Pathophysiology
Summary
Hereditary hemochromatosis is an autosomal recessive disorder characterized by excessive iron overload in various organs, including the liver, pancreas, heart, and the pituitary gland. The most common genetic basis for hereditary hemochromatosis is a missense mutation in the HFE gene located on chromosome 6, which is linked to the HLA-A3 locus.
Mutations in the HFE gene result in impairment of the liver’s iron-sensing capabilities, resulting in upregulated absorption of iron from the GI tract and increased loading of iron onto transferrin by enterocytes. This defective sensing mechanism also results in decreased hepatic production of hepcidin—a hormone that usually ‘locks’ iron inside enterocytes—thereby increasing iron absorption. The resultant iron overload leads to deposits of iron in the form of hemosiderin, appearing as golden-yellow granules in the cytoplasm of affected cells. This overload also generates hydroxyl free radicals that cause more cellular damage.
Clinically, the iron accumulation can lead to liver fibrosis and eventually cirrhosis, which increases the risk of developing hepatocellular carcinoma (HCC). Additionally, hereditary hemochromatosis can cause skin hyperpigmentation (‘bronze hyperpigmentation’) and diabetes mellitus (‘bronze diabetes’) due to iron-induced free radical damage of beta islet cells in the pancreas. Further, iron overload results in steatorrhea & malabsorption due to injury to the exocrine pancreas.
Cardiovascular manifestations such as dilated cardiomyopathy and restrictive cardiomyopathy can arise due to myocardial iron deposition. Hormonal imbalances such as decreased sex hormones and secondary hypergonadism can occur due to iron deposition in the anterior pituitary. Degenerative joint disease is also a potential complication due to iron-induced chondrocalcinosis.
Laboratory findings in hemochromatosis show increased serum iron & ferritin and decreased total iron-binding capacity (TIBC). This results in an increased transferrin saturation, often used as the initial test for screening. Liver biopsies reveal hemosiderin deposits that appear blue on Prussian blue stain. Treatment options include phlebotomy and the use of deferoxamine as an iron-chelating agent.
Notably, conditions that need frequent blood transfusions, such as sickle cell anemia and thalassemia major can lead to secondary hemochromatosis. Ineffective erythropoiesis, as seen in beta-thalassemia, also contributes to iron overload.
Wilson disease is another autosomal recessive disorder, but is instead characterized by copper overload due to a mutation in the hepatocyte copper-transporting ATPase (ATP7B). A mutation in ATP7B results in decreased copper incorporation into apoceruloplasmin and a subsequent decrease in copper excreted into bile. This leads to a decrease in serum ceruloplasmin, which usually transports copper in the blood, as well as an increase in free serum copper, which deposits in various tissues. Lab findings in Wilson’s disease are therefore decreased total serum copper, increased free serum copper and increased urinary copper.
Wilson disease can manifest with hepatosplenomegaly, liver fibrosis progressing to cirrhosis, and hemolytic anemia due to excess circulating copper. Neurologically, it is may result in dysarthria, Parkinsonian symptoms, and other movement disorders like dystonia, tremors, & choreoathetosis, as well as dementia. The free radical-induced injury presents similarly to hemochromatosis, along with characteristic Kayser-Fleischer rings, which arise from copper deposition in the cornea. Treatment for Wilson disease involves copper chelators like penicillamine, which both chelates copper and inhibits its absorption.
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FAQs
Hereditary hemochromatosis is an autosomal recessive disorder most commonly caused by a missense mutation in the HFE gene on chromosome 6. Mutations in the HFE gene result in impairment of the liver’s iron-sensing capabilities, resulting in upregulated absorption of iron from the GI tract and increased loading of iron onto transferrin by enterocytes. Hepcidin, which normally promotes the degradation of ferroportin and ‘locks’ iron inside enterocytes, is due to this defective sensing mechanism. Consequently, iron overload occurs, leading to iron deposits in organs such as the liver, pancreas, heart, pituitary, and joints. These deposits mainly occur in the form of hemosiderin, appearing as golden yellow granules in the cytoplasm of cells. Excess iron generates hydroxyl free radicals that cause cellular damage, leading to symptoms such as liver fibrosis, cirrhosis, bronze hyperpigmentation, diabetes mellitus (also known as "bronze diabetes"), and cardiac conditions among others.
Hereditary hemochromatosis is often diagnosed through multiple tests. A common initial screening test is to measure transferrin saturation, as it tends to be elevated in these conditions. In patients diagnosed with hemochromatosis, serum iron and ferritin levels are usually increased, while the total iron binding capacity (TIBC) is low. Additionally, a liver biopsy may be conducted, showing golden granules of hemosiderin that stain blue with Prussian blue stain. Genetic testing may also be used to identify the HFE mutation associated with hemochromatosis.
The primary treatment for hereditary hemochromatosis is phlebotomy, which helps to reduce the iron overload in the body. Additionally, iron chelators like deferoxamine may be used to bind and expel excess iron. Maintaining a low-iron diet and avoiding the use of iron supplements or vitamin C, which enhances iron absorption, is also recommended.
Wilson's disease, or hepatolenticular degeneration, is an autosomal recessive disorder caused by a mutation in the hepatocyte copper-transporting ATPase (ATP7B). This mutation results in the inability of hepatocytes to transport copper into bile for excretion, leading to copper accumulation and the formation of free radicals, resulting in cellular damage. Copper deposits in various tissues lead to symptoms like Kayser-Fleischer rings, hepatosplenomegaly, liver fibrosis, cirrhosis, hemolytic anemia, dysarthria, Parkinsonian symptoms, and even dementia.
Diagnosis of Wilson's disease is often achieved through tests that measure serum and urine copper levels. In Wilson's disease, total serum copper is usually low due to low ceruloplasmin levels, but free serum copper and urine copper levels are elevated. Additionally, Kayser-Fleischer rings can be detected by an ophthalmologist. Treatment typically involves the use of copper chelators like penicillamine, which bind copper and prevent its absorption in the intestines. Dietary modifications may also be prescribed to reduce copper intake.
