Hereditary Haemochromatosis

Question 1

Excess iron is stored either as ferritin or ____________

Answer 1

haemosiderin.

Question 2

What’s the bad kind of iron storage form?

Think the bad guy from toy story. Him and Sid are in there torturing toys.

Answer 2

Haemosiderin.

Question 3

When does HH set in for men?

For women?

Answer 3

40s/50s

Women: after menopause

Question 4

What organs are affected by iron overload?

Answer 4

Liver
Pancreas
Heart
Skin
Gonads
Adrenal Cortex

DON’T FORGET BACTERIAL INFECTIONS

Question 5

What’s the effect on adrenal cortex with iron overload?

Answer 5

hypocortisolism (Addison’s)

Question 6

How can HH end up in diabetes?

Answer 6

Pancreas damage.

Question 7

What are three things to list as liver damage in iron overload?

Answer 7

Cirrhosis
Cancer (C282Y = 20 fold risk)
hepatomegaly

Question 8

Clinical presentation of HH is pretty non-specific. What are the two common complaints?

Answer 8

Fatigue

Arthralgia

Question 9

What are some rarer complaints when people present with HH?

Answer 9

Cataracts
Retinal degeneration
Neuropathy (ataxia, dementia)

Question 10

What are other frequent complaints when people present with HH?

Rhett’s cat thinks he’s a degenerate. Brain problems.

Answer 10

Cataracts
Neurological problems (ataxia, dementia)
Retinal degeneration

Question 11

Type 1 HH is also called

Answer 11

HFE-1 haemochromatosis.

Question 12

Short answer reminder: Two features of HFE and its C282Y mutation.

Answer 12

HFE gene is MHC-like

C282Y screws up disulfide bond in the alpha3 domain - can’t interact with B2-mic.

Question 13

Free iron is a problem for two reasons. What are they (not haemosiderin yet)

Answer 13

Favours bacterial growth

Produces superoxides

Question 14

Refresher: what’s transferrin?

Answer 14

Transferrin is THE transport protein for iron in the blood. Can be monoferric or diferric.

Question 15

Refresher: what’s ferritin?

Answer 15

That’s the hollow profiterole thing that’s used for iron STORAGE.

Question 16

What by far are the two largest iron compartments of our system?

Answer 16

Haemoglobin and Ferritin

Question 17

Apart from hepatocytes, where is iron stored [in ferritin]?

Answer 17

RES Kuppfer cells

Question 18

HH is primary or secondary?

Answer 18

PRIMARY

Question 19

What’s an example of secondary iron overload?

Answer 19

Thalassaemia.

Also chronic liver disease and alcoholism

Question 20

Briefly, how does thalassaemia lead to iron overload?

Answer 20

Circulating iron gets stolen by the erythropoietic compartment (BMP stimulation)- diferric Tf doesn’t perfuse the liver as much - HFE downregulated.
Chelation therapy preferred.

Question 21

T or F: Transferrin saturation is relatively elevated in HH.

Answer 21

FALSE (basically wrong). In HH transferrin is almost COMPLETELY SATURATED.

Question 22

How much dietary iron do we absorb?

What’s the RDI?

Answer 22

Only about 10% (1-3g)

10-30g

Question 23

Why do people take vitamin C when they’re eating spinach to load up on iron?

Answer 23

Because it’s a reducing agent.

Recall absorption ferrous>ferric.

Question 24

What are the four main players (compartment wise) in iron regulation?

Answer 24

Duodenal enterocytes
RES macrophages
Hepatocytes
RBC progenitors (marrow)

Question 25

What protein represents the plasma compartment of iron?

Answer 25

transferrin. Bonus: transferrin iron turned over 10-20 times per day.

Question 26

What's a nice term to use for an exam question on iron haemostasis?

Answer 26

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.

Question 27

Transferrin is normally ____ saturated. | It binds _______ ferr__ ions per molecule.

Answer 27

25-50% | Ferric.

Question 28

Transferrin is _________ in iron overload and _________ in iron deficiency.

Answer 28

overload: INCREASE in transferrin. deficiency: DECREASE in transferrin.

Question 29

How does unsaturated transferrin protect against infection?

Answer 29

It competes for iron with iron-dependent pathogens like VIBRIO VULNIFICUS (a marine halophile).

Question 30

What's the name of the marine halophile that can infect when transferrin is saturated? This volcano sure is nifty cos it vibrates!

Answer 30

Vibrio vulnificus

Question 31

What's the name of the marine halophile that can infect when transferrin is saturated? No prompt

Answer 31

Vibrio vulnificus

Question 32

What's are the terms to use in the sentence about the dangers of free iron?

Answer 32

Transferrin saturation = free iron = oxidative stress and tissue damage

Question 33

Transferrin saturation. What's the problem? Go.

Answer 33

1. Vibrio vulnificus | 2. Free iron (oxidative stress + tissue damage)

Question 34

Three points about ferritin structure:

Answer 34

1. 460000 kDa 2. 4500 ferric ions storage capacity. 3. Saturation = 30% dw is iron.

Question 35

_______ binding is favoured in high-Fe state, ______ binding is favoured in the low-Fe state.

Answer 35

High-Fe: ferritin binding | Low-Fe: transferrin binding

Question 36

How many ferric ions can make up a full chocolate centre to the ferritin profiterole?

Answer 36

4500

Question 37

IRP2 _________. IRP1 _________. Think response to iron.

Answer 37

IRP2 PRESERVES TfR mRNA by binding to the 3' IRE. IRP1 INHIBITS ferritin mRNA by binding to the 5' IRE.

Question 38

mRNA translation starts at the _' end and proceeds toward the _' end.

Answer 38

Starts at 5', ends at 3'. | Translation is 5' to 3'.

Question 39

IRPs 1&2 bind to what kind of structures?

Answer 39

mRNA stem loops

Question 40

Together, IRPs 1IRP;2 favour...

Answer 40

... transferrin binding of iron (i.e. plasma uptake)

Question 41

What do we call the stem loops on TfR and ferritin mRNAs?

Answer 41

the 3' and 5' flanking iron responsive elements (IREs).

Question 42

How does high Fe favour ferritin storage?

Answer 42

Fe causes a conformation change in IRPs. No binding to IREs = degraded TfR and disinhibited ferritin translation.

Question 43

Why do we need duodenal cytochrome b ferroreductase? | Dcytbf.

Answer 43

Because ferric iron won't be taken up by the DMT1.

Question 44

What protein is responsible for absorbing heme?

Answer 44

HCP1 | Haem carrier protein 1

Question 45

Does FPN export Fe3+?

Answer 45

NO.

Question 46

HO and DMT1 both feed the ______.

Answer 46

labile iron pool (LIP).

Question 47

What two enzymes respectively provide substrates for DMT1 and HO?

Answer 47

Dcytbf | HCP1

Question 48

What's hephaestin's job?

Answer 48

It oxidises ferrous iron to ferric iron.

Question 49

Ferrous iron spontaneously oxidises after FPN export. T or F?

Answer 49

FALSE | It's oxidised by hephaestin.

Question 50

What other REALLY IMPORTANT cell expresses FPN?

Answer 50

RES macrophages - therefore hepcidin also regulates liberation of RES-stored iron from storage into circulation.

Question 51

Where do RES macrophages get their iron?

Answer 51

They scavenge dead RBCs.

Question 52

Is hepcidin a hormone?

Answer 52

No. | Hormones signal

Question 53

What event in hepatocytes involves TfR2 (aot TfR1)

Answer 53

HFE binding to TfR2 initiates the BMP/SMAD signalling cascade that increases HFE expression.

Question 54

What are two other things that increase hepcidin expression?

Answer 54

Hypoxia (low O2) | IL-6 (inflammation)

Question 55

Where in the picture is haemojuvulin (Hjv) important?

Answer 55

It's associated with TfR2 and required for BMP/SMAD signalling. It lets BMPII&I phosphorylate SMAD1/5/8.

Question 56

Write the big complex of five major components involved in hepcidin upregulation via BMP/SMAD initiation.

Answer 56

HFE/TfR2/HJV/BMPR/BMPligand bonus: phosphorylates SMAD1/5/8

Question 57

Name the four regulatory pathways for hepcidin expression (think of things Fe load relates to)

Answer 57

Iron status Erythropoiesis Inflammation Oxygen tension

Question 58

The hypoxia aspec, the bone-morphogenetic aspect and the iron-status aspect all act through the _____ pathway.

Answer 58

BMP/SMAD

Question 59

Decreased oxygen tension leads to _______ hepcidin expression.

Answer 59

decreased hepcidin expression

Question 60

How does decreased oxygen tension increase iron intake?

Answer 60

Matriptase2 expressed Matriptase2 cleaves HJV from the cell surface. HJV is a BMPr coreceptor. No BMP/SMAD pathway.

Question 61

What three proteins do you think of when you think of hypoxia?

Answer 61

HIF (hypoxia induced factor) Furin Matriptase 2

Question 62

IMPORTANT: what's the hepcidin gene called?

Answer 62

HAMP.

Question 63

What pathway does inflammation (IL-6) act down?

Answer 63

JAK-STAT.

Question 64

Inflammation acts on the ___ pathway; the rest act on the ___ pathway.

Answer 64

IL-6; JAK-STAT | Else: BMP/SMAD

Question 65

The abbreviation for matriptase 2 is ...

Answer 65

... TMPRSS6

Question 66

Matriptase 2 ______ HJV, while furin does what?

Answer 66

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.

Question 67

What's the actual name of the BMPR ligand?

Answer 67

BMP-6.

Question 68

EXAM: R-SMAD-(P) binds to ....

Answer 68

SMAD4.

Question 69

Think hepcidin; think which STAT protein?

Answer 69

STAT6.

Question 70

The BMPr is a ...

Answer 70

heterodimer made of BMPRI and II.

Question 71

IRPs are bound/unbound to Fe in order to active?

Answer 71

UNBOUND. Fe-IRPs CAN'T bind to IREs.

Question 72

Think translational regulation; think...

Answer 72

IRPs.

Question 73

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.

Answer 73

Erythroferrone.

Question 74

C282Y is a ______ mutation It is an 835 ___ mutation. Gary hates this mutation.

Answer 74

MISSENSE | G845A

Question 75

H63D is way more ______ but way less ______ than C282Y.

Answer 75

Prevalence: H63D Penetrance: C282Y

Question 76

Who's more likely to get HH - a C282Y/H63D heterozygote or a H63D homozygote?

Answer 76

heterozygote.

Question 77

What's TIBC?

Answer 77

Total iron binding capacity (transferrin saturation)

Question 78

Just cos you should know - what are the liver enzymes in routine blood tests?

Answer 78

AST, ALT

Question 79

3 things in blood tests for diagnosis.

Answer 79

TIBC (transferrin saturation) ferritin level liver function test

Question 80

What's the only confirmatory test?

Answer 80

Liver biopsy - looking for iron deposition.

Question 81

What are the 5 treatments mentioned in the lecture?

Answer 81

Phlebotomy Iron chelators Proton pump inhibitors (decreases apical absorption). Erythrocytaphoresis Hepcidin agonists

Question 82

What's that newfangled RBC removal therapy called?

Answer 82

Erythrocytaphoresis

Question 83

What are the two newfangled treatments?

Answer 83

Hepcidin agonists | Erythracytaphoresis