Hereditary Haemochromatosis Flashcards
Excess iron is stored either as ferritin or ____________
haemosiderin.
What’s the bad kind of iron storage form?
Think the bad guy from toy story. Him and Sid are in there torturing toys.
Haemosiderin.
When does HH set in for men?
For women?
40s/50s
Women: after menopause
What organs are affected by iron overload?
Liver Pancreas Heart Skin Gonads Adrenal Cortex
DON’T FORGET BACTERIAL INFECTIONS
What’s the effect on adrenal cortex with iron overload?
hypocortisolism (Addison’s)
How can HH end up in diabetes?
Pancreas damage.
What are three things to list as liver damage in iron overload?
Cirrhosis
Cancer (C282Y = 20 fold risk)
hepatomegaly
Clinical presentation of HH is pretty non-specific. What are the two common complaints?
Fatigue
Arthralgia
What are some rarer complaints when people present with HH?
Cataracts
Retinal degeneration
Neuropathy (ataxia, dementia)
What are other frequent complaints when people present with HH?
Rhett’s cat thinks he’s a degenerate. Brain problems.
Cataracts
Neurological problems (ataxia, dementia)
Retinal degeneration
Type 1 HH is also called
HFE-1 haemochromatosis.
Short answer reminder: Two features of HFE and its C282Y mutation.
HFE gene is MHC-like
C282Y screws up disulfide bond in the alpha3 domain - can’t interact with B2-mic.
Free iron is a problem for two reasons. What are they (not haemosiderin yet)
Favours bacterial growth
Produces superoxides
Refresher: what’s transferrin?
Transferrin is THE transport protein for iron in the blood. Can be monoferric or diferric.
Refresher: what’s ferritin?
That’s the hollow profiterole thing that’s used for iron STORAGE.
What by far are the two largest iron compartments of our system?
Haemoglobin and Ferritin
Apart from hepatocytes, where is iron stored [in ferritin]?
RES Kuppfer cells
HH is primary or secondary?
PRIMARY
What’s an example of secondary iron overload?
Thalassaemia.
Also chronic liver disease and alcoholism
Briefly, how does thalassaemia lead to iron overload?
Circulating iron gets stolen by the erythropoietic compartment (BMP stimulation)- diferric Tf doesn’t perfuse the liver as much - HFE downregulated.
Chelation therapy preferred.
T or F: Transferrin saturation is relatively elevated in HH.
FALSE (basically wrong). In HH transferrin is almost COMPLETELY SATURATED.
How much dietary iron do we absorb?
What’s the RDI?
Only about 10% (1-3g)
10-30g
Why do people take vitamin C when they’re eating spinach to load up on iron?
Because it’s a reducing agent.
Recall absorption ferrous>ferric.
What are the four main players (compartment wise) in iron regulation?
Duodenal enterocytes
RES macrophages
Hepatocytes
RBC progenitors (marrow)
What protein represents the plasma compartment of iron?
transferrin.
Bonus: transferrin iron turned over 10-20 times per day.
What’s a nice term to use for an exam question on iron haemostasis?
FLUX. Iron is in a constant state of flux. Transferrin iron is turned over 10-20 times per day.
We absorb 1-3 mg per day 1-2mg of iron per day.
Transferrin is normally ____ saturated.
It binds _______ ferr__ ions per molecule.
25-50%
Ferric.
Transferrin is _________ in iron overload and _________ in iron deficiency.
overload: INCREASE in transferrin.
deficiency: DECREASE in transferrin.
How does unsaturated transferrin protect against infection?
It competes for iron with iron-dependent pathogens like VIBRIO VULNIFICUS (a marine halophile).
What’s the name of the marine halophile that can infect when transferrin is saturated?
This volcano sure is nifty cos it vibrates!
Vibrio vulnificus
What’s the name of the marine halophile that can infect when transferrin is saturated?
No prompt
Vibrio vulnificus
What’s are the terms to use in the sentence about the dangers of free iron?
Transferrin saturation = free iron = oxidative stress and tissue damage
Transferrin saturation. What’s the problem? Go.
- Vibrio vulnificus
2. Free iron (oxidative stress + tissue damage)
Three points about ferritin structure:
- 460000 kDa
- 4500 ferric ions storage capacity.
- Saturation = 30% dw is iron.
_______ binding is favoured in high-Fe state, ______ binding is favoured in the low-Fe state.
High-Fe: ferritin binding
Low-Fe: transferrin binding
How many ferric ions can make up a full chocolate centre to the ferritin profiterole?
4500
IRP2 _________.
IRP1 _________.
Think response to iron.
IRP2 PRESERVES TfR mRNA by binding to the 3’ IRE.
IRP1 INHIBITS ferritin mRNA by binding to the 5’ IRE.
mRNA translation starts at the _’ end and proceeds toward the _’ end.
Starts at 5’, ends at 3’.
Translation is 5’ to 3’.
IRPs 1&2 bind to what kind of structures?
mRNA stem loops
Together, IRPs 1IRP;2 favour…
… transferrin binding of iron (i.e. plasma uptake)
What do we call the stem loops on TfR and ferritin mRNAs?
the 3’ and 5’ flanking iron responsive elements (IREs).
How does high Fe favour ferritin storage?
Fe causes a conformation change in IRPs. No binding to IREs = degraded TfR and disinhibited ferritin translation.
Why do we need duodenal cytochrome b ferroreductase?
Dcytbf.
Because ferric iron won’t be taken up by the DMT1.
What protein is responsible for absorbing heme?
HCP1
Haem carrier protein 1
Does FPN export Fe3+?
NO.
HO and DMT1 both feed the ______.
labile iron pool (LIP).
What two enzymes respectively provide substrates for DMT1 and HO?
Dcytbf
HCP1
What’s hephaestin’s job?
It oxidises ferrous iron to ferric iron.
Ferrous iron spontaneously oxidises after FPN export. T or F?
FALSE
It’s oxidised by hephaestin.
What other REALLY IMPORTANT cell expresses FPN?
RES macrophages - therefore hepcidin also regulates liberation of RES-stored iron from storage into circulation.
Where do RES macrophages get their iron?
They scavenge dead RBCs.
Is hepcidin a hormone?
No.
Hormones signal
What event in hepatocytes involves TfR2 (aot TfR1)
HFE binding to TfR2 initiates the BMP/SMAD signalling cascade that increases HFE expression.
What are two other things that increase hepcidin expression?
Hypoxia (low O2)
IL-6 (inflammation)
Where in the picture is haemojuvulin (Hjv) important?
It’s associated with TfR2 and required for BMP/SMAD signalling.
It lets BMPII&I phosphorylate SMAD1/5/8.
Write the big complex of five major components involved in hepcidin upregulation via BMP/SMAD initiation.
HFE/TfR2/HJV/BMPR/BMPligand
bonus: phosphorylates SMAD1/5/8
Name the four regulatory pathways for hepcidin expression (think of things Fe load relates to)
Iron status
Erythropoiesis
Inflammation
Oxygen tension
The hypoxia aspec, the bone-morphogenetic aspect and the iron-status aspect all act through the _____ pathway.
BMP/SMAD
Decreased oxygen tension leads to _______ hepcidin expression.
decreased hepcidin expression
How does decreased oxygen tension increase iron intake?
Matriptase2 expressed
Matriptase2 cleaves HJV from the cell surface.
HJV is a BMPr coreceptor.
No BMP/SMAD pathway.
What three proteins do you think of when you think of hypoxia?
HIF (hypoxia induced factor)
Furin
Matriptase 2
IMPORTANT: what’s the hepcidin gene called?
HAMP.
What pathway does inflammation (IL-6) act down?
JAK-STAT.
Inflammation acts on the ___ pathway; the rest act on the ___ pathway.
IL-6; JAK-STAT
Else: BMP/SMAD
The abbreviation for matriptase 2 is …
… TMPRSS6
Matriptase 2 ______ HJV, while furin does what?
TMPRSS6 cleaves HJV preventing it’s coreceptor fucntion.
Furin cleaves is DURING PROCESSING to produce a soluble form that acts as a decoy receptor for iron.
What’s the actual name of the BMPR ligand?
BMP-6.
EXAM: R-SMAD-(P) binds to ….
SMAD4.
Think hepcidin; think which STAT protein?
STAT6.
The BMPr is a …
heterodimer made of BMPRI and II.
IRPs are bound/unbound to Fe in order to active?
UNBOUND.
Fe-IRPs CAN’T bind to IREs.
Think translational regulation; think…
IRPs.
What is the name of the hormone released by RBCs in response to erythropoietin that suppresses hepcidin to enhance stress erythropoiesis?
Blood all over the floor smells bad. I’d rather smell someone’s pheromones than their penny blood.
Erythroferrone.
C282Y is a ______ mutation
It is an 835 ___ mutation.
Gary hates this mutation.
MISSENSE
G845A
H63D is way more ______ but way less ______ than C282Y.
Prevalence: H63D
Penetrance: C282Y
Who’s more likely to get HH - a C282Y/H63D heterozygote or a H63D homozygote?
heterozygote.
What’s TIBC?
Total iron binding capacity (transferrin saturation)
Just cos you should know - what are the liver enzymes in routine blood tests?
AST, ALT
3 things in blood tests for diagnosis.
TIBC (transferrin saturation)
ferritin level
liver function test
What’s the only confirmatory test?
Liver biopsy - looking for iron deposition.
What are the 5 treatments mentioned in the lecture?
Phlebotomy
Iron chelators
Proton pump inhibitors (decreases apical absorption).
Erythrocytaphoresis
Hepcidin agonists
What’s that newfangled RBC removal therapy called?
Erythrocytaphoresis
What are the two newfangled treatments?
Hepcidin agonists
Erythracytaphoresis
