A 49-year-old man presents to the emergency department with worsening dyspnea and anasarca. He was discharged from the Cardiac Unit three weeks prior, following treatment for congestive heart failure. He has been on the transplant list for the last six years but has not found a suitable donor. He has a family history of relatives (mostly cousins) who also suffered from similar heart failure and died before they were 40 years of age. One of his recent previous hospitalizations had necessitated blood transfusions, due to acute blood loss (road traffic accident). His current hospitalization is complicated by progressive pulmonary and renal failure. He dies one week following admission. An autopsy is performed. His heart at autopsy is 20.0 x 20.0 x 14.0 cm and weighs 490 grams. The ventricular muscle is not hypertrophied (1.0 - 2.1 cm; mean width 1.6 cm). An H&E slide section of his myocardium is presented for review.

Master List of Diagnoses

  • Cardiac amyloidosis
  • Cardiac hemochromatosis
  • Dilated cardiomyopathy
  • Hypereosinophilic syndrome with eosinophilic myocarditis
  • Hypertrophic cardiomyopathy
  • Post-rheumatic mitral and aortic valvular stenosis
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 22, and is cardiac hemochromatosis of the heart.

Criteria for Diagnosis and Comments

Histological features include the presence of hemosiderin deposits both in the interstitium and within the sarcoplasm of the ventricular myocardium. A Prussian blue stain for iron confirms the iron deposition. Minimal to mild interstitial fibrosis and rare lymphocytic infiltrate is seen in select sections. Increased collagen deposition or marked fibrosis is absent. Grossly, the heart was normal in size with no visible ventricular outlet obstruction. Overall, the gross and microscopic features are consistent with cardiac hemochromatosis (CH).

CH or primary iron-overload cardiomyopathy shows iron deposited in cardiac tissues in primarily a sarcoplasmic pattern. The tissue iron quantity correlates well with the level of myocardial dysfunction. Microscopy shows myocardial fibrosis and myocyte fatty degeneration. Normal myocardium should not have any stainable iron within the sarcomere or in the interstitium. The presence of significant hemosiderin deposition is suggestive of long standing and end-stage cardiac dysfunction due to hemochromatosis. In this patient, the family history is consistent with a genetic cause; peripheral blood testing for the gene HFE showed the presence of HFE gene mutation HFE C282Y.

Cardiac hemochromatosis is the leading cause of death in patients with genetic hemochromatosis, with one-third of patients dying due to cardiac impairments. Cardiac failure is usually late in onset. Typically, other organs such as liver and pancreas show dysfunction earlier, leading to cirrhosis and diabetes. The classic clinical triad of cirrhosis, “bronze skin,” and diabetes is rarely seen today since most cases are diagnosed and managed early. Cardiac hemochromatosis is characterized by dilated cardiomyopathy, dilated ventricles, reduced ejection fraction and reduced fractional shortening. The vessels or conduction system are not typically involved. Exertional dyspnea is the typical presenting symptom. Cardiac biopsies can be considered (endomyocardial biopsy) but since it is an invasive procedure and the biopsy can be falsely negative, it is seldom required.

Primary genetic hemochromatosis has four major types. Type I, classical hemochromatosis is due to genetic mutations in HFE gene. It is an autosomal recessive disorder with a missense mutation frequently in C282Y or H63D; compound heterozygosity of both genes may also be seen. This disease, as in our case, is typically seen in middle aged patients (greater than 40 years of age). Type 2 hemochromatosis is also called juvenile hemochromatosis and is due to mutations in the hepcidin (HAMP) gene. As the name implies, Type 2 hemochromatosis is seen in much younger (less than 30 years of age; typically, 15-20 years of age) patients. Type 3 hemochromatosis is due to mutations in the gene transferrin receptor-2 (TFR2). Type 4 hemochromatosis involves the gene ferroportin (SLC40A1).

The differential diagnosis includes diseases affecting myocardium such as dilated and hypertrophic cardiomyopathy, amyloidosis, and infectious/inflammatory conditions. Since the genetic diagnosis is now readily accessible for patients with cardiomyopathy, understanding the complexity of underlying genetic lesions provides useful information for prognosis and associated risks.

Cardiac amyloidosis is a manifestation of one of several systemic diseases known as “amyloidosis.” The common feature of this group of diseases is the extracellular deposition of a proteinaceous material that, when stained with Congo red, demonstrates apple-green birefringence under polarized light and that has a distinct color when stained with sulfated Alcian Blue. Regardless of the underlying pathogenesis of amyloid production, cardiac amyloidosis is a myocardial disease characterized by extracellular amyloid deposition throughout the myocardium, including the ventricles and atria, small vessels, and the valves. It may also involve the conduction system.

Dilated cardiomyopathy (DCM) is characterized by an extremely heterogeneous and complex genetic background with associated mutations found in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium channel proteins. The familial form of DCM is primarily inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity. Occasional mitochondrial mutations with autosomal recessive and X-linked recessive inheritance, however, have also been described. Approximately 30% - 40% of DCM mutations occur in genes encoding sarcomere elements with the majority of mutations (approximately 25%) occurring in a gene called TTN located on chromosome 2. TTN encodes a giant protein named titin that acts as a stretch sensor within sarcomere. TTN gene mutations are mostly frameshifts, nonsense and predicted splice site mutations leading to truncation of the A band of titin protein. Interestingly, nearly all TTN mutations are heterozygous. Additional mutations described in DCM involve genes encoding thin filaments (ACTC1 gene), tropomyosin (TPM1 D230N), and troponin subunits (TNNT2 del210K, TNNC1 G159D, and TNNI3 genes) as well as mutations in the β-myosin heavy chain (MYH7, S532P, and F764L) and myosin binding protein C (MYBPC3 gene). Some of these mutations can act in a dominant negative manner. DCM has also been associated with mutations affecting genes encoding Z band proteins and the costamere. These include mutations in the MLP gene encoding muscle LIM protein, CARP gene mutations encoding cardiac Ankyrin repeat protein, and mutations in genes encoding myopalidin, α-actinin 2, TCAP, and nexilin. The mutations often lead to disruption of Z band protein phosphorylation or nuclear translocation of Z band elements. Nucleoskeleton and nuclear membrane defects have also been described as potential causes of DCM with over 200 mutations affecting the LMNA gene encoding Lamin A and C. Interestingly DCM with frameshift mutations in the LMNA gene have been shown to have the highest risk for ventricular arrhythmias.

Eosinophilic myocarditis is characterized by progressive myocardial damage that microscopically shows three stages. Stage 1 is characterized by acute necrosis due to infiltration and extracellular deposition of eosinophils. Stage 2 is characterized by layered thrombus formation along the damaged endocardium due to activation of tissue factor by eosinophils. Stage 3 is characterized by myocardial fibrosis.

Findings of chronic rheumatic valve disease include neovascularization, chronic inflammation, and relatively mild calcification. Aschoff nodules are considered pathognomonic for rheumatic heart disease; these are interstitial fibroinflammatory lesions with macrophages and collagen necrosis. Anitschkow cells, also called caterpillar cells due to unusual wavy nuclear outlines, are also typically present, but are not specific and can be seen in other conditions.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder affecting 0.2% of the population. Males are affected one and one-half times as frequently as females and the mean age at presentation is approximately 45 years. There is a bimodal distribution, which peaks in early and later adulthood. Grossly, the HCM heart weight ranges from 600 grams to over 1000 grams. The classic form of HCM is characterized by symmetrical or asymmetrical left ventricular hypertrophy that usually affects the basal anterior septum, which protrudes beneath the subaortic valvular apparatus. This leads to blood flow obstruction and mitral regurgitation that subsequently causes endocardial fibrosis over the septum. In the symmetrical form of HCM (less than a half of patients), typically, concentric thickening of the left ventricle is seen with small ventricular cavity dimensions. Other morphological variants include midventricular cavity obstruction and segmental hypertrophy. End stage HCM shows ventricular dilatation that may be indistinguishable from dilated cardiomyopathy.

Genetic alterations are responsible for a growing number of cardiomyopathies with more than 50 genes identified to date which are now routinely tested for diagnosis. HCM is most commonly associated with mutations in genes encoding sarcomere elements, namely genes encoding myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3). These mutations account for up to 75% of genetic alterations in HCM and the clinical spectrum of HCM has been shown to correlate with particular genotype. Mutations Arg403Gln, Arg453Gln, Arg719Trp lead to a severe form of HCM with early onset, complete penetrance, and high risk of sudden cardiac death (SCD) while mutations Leu908Val and Val606Met are considered low-risk and are associated with near-normal life expectancy. Mutations in the PRKAG2 gene, which encodes the β-2 subunit of AMP-activated-protein kinase (AMPK), have been found to cause HCM with Wolff-Parkinson-White syndrome while mutations in the mitochondrial tRNA(Lys) gene (G8363A), involved in energy production, lead to HCM associated with sensorineural hearing loss and encephalomyopathy. Mutations in the troponin T gene cause minimal ventricular hypertrophy and have a poor prognosis due to high risk of SCD.

  1. Which of the following is true regarding cardiomyopathies?

    1. Dilated cardiomyopathy is most commonly associated with mutations in genes encoding sarcomere elements, namely genes encoding myosin heavy chain.
    2. Eosinophilic myocarditis is characterized by progressive myocardial damage due to iron deposition.
    3. Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by myocyte disarray due to extracellular amyloid deposition throughout the myocardium.
    4. HCM is an autosomal recessive genetic disorder.
    5. The classic variant of HCM usually affects the basal anterior septum, which protrudes beneath the subaortic valvular apparatus.
  2. Which of the following is correct regarding the diagnosis of cardiac hemochromatosis?

    1. Bronze diabetes is typical of cardiac hemochromatosis.
    2. Cardiac hemochromatosis always requires histopathological confirmation with an endomyocardial biopsy sample.
    3. Cardiac hemochromatosis can be diagnosed in patients with genetic testing and with appropriate cardiac (clinical, imaging, and electrophysiology) testing.
    4. Cardiac iron deposition is earlier than liver iron deposition in hemochromatosis.
    5. Narrowing of the lumens and hypertrophy of the media of small intramural branches of coronary arteries are characteristic of hemochromatosis and is seen in angiograms.
  3. Various genetic mutations resulting in several defective gene products (protein) have been identified in dilated cardiomyopathy. What protein defect is identified in a significant number of cases (~30%)?

    1. Actin alpha subunit
    2. Hypertrophin
    3. Myosin heavy chain
    4. Myosin light chain
    5. Titin


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Pawel Mroz, MD, PhD
Hematopathology Fellow
University of Michigan
Ann Arbor, MI

Rajan Dewar, MD, PhD
Associate Professor of Pathology
University of Michigan
Ann Arbor MI

Answer Key

  1. The classic variant of HCM usually affects the basal anterior septum, which protrudes beneath the subaortic valvular apparatus. (e)
  2. Cardiac hemochromatosis can be diagnosed in patients with genetic testing and with appropriate cardiac (clinical, imaging, and electrophysiology) testing. (c)
  3. Titin (e)