Metabolic liver diseases Flashcards
1
Q
Features common to wilson’s disease and hereditary hemochromatosis
A
- Both are due to metal overload (Cu and Fe)
- Tissue injury secondary to ROS generation from the metals
- Require life-long Rx
- Genetic testing for carriers before Sxs begin
2
Q
Fe absorption and metabolism 1
A
- Fe is highly insoluble, is absorbed at proximal duodenum
- No excretory pathway: lost in sweat and desquamation of epithelial cells
- Fe exists in ferrous (Fe3+) form outside the cell, and ferric form (Fe2+) inside the cell
- Fe3+ in gut lumen converted to Fe2+ by DCYTB
- Fe2+ absorbed by enterocyte by DMT1 and bound by ferritin w/in the cell (storage form)
3
Q
Fe absorption and metabolism 2
A
- Fe crosses the basolateral membrane by ferroportin and is oxidized to ferrous Fe3+ outside the cell to be picked up by transferrin (Tf) for blood travel
- Tf brings the Fe to the liver, and binds to its receptor (TfFR-2), then the complex is internalized
- Fe is removed from Tf and sent to ferritin for storage
- The liver senses Fe levels based on TfFR
4
Q
Hepcidin 1
A
- Is the negative regulator of Fe uptake in enterocytes and macs
- Hepcidin is synthesized in liver and is released when Fe levels are high
- Hepcidin expression is reduced when Fe levels are low
- It inhibits Fe uptake into body by binding to ferroportin on enterocyte and causing it to degrade
- This prevents Fe movement across the basolateral membrane of enterocytes
5
Q
Hepcidin 2
A
- Hepcidin expression increased by Fe overload and inflammation
- Hepcidin expression is reduced when Fe is needed: Fe def, hypoxia, increased erythropoiesis
- Expression of hepcidin regulated (increased) by: hemojuvelin, inflammation, HFE-TfFR
- HFE mutations are most common form of hereditary hemochromatosis
6
Q
Hereditary hemochromatosis (HH) type I 1
A
- Due to mutations in HFE (autosomal recessive) that prevent it from binding to TfR (C282Y substitution)
- HFE-TfR complex formation is required for increasing Hepcidin transcription
- When HFE and TfR do not form a complex there is no increase in hepcidin transcription as Fe levels rise
- This means Fe absorption will continue even when there is Fe overload (inappropriately low hepcidin expression for Fe level)
7
Q
Hereditary hemochromatosis (HH) type I 2
A
- Clinical manifestations of HH: around 3-4th decade can see fatigue, osteoarthritis (primarily MCPs), mild elevation of AST/ALT, hyperpigmentation
- 4-5th decade can see diabetes, cirrhosis, cardiomyopathy, hypogonadism, chondrocalcinosis (pseudogout)
- Can develop into HCC around 5-6th decade or later
8
Q
Dx of HH type I
A
- Dx via liver biopsy: can quantitate the Fe content, asses fibrosis/liver injury, use hepatic Fe index (>1.9 is diagnostic)
- Non-invasive methods: MRI, CT
- Lab tests: TIBC not very useful, ferritin level (general reflection of total Fe stores) can be used; >1000 is suggestive but not diagnostic
- Low ferritin means they are Fe def, but a high ferritin is not diagnostic for Fe overload, other conditions can elevate ferritin
- Genetic testing: incidence of C282Y mutation greatest in northern european (celtic) and australian descent, but genetic testing is not used for screening, only for Dx
- How to make Dx: clinical and lab suspicion indicate biopsy/imaging, genetic testing if target ethnic group
- Then follow Fe levels after phlebotomy
9
Q
Rx of HH type I
A
- Phlebotomy of 500cc blood every 1-3 mo for life
- Monitor Hb/Hct, Tf sat% (want below 45%), ferritin level (want <50)
- There is improvement of fibrosis and longevity after Rx, but no improvement in cirrhosis or arthropathy
10
Q
Secondary Fe overload
A
- Not related to liver
- Excess Fe: supplements, transfusion
- Chronic hemolytic syndromes
- Sideroblastic anemias (Pb poisoning)
11
Q
Cu homeostasis
A
- Cu is taken up by enterocyte and in blood it binds to albumin to get to liver
- Cu is then taken up by hepatocytes which incorporate it into ceruloplasmin (same function as transferrin- Cu plasma transport protein)
- Ceruloplasmin-Cu complex is released from liver into systemic circulation
- Excess copper is excreted into bile
- Mutations in Cu transporters in enterocyte/hepatocyte can lead to Cu def/overload, respectively
- Mutations of ATP7A transport (menace’s disease) protein in enterocyte prevents Cu from exiting the enterocyte into ISF, thus Cu cannot get to the blood and results in Cu def
- Mutations in ATP7B transport protein (wilson’s disease) in hepatocyte prevent Cu from exiting the hepatocyte into bile or golgi (and thus blood w/ CP), thus Cu builds up in hepatocytes leading to Cu overload
12
Q
Wilson’s disease
A
- Autosomal recessive mutation of ATP7B
- But unlike HH there is no single mutation responsible, can be a number of mutations
- ATP7B is responsible for excreting Cu into bile, for moving it into golgi so it can be bound by ceruloplasmin and released into circulation
- Inability to do both of these leads to buildup of Cu in hepatocytes
13
Q
Clinical presentation of WD
A
- Chronic or acute hepatitis (usually low alk phos, mild increase in AST/ALT), fulminant hepatic failure
- Renal injury: nephrocalcinosis, uricosuria, hypercalcuria, nephrolithiasis
- Neuropsych Sx: rare before puberty (trouble in school), most present after 20 yrs
- Earliest neuro Sx are difficulty speaking, drooling, clumsiness of hands, change in personality
- Eventually get tremor, dysarthria/dysphagia, other psych d/o (depression)
- Hemolytic anemia: may be associated w/ fulminant hepatic failure
14
Q
Diagnosis of WD 1
A
- Ceruloplasmin: serum levels should be low, but can be elevated up to low-nl levels due to liver injury, inflammation, estrogen
- CP levels are low b/c the liver still releases CP even though there isn’t any Cu bound to it
- In this form CP is unstable, is broken down and excreted by kidneys
- CP levels may also be falsely low, which is seen in nephrotic syndrome, PLE, etc
15
Q
Diagnosis of WD 2
A
- Kayser-fleischer (KF) ring (not diagnostic for WD, also seen in chronic cholestatic d/os), sunflower cataracts
- Calcification of basal ganglia
- 24hr urinary Cu >100 if symptomatic (>1000 if fulminant), nl/ASx is <40
- 24 urinary Cu also elevated in cholestasis, acute liver injury
- Liver biopsy: histopath, stains, Cu measurement
- Must identify carriers (screen ASx family members)
- CRITERIA for Dx (2 out of 3): KF ring, low ceruloplasmin, increased hepatic Cu
