Clinical History:

A 45-year-old man has become increasingly short of breath over the past year. He has also noted a darker color to his skin, even though he has a job in a bank and does not go out in the sun much. He has worsening joint pain, but no joint deformity. His physician notes a firm liver edge on physical examination, but no abdominal pain or masses. A stool sample is negative for occult blood. Laboratory findings include: sodium 148 mmol/L, potassium 4.2 mmol/L, chloride 97 mmol/L, CO2 24 mmol/L, urea nitrogen 19 mg/dL, creatinine 1.2 mg/dL, glucose 178 mg/dL, total protein 5.9 g/dL, albumin 3.4 g/dL, alkaline phosphatase 30 U/L, AST 43 U/L, ALT 40 U/L, and total bilirubin 0.8 mg/dL. The gross appearance of organs of a patient at autopsy with the same underlying condition are shown in image 9.1.

1. What underlying condition do you suspect?

   The dark brown color of the organs in image 9.1 suggests excessive iron deposition--hemochromatosis

2. What laboratory test finding in his history given above is most signficant?

   The elevated serum glucose is consistent with diabetes mellitus.

3. What other laboratory test on his serum would be abnormal?

   The serum ferritin is a measure of iron stores. This patient's serum ferritin was 7800 ng/mL (normal 7 - 340).

4. What special stain would you perform on a liver biopsy?

   Image 9.2 demonstrates brown, granular pigment in the hepatocytes consistent with hemosiderin, and this is confirmed with the iron stain in image 9.3 (Perl's iron stain, with Prussian blue reaction).

5. What other pigments could be present in liver?

   Image 9.4 demonstates light brownish-yellow lipochrome (lipofuscin) pigment, which is a "wear-and-tear" pigment that accumulates with aging, but it has no pathologic effect on liver function. Image 9.5 demonstrates cholestasis with bile pigment distending small bile ducts and canaliculi; this is abnormal. In parts of the world where malaria is endemic, brown to black malarial pigment, seen as small grains, may collect in liver, particularly in Kupffer cells.

Questions:

1. What complication will develop in the liver if he is untreated?

There is extensive bridging portal fibrosis with nodular regeneration seen in image 9.6 (also with iron stain). The pattern of cirrhosis with hemochromatosis is typically micronodular.

2. Describe the pathologic findings that you expect to be present in this patient.

The iron deposition can occur in many tissues. However, some organs are affected more than others. Iron accumulation in the heart leads to an infiltrative cardiomyopathy, which explains the heart failure in this case. Pancreatic iron deposition leads to "bronze diabetes" and explains the hyperglycemia in this case. Patients may also have polyarthritis. Of course, the hepatic hemochromatosis leads to cirrhosis and liver failure. Deposition of iron in skin produces the darker pigmentation noticed in light-skinned persons.

3. What diseases may produce the gross and microscopic findings in the liver as seen in this case?

Persons with anemia from ineffective erythropoiesis that can be seen with thalassemias can absorb excessive iron. Persons with refractory anemias requiring chronic transfusion therapy will also accumulate excessive iron.

This patient has hereditary hemochromatosis (HHC). It is inherited as an autosomal recessive trait, and the hemochromatosis gene (HFE) is closely linked to the HLA locus on chromosome 6. Genetic studies suggest that this mutation arose in a Celtic population in Europe 60 to 70 generations ago and may have had a selective advantage to a population at risk for iron deficiency. A single mutation, a substitution of cysteine to tyrosine at amino acid 282, called C282Y, is responsible for most cases. Treatment is removal of iron by phlebotomy (250 mg of iron per unit of blood removed). Family members also need to be screened by genetic testing with a blood sample to identify affected members before tissue damage develops.