Self Study 2: Hemochromatosis Objectives
1. How is hemojuvelin (HJV) involved in the regulation of hepcidin expression?
A. recessive mode of transmission of mutated HJV protein, affects chromosome 1
1. incites juvenile hemochromatosis (type 2A)
2. affects young patients/adults < 30 years old with dominant cardiac and endocrine impact
B. HJV = member of bone morphogenic protein (BMP) co-receptor family
1. used in BMP signaling pathway to up-regulate hepcidin expression
2. membrane-bound by glycosylphosphatidylinositol (GPI) anchor; though soluble HJV (sHJV) competitively
inhibits hepcidin expression
C. hepcidin deficiency
1. iron overload in liver, pancreas, and heart, but decreased iron in macrophages
2. see question two with regards to elaboration of regulation of hepcidin expression (part of types 1, 2, 3
hemochromatosis)
2. Explain how hepcidin deficiency leads to types 1, 2, and 3 hemochromatosis. What are the target organs/cells for this hormone?
A. hepcidin deficiency leads to increased activity of export protein ferroportin
1. increased entry of excessive plasma iron into cells (predominantly parenchyma)
2. decreased hepatic hepcidin production, decreased circulating hepcidin, increased duodenal iron
absorption, further decreased circulating hepcidin, decreased hepcidin binding to ferroportin, internalization
but decreased ferroportin degradation, increased ferroportin, increased iron release due to increased
ferroportin activity, increased iron release from macrophages, increased plasma iron concentration,
increased hepatic uptake of iron, parenchymal (hepatocyte) iron excess
B. treatment: hepcidin administration or hepcidin synthesis stimulation
1. avoid iron overload for “at risk” patients”
2. avoid reconstitution of iron excess once iron depletion has been obtained (instead of chronic venesections)
3. What is the defective protein involved in type 4A hemochromatosis and how does this defect lead to iron accumulation in tissues?
A. ferroportin failure: type 4A hemochromatosis ferroportin disease; decreased cellular iron egress
1. only type with dominant mode of transmission; most frequent form of ferroportin disease
2. hyperferritinemia
B. decreased iron release from macrophages
1. results in low circulating iron
2. sucks for erythropoiesis
4. How does aceruloplasminemia lead to hemochromatosis?
A. ferroportin failure: the unofficial fifth type of hematochromatosis
1. recessive mode of transportation, affects chromosome 3 (incites anemia and neurological symptoms from
iron overload)
2. ceruloplasmin (mutated protein)
a. mutation either totally inhibits ceruloplasmin production or its ferroxidase activity
-excessive ferroportin degradation; decreased cellular iron egress (esp from macrophages)
-low circulating iron; also sucks for erythropoiesis
b. normally oxidizes ferrous iron into ferric iron
-transferrin only transfers ferric iron in the blood
5. What effect does hepcidin deficiency have on non-transferrin-bound iron (NTBI) and how is NBTI involved in iron accumulation in tissues?
A. NTBI has important role in cellular iron excess and damage
1. can very rapidly be taken up by liver, pancreas, and heart
a. produces parenchymal iron excess (hepatocytes for liver)
B. component, labile plasma iron (LPI) appears whenever plasma transferrin saturation > 75%, corresponds to a
potentially damaging iron species due to its high propensity for generating reactive oxygen species
6. How do the following affect plasma ferritin levels? All increase plasma ferritin levels (hyperferritinemia).
A. Alcoholism
1. elevated plasma ferritin levels; induces ferritin synthesis
B. Polymetabolic (metabolic) syndrome
1. usual clinical profile: obesity (high BMI), increase BP non-insulin-dependent diabetes, hyperlipidemia,
hyperuricemia
2. aka insulin resistance associated iron over-load or dymetabolic hepatosiderosis
3. iron excess, but elevated plasma ferritin levels
C. Inflammatory conditions
1. low serum iron levels, presence of anemia
2. elevated plasma ferritin levels
D. Acute or chronic hepatitis
1. cytolysis (hepatocyte damage) damages cell membrane or alters cell membrane permeability
2. release of intracellular ferritin into bloodstream
3. elevated plasma ferritin levels