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3A week 3 - the liver > metabolic liver disease > Flashcards

metabolic liver disease Flashcards

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1
Q

what 2 conditions are encompased withing NAFLD

A
  1. non alcoholic fatty liver (75%)
  2. non alcoholic steaoto-hepatitis (25%)
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2
Q

other causes of liver steatosis (not NAFLD - 6)

A
  1. hep C
  2. alcohol excess
  3. genetic disorders
  4. medications
  5. hypothyroidism
  6. metabolic dysfunction
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3
Q

what is the principle cause of NAFL

A

matabolic associated dysfunction i.e. insulin resistance -> liver and adipose insulin resistance

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4
Q

how does metabolic associated dysfunction result in NAFL

A

too many calories intake -> increased visceral fat -> insulin resistance -> fat spills into portal circulation -> taken up by liver cells

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5
Q

what tests can be done to look for metabolic associated dysfunction

A

surrogates of insulin resistance
1. BM1 (>25)
2. waist size (>94 for M >80 for F)
3. OGGT (>7.8mmol/L) or Hba1c (>32mmol/L)
4. BP (130/85)
5. plasma triglycerides (>1.70)
6. HDL (<1.0 or on statins)

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6
Q

what are key histological features seen in NASH (4)

A
  1. steatosis (build up of fat)
  2. ballooning (hallmark of liver cell injury)
  3. inflammation
  4. fibrosis
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7
Q

at what stage does bridging occur in NAFLD

A

stage 3

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8
Q

what are the fibrosis stages of NALFD

A

0 - no fibrosis
1a - mild perisinusoidal
1b - moderate perisinusoidal
1c - portal-periportal fibrosis
2 - perisinusoidal and portal fibrosis
3 - bridging fibrosis
4 - cirrhosis

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9
Q

what cancer are ppl w NALFD at a higher risk of

A

hepatocellular carcinoma (HCC)

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10
Q

what happens to the AST:ALT ratio with increased scarring

A

the ratio increases

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11
Q

ferrous vs ferric

A

ferrous is iron (II) compounds;
ferric is iron (III) compounds

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12
Q

what is haemachromatosis

A

a common autosomal recessive condition with a mutation in the iron sensititvity proteins leading to accumulation in the tissue

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13
Q

role of hepcidin

A

decreases the level of iron by reducing dietary absorption and inhibiting iron release from cellular storage

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14
Q

what are the 2 mutations commonly seen in haemachromatosis !

A
  1. cystine 282 tyrosine
  2. H63D
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15
Q

what are the mutation combinations seen in haemachromatosis

A

must have 2 mutated alleles, either:
1. homozygous cys282tyrosine
2. compound heterozygous (1 cys282tyrosine and 1 H63D)

nb H63D homozygous will not result in hameochromatosis!

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16
Q

what gene is affected in haemachormatosis

A

HFE -> this is found in the HLA region

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17
Q

what is ferroportin

A

a transmembrane protein that transports iron from the inside of a cell to the outside of the cell -> liver determines the amount released (via hepcidin signalling)

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18
Q

what forms does iron exist in in the body (6)

A
  1. Hb
  2. myoglobin
  3. enzymes (Fe/S clusters)
  4. haem containing cytochromes
  5. stored as ferratin/haemosiderin
  6. plasma transferrin bound iron
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19
Q

3 ways to lose iron

A
  1. menstruation
  2. intestinal shedding into bowel
  3. skin shedding

i.e. it is hard to lose iron, so absorption must be regulated

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20
Q

what enzyme is responsible for the reduction of Fe3+ to Fe2+ in the body

A

duodenal cytochrome b (a ferrireducatase)

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21
Q

what vitamin is essential for the functioning of ferrireducatse enzymes

A

vit C -> the enzyme os dependent on vit C so the presence of vit C enhances absorption

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22
Q

how does Fe3+ enter enterocytes from the gut lumen

A

Fe3+ –(dcytB8)–> Fe2+ –(DMT1)–> enters enterocyte

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23
Q

how does Fe2+ enter the blood from the enterocyte

Study These Flashcards
A

fe2+ –(ferroportin)–> blood –(hephastin)–> Fe3+ -> binds to transferrin

24
Q

what is the transporter responsible for transporting organic iron (e.g. in heme) into the enterocyte

25
what does a saturated transferrin % indicate
iron overload
26
iron overload criteria
1. Serum ferritin raised (>300 ng/ml in males and >150 -200 ng/ml in menstruating females) 2. transferrin saturation
27
what aretransferrins
iron binding blood plasma glycoprotein that control the level of free iron in biological fluids
28
what is the cellular storage protein for iron
ferratin
29
what does raised ferratin indicate
inflammation - it is an APP or iron overload
30
why does ferratin increase in inflammation
the response to inflammation is to save the iron in stores so that it is less available to microbes
31
what is the iron response element (IRE)
a short conserved stm-loop which is bound by iron response proteins -> regulates gene expression of ferratin in low iron concentration, it binds to IRPs and reduced translation of proteins required for ferratin
32
what is hypotransferrinemia
a very rare inherited and life-threatening disorder characterized by low transferrin levels, systemic iron overload and anemia
33
how do iron stores affect hepcidin expression
low iron stores - hepcidin expression reduced high iron stores -hepcidin expression increased
34
what is the target of hepcidin
ferroportin -> inhibits ferroportin expression
35
function of ferroportin
transport of Fe from cells to blood
36
how does iron overload cause damage
iron enters tissues -> free iron caauses oxidative stress, tissue injury and cellular apoptosis -> wound healing response -> fibrosis
37
consequences of iron overload (6 organs + its effect on them)
1. pituitary gland - impaired growth, infertility 2. thyroid gland - hypo(para?)thyroidism 3. heart - dilated cardiomyopathy, cardiac failure 4. liver - hepatic cirrhosis, increased risk of liver cancer 5. pancreas - T1DM (beta cells damaged) 6. gomads - hypogonadism
38
what does the HFE mutation result in (haemachromatosis)
increased duodenal absoprtion of iron leading to iron overload
39
what chromosome is the HFE gene located on
chromasome 6
40
what are the 3 phases of haemachromotosis T1
1. latency 2. biochemical expression - increase of iron parameter levels 3. clinical expression - clinical picture w fatigue, arthritis (build up of iron in 2nd/3rd MCPs), hepatomegaly, skin pigmentation
41
what is wilson's disease
an autosomal recessive mutation in the gene involved in making a copper transport enzyme leading to accumulation of copper in the liver and brain
42
what gene is mutated in wilsons
ATP7B on chromosome 13
43
where does copper removal normally happen in the body
via the liver -> removed in bile
44
what is ceruloplasmin
a protein made by the liver that stores and carries the mineral copper around your body Cu + aceruloplasmia = ceruloplasmin
45
what will the copper levels of someone with wilson's look like on a blood test !!
low -> this is because there is a lack of ceruloplasmin which means that Cu is not bound to anything, free Cu levels are high but this cannot be measured alone
46
what can Cu build up in the brain lead to
early parkinsonian tremor
47
what can Cu build up present as in the eyes
Kayser-Fleischer Rings
48
wilson's disease mgx
give them Cu chelating agents e.g. Penicillamine link (Cupramine, Depen) and trientine (Syprine) these allow copper to be extracted from the blood
49
what is a common cause of paediatric liver disease
alpha-one-antitrypsin
50
what is the inheritance pattern of alpha-one-antitrypsin
autosomal co-dominant
51
what are the 3 allele variations seen in alpha-one-antitrypsin
1. Wild type 2. null allelle (homozygous mutated, no protein produced) 3. suboptimal (less protein produced)
52
what does a heterozygous alpha-one-antitrypsin mutation lead to (liver)
accelarated NAFLD with faster cirrhosis risk
53
what type of molecule is alpha-one-antitrypsin
serpins - molecules that inhibit other enzymes
54
why does alpha-one-antitrypsin deficency result in early emphysema
alpha-one-antitrypsin stop the action of neutrophils releasing elastease in the lungs which would detroy the elastin in the alveloi walls (i.e. stops the destruction of the alveoli)
55
how else can alpha-one-antitrypsin be inhibted
smoking -> leads to emphysema
56
what is a potential treatment for alpha-one-antitrypsin deficency
targeting mRNA
57
how can alpha-one-antitrypsin polymerisation cause damage
polymerisation means the molecules are too big to leave the hepatocytes -> cell apoptosis due to build up -> inflammation -> scarring -> cirrhosis

3A week 3 - the liver (9 decks)

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