I. Hereditary Hemochromatosis

II. Secondary Hemochromatosis

••••A. Parenteral iron overload

•••••••Transfusions

••••••••••Long-term hemodialysis

••••••••••Aplastic anemia

••••••••••Sickle cell disease

••••••••••Myelodysplastic syndromes

••••••••••Leukemias

•••••••Iron-dextran injections

••••B. Ineffective erythropoiesis with increased erythroid activity

•••••••b-Thalassemia

•••••••Sideroblastic anemia

•••••••Pyruvate kinase deficiency

••••C. Increased oral intake of iron

•••••••African iron overload (Bantu siderosis)

••••D. Congenital atransferrinemia

••••E. Chronic liver disease

•••••••Chronic alcoholic liver disease

•••••••Porphyria cutanea tarda

In white populations of northern European extraction, the frequency of the C282Y mutation is estimated at 6.4% to 9.5%.[4] The frequency of homozygosity is 0.45% (1 of every 220

persons), and that for heterozygosity is 11% (1 of every 9 persons), making hereditary hemochromatosis one of the most common genetic disorders in humans. However, the penetrance of

this disorder is only about 20% in patients with the homozygous C282Y mutation, so the genetic condition does not lead to disease in all individuals.

Pathogenesis.

It may be recalled that the total body content of iron is tightly regulated, as the limited daily losses of iron are matched by gastrointestinal absorption. In hereditary hemochromatosis,

regulation of intestinal absorption of dietary iron is lost, leading to net iron accumulation of 0.5 to 1.0 gm/year. The disease manifests itself typically after 20 gm of storage iron have

accumulated.

The critical site for HFE expression appears to be the basolateral surface of the small intestinal crypt epithelial cell, where it is prominently expressed. According to the current hypothesis

( Fig. 18-27 ),[32] [33] HFE complexes with the transferrin receptor, TfR, enabling the binding of plasma transferrin and its bound iron. The TfR-Tf-iron complex is endocytosed into the

crypt enterocyte; acidification of the endosome releases iron into the regulatory iron pool of the crypt cell. This is a sensing mechanism for the systemic iron balance, as increased levels of

circulating iron bound to transferrin will lead to an increased iron regulatory pool in enterocytes. This pool "sets" the level of expression of apical iron uptake systems. Crypt cells with

mutant HFE lack the facilitating effect on TfR-dependent iron uptake, thus decreasing the regulatory iron pool in the crypt cell. As small intestinal crypt cells are the progenitors of villus

absorptive cells, these cells are preprogrammed to absorb dietary iron regardless of the systemic iron overload.

Excessive iron appears to be directly toxic to host tissues, by the following mechanisms: (1) lipid peroxidation via iron-catalyzed free radical reactions, (2) stimulation of collagen

formation, and (3) interactions of reactive oxygen species and of iron itself with DNA, leading to lethal injury or predisposition to hepatocellular carcinoma. Whatever the actions of iron,

they are reversible in cells that are not fatally injured, and removal of excess iron during therapy promotes recovery of tissue function.

The most common causes of secondary hemochromatosis are the hemolytic anemias associated with ineffective erythropoiesis, discussed in Chapter 13 . In these disorders, the excess iron

may result not only from transfusions, but also from increased absorption. Transfusions alone, as in aplastic

Figure 18-27Schematic diagram of HFE function in the intestine. The crypt epithelial cell expresses HFE on its basolateral surface; complexing of HFE with b2 -microglobulin is required

for its expression on the cell surface. HFE-b2 -microglobulin complexes with the transferrin receptor (TfR) to bind circulating transferring (Tf). Endocytosis ensues; on acidification of the

recycling endosome, transferrin-bound iron (Fe(II)) is released and enters into the cytoplasm. High levels of cytoplasmic iron downregulate levels of the iron-regulatory proteins (IRP), a

family of proteins with potent effects on nuclear transcription. With low levels of cytoplasmic iron, the IRP content of the cell remains high. IRPs upregulate nuclear transcription of the

genes for several proteins required for intestinal absorption of dietary iron: Dcytb (duodenal cytochrome B), DMT1 (divalent metal transporter 1), ferritin (a cytoplasmic iron-binding

protein), and FP1 (ferroportin 1). A mutation in HFE prevents "sensing" of circulating iron levels by the crypt epithelial cell, leading to unregulated expression of these four proteins. The

crypt epithelial cell is the precursor cell of the mature absorptive enterocyte on the tip of the villus, through migration up the villus axis. On the apical membrane of the absorptive

enterocyte, Dcytb reduces dietary ferric iron (Fe(III)) to ferrous iron (Fe(II)). Fe(II) is then taken up by DMT1 into the enterocyte. Iron can be bound to ferritin (and hence sloughed back

into the gut lumen) or transported across the basolateral plasma membrane by FP1 for binding to transferrin and entry into the systemic circulation. In the patient with mutant HFE, the

inability to downregulate expression of these four proteins leads to lifelong excessive absorption of dietary iron.

Figure 18-28Hereditary hemochromatosis. Hepatocellular iron deposition is blue in this Prussian blue-stained section of an early stage of the disease, in which parenchymal architecture is

normal.

Figure 18-29a1 -Antitrypsin deficiency. Periodic acid-Schiff stain of the liver, highlighting the characteristic red cytoplasmic granules. (Courtesy of Dr. I. Wanless, Toronto General

Hospital, Toronto, Ontario, Canada.)

TABLE 18-10-- Major Causes of Neonatal Cholestasis

Bile duct obstruction

••Extrahepatic biliary atresia

Neonatal infection

••Cytomegalovirus

••Bacterial sepsis

••Urinary tract infection

••Syphilis

Toxic

••Drugs

••Parenteral nutrition

Metabolic disease

••Tyrosinemia

••Niemann-Pick disease

••Galactosemia

••Defective bile acid synthetic pathways

••a1 -Antitrypsin deficiency

••Cystic fibrosis

Miscellaneous

••Shock/hypoperfusion

••Indian childhood cirrhosis

••Alagille syndrome (paucity of bile ducts)

Idiopathic neonatal hepatitis

Date: 2016-04-22; view: 581