Melanin

1.  
    
   1.  
      Melanin
       
      1.  
         This pigment is formed from tyrosine by the action of tyrosinase, synthesized in melanosomes of melanocytes within the epidermis, and transferred by melanocytes to adjacent clusters of keratinocytes and also to macrophages (melanophores) in the subjacent dermis.
      2.  
         Increased melanin pigmentation is associated with sun tanning and with a wide variety of disease conditions.
      3.  
         Decreased melanin pigmentation is observed in albinism (inherited disorder with little to no pigment) and vitiligo (unknown etiology, loss of pigment with sharp edges).
   2.  
      Bilirubin
       
      1.  
         This pigment is a catabolic product of the heme moiety of hemoglobin and, to a minor extent, myoglobin.
      2.  
         In various pathologic conditions, bilirubin accumulates and stains the blood, sclerae, mucosae, and internal organs, producing a yellowish discoloration called jaundice.
          
         1.  
            Hemolytic jaundice, which is associated with the destruction of red cells, is discussed in more depth in Chapter 11.
         2.  
            Hepatocellular jaundice, which is associated with parenchymal liver damage, and obstructive jaundice, which is associated with intra- or extrahepatic obstruction of the biliary tract, are discussed more fully in Chapter 16.
   3.  
      Hemosiderin
       
      1.  
         This iron-containing pigment consists of aggregates of ferritin. It appears in tissues as golden brown amorphous aggregates and can be positively identified by its staining reaction (blue color) with Prussian blue dye. It exists normally in small amounts as physiologic iron stores within tissue macrophages of the bone marrow, liver, and spleen.
      2.  
         It accumulates pathologically in tissues in excess amounts (sometimes massive) (Table 1.3).
          

         TABLE 1.3

         Abnormal Deposition of Hemosiderin

         Type	Pathologic Features	Mechanisms
         Local hemosiderosis	Local deposition of hemosiderin	Most often results from hemorrhage into tissue; hemosiderin derived from breakdown of hemoglobin
         Systemic hemosiderosis	Generalized hemosiderin deposition without tissue or organ damage	May result from hemorrhage, multiple blood transfusions, hemolysis, and excessive dietary intake of iron, often accompanied by alcohol consumption
         Hemochromatosis	Damage to many tissues and organs; scarring and organ dysfunction manifested as hepatic cirrhosis and fibrosis of pancreas, leading to diabetes mellitus; increased melanin pigmentation in skin	More extensive accumulation than hemosiderosis; can result from any of the causes of systemic hemosiderosis; most often a hereditary disorder characterized by increased iron absorption (hereditary hemochromatosis)

          
         1.  
            Hemosiderosis is defined by accumulation of hemosiderin, primarily within tissue macrophages, without associated tissue or organ damage.
         2.  
            Hemochromatosis is more extensive accumulation of hemosiderin, often within parenchymal cells, with accompanying tissue damage, scarring, and organ dysfunction. This condition occurs in both hereditary (primary) and secondary forms.
             
            1.  
               Hereditary hemochromatosis is most often caused by a mutation in the Hfe gene on chromosome 6. Over 20 distinct mutations have been identified, the most common of which is the C282Y mutation, followed by the H63D mutation (Figure 1.6).
                
               1.  
                  Hemosiderin deposition and organ damage in the liver, pancreas, myocardium, and multiple endocrine glands are characteristic, as well as melanin deposition in the skin.
                   

                  FIGURE 1.6

                  

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                  Hereditary hemochromatosis. Prussian blue staining marks the intraparenchymal deposition of hemosiderin.

                  (Reprinted with permission from Rubin R, Strayer D et al., eds.: Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed. Baltimore, Lippincott Williams & Wilkins, 2012, Figure 1-23G, p. 21.)
               2.  
                  This results in the triad of micronodular cirrhosis, diabetes mellitus, and skin pigmentation. This set of findings is referred to as “bronze diabetes.” Laboratory abnormalities of note include marked elevation of the serum transferrin saturation because of the combination of increased serum iron and decreased total iron-binding capacity (TIBC).
            2.  
               Secondary hemochromatosis is most often caused by multiple blood transfusions administered to subjects with hereditary hemolytic anemias such as β-thalassemia major.
   4.  
      Lipofuscin
       
      1.  
         This yellowish, fat-soluble pigment is an end product of membrane lipid peroxidation.
      2.  
         It is sometimes referred to as “wear-and-tear” pigment.
      3.  
         It commonly accumulates in elderly patients, in whom the pigment is found most often within hepatocytes and at the poles of nuclei of myocardial cells. The combination of lipofuscin accumulation and atrophy of organs is referred to as brown atrophy.
2.  
   Pathologic calcifications
    
   1.  
      Metastatic calcification
       
      1.  
         The cause of metastatic calcification is hypercalcemia.
      2.  
         Hypercalcemia most often results from any of the following causes:
          
         1.  
            Hyperparathyroidism
         2.  
            Osteolytic tumors with resultant mobilization of calcium and phosphorus
         3.  
            Hypervitaminosis D
         4.  
            Excess calcium intake, such as in the milk-alkali syndrome (nephrocalcinosis and renal stones caused by milk and antacid self-therapy)
   2.  
      Dystrophic calcification
       
      1.  
         Dystrophic calcification is defined as calcification in previously damaged tissue, such as areas of old trauma, tuberculosis lesions, scarred heart valves, and atherosclerotic lesions (Figure 1.7).
          

         FIGURE 1.7

         

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         Calcific aortic stenosis.

         This is an example of dystrophic calcification, that is, calcification of a previously damaged structure.

         (Reprinted with permission from Rubin R, Strayer D et al., eds.: Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed. Baltimore, Lippincott Williams & Wilkins, 2012, Figure 1-10, p. 13.)
      2.  
         The cause is not hypercalcemia; typically, the serum calcium concentration is normal.

Cellular Response to Physiologic and Pathologic Conditions

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