8%) showed pattern B, and 3 (0.6%) showed pattern C. The GS in patterns A and B was always focal or patchy (1+ to 2+), whereas in pattern C it was generally diffuse and strong (2+ to 3+). A history of oral iron medication was present in 2 (n=11, 0.4%) patients with pattern A, in all patients with pattern B (n=4, 100%), and in none of patients with pattern C (n=3, 0%). Varying degrees of mucosal inflammation were noted in patients with pattern A cases, and 2 had evidence of active Helicobacter pylori infection. Of the 3 cases with known hemochromatosis, only one gastric biopsy showed pattern C GS (1+).

In conclusion, gastric mucosal siderosis is relatively uncommon (3%) but is important to look for as it may lead to a diagnosis of hemochromatosis in some cases.

Three patterns are recognized: A) a "nonspecific" stromal cell predominant pattern, which may be associated with gastric inflammation, possibly prior mucosal hemorrhages or iron medications; B) extracellular coarse clumps of crystalline iron deposition associated with oral iron medications, mild gastritis, and reactive gastropathy type changes ("Iron-pill gastritis"); and C) gastric glandular siderosis, which may be associated with systemic iron overload/hemochromatosis.

Primary Liver Carcinoma in Genetic Hemochromatosis Reveals a Broad Histologic Spectrum

Mohib Morcos, MD
Sylvie Dubois, MSc
Marie-Pierre Bralet, MD
Jacques Belghiti, MD
Claude Degott, MD
Benoţt Terris, MD

Am J Clin Pathol 2001;116:738-743 Abstract quote

Hepatocellular carcinoma (HCC) is a well-known complication of genetic hemochromatosis (GH). However, the frequency of primary liver carcinoma (PLC) with biliary differentiation, such as cholangiocarcinoma (CC) and combined hepatocholangiocarcinoma (CHCC), in GH remains unclear.

We analyzed the histologic type of 20 PLCs occurring in the background of GH; all patients were homozygotic for the C282Y mutation. Ten were depleted of iron by successive phlebotomies, while the remaining 10 were untreated. Histologically, 13 cases were classified as HCC, 3 as CC, and 4 as CHCC. Immunohistochemical detection of Hep Par 1, cytokeratin 19 (CK19), and MUC1 supported this classification; PLC with biliary differentiation was immunoreactive for MUC1 in 86% (6/7) of cases and for CK19 in 100% (7/7) of cases. The nontumoral liver exhibited no cirrhosis or extensive fibrosis in 6 cases. Von Meyenburg complexes were present in 11 cases and intraparenchymal bile duct adenomas in 3.

These data suggest that PLCs in patients with GH present a wide histologic spectrum, with tumors showing frequent biliary differentiation; may arise on a nonfibrotic or a cirrhotic liver; and often are associated with Von Meyenburg complexes and to a lesser extent with bile duct adenomas.

Variability in Hepatic Iron Concentration in Percutaneous Needle Biopsy Specimens From Patients With Transfusional Hemosiderosis

Ellen Butensky, PhD, PNP, etal.
Am J Clin Pathol 2005;123:146-152 Abstract quote

In patients with sickle cell disease or b-thalassemia receiving RBC transfusions for a long period, a precise knowledge of the liver iron concentration (LIC) is essential for treatment. Patients underwent LIC and liver pathology assessment by duplicate biopsies in 2 passes from the same local liver site.

Fresh tissue cores in trace element–free containers and tissues from dissolved paraffin-embedded cores were analyzed. LIC measurements in each of 2 paraffin-embedded cores did not differ significantly (median, 12,455 vs 12,153 µg/g dry weight; n = 29). A significant difference was observed when 1 fresh tissue sample and 1 paraffin-embedded core were analyzed (median, 11,716 vs 12,864 µg/g dry weight; n = 16; P < .001) with a median disagreement between LIC measurements of 23.0%.

We found high agreement in LICs between liver biopsy specimens processed by the paraffin-embedding technique but overestimation of LICs in comparison with desiccated fresh tissue samples.


Special stains Prussian blue stain for iron
Perl's stain



Histologic Features of the Liver in Insulin ResistanceľAssociated Iron Overload A Study of 139 Patients

Bruno Turlin, MD, Michel H. Mendler, MD, Romain Moirand, MD, PhD, Dominique Guyader, MD, PhD, Anne Guillygomarc'h, MD, and Yves Deugnier, MD

Am J Clin Pathol 2001;116:263-270 Abstract quote

The aim of the present study was to describe histologic features of the liver in insulin resistance-associated hepatic iron overload (IR-HIO), defined as the association of metabolic disorders and hepatic iron overload.

We included 139 patients in the study on the basis of one or more metabolic disorders and liver iron overload unrelated to usual causes. Liver biopsy specimens were reviewed, and histologic data were compared with those of a previously published, well-defined population with genetic hemochromatosis. Iron overload was characterized by a mixed pattern with iron deposits in hepatocytes and sinusoidal cells. Steatosis was present in 59.7% of patients with inflammation in 32.4% of cases. Periportal fibrosis was found in 67.4% of patients. These patients were older, had higher sinusoidal iron scores, and had a higher prevalence of steatosis and inflammation than patients without fibrosis.

Iron overload in IR-HIO was histologically different from that in genetic hemochromatosis.


Prognostic Factors  

Death results either from cirrhosis or cardiac disease

Hepatocellular carcinoma may also develop (200x increased risk vs. general population)

Treatment If homozygotes are diagnosed early enough in the subclinical precirrhotic stage, regular phlebotomy may control the iron buildup leading to normal life span

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Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
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Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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Last Updated April 28, 2006

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