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

metabolic liver disease Flashcards

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

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

A

HCP1

25
Q

what does a saturated transferrin % indicate

A

iron overload

26
Q

iron overload criteria

A
  1. Serum ferritin raised (>300 ng/ml in males and >150 -200 ng/ml in menstruating females)
  2. transferrin saturation
27
Q

what aretransferrins

A

iron binding blood plasma glycoprotein that control the level of free iron in biological fluids

28
Q

what is the cellular storage protein for iron

A

ferratin

29
Q

what does raised ferratin indicate

A

inflammation - it is an APP
or iron overload

30
Q

why does ferratin increase in inflammation

A

the response to inflammation is to save the iron in stores so that it is less available to microbes

31
Q

what is the iron response element (IRE)

A

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
Q

what is hypotransferrinemia

A

a very rare inherited and life-threatening disorder characterized by low transferrin levels, systemic iron overload and anemia

33
Q

how do iron stores affect hepcidin expression

A

low iron stores - hepcidin expression reduced
high iron stores -hepcidin expression increased

34
Q

what is the target of hepcidin

A

ferroportin -> inhibits ferroportin expression

35
Q

function of ferroportin

A

transport of Fe from cells to blood

36
Q

how does iron overload cause damage

A

iron enters tissues -> free iron caauses oxidative stress, tissue injury and cellular apoptosis -> wound healing response -> fibrosis

37
Q

consequences of iron overload (6 organs + its effect on them)

A
  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
Q

what does the HFE mutation result in (haemachromatosis)

A

increased duodenal absoprtion of iron leading to iron overload

39
Q

what chromosome is the HFE gene located on

A

chromasome 6

40
Q

what are the 3 phases of haemachromotosis T1

A
  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
Q

what is wilson’s disease

A

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
Q

what gene is mutated in wilsons

A

ATP7B on chromosome 13

43
Q

where does copper removal normally happen in the body

A

via the liver -> removed in bile

44
Q

what is ceruloplasmin

A

a protein made by the liver that stores and carries the mineral copper around your body

Cu + aceruloplasmia = ceruloplasmin

45
Q

what will the copper levels of someone with wilson’s look like on a blood test !!

A

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
Q

what can Cu build up in the brain lead to

A

early parkinsonian tremor

47
Q

what can Cu build up present as in the eyes

A

Kayser-Fleischer Rings

48
Q

wilson’s disease mgx

A

give them Cu chelating agents e.g. Penicillamine link (Cupramine, Depen) and trientine (Syprine)

these allow copper to be extracted from the blood

49
Q

what is a common cause of paediatric liver disease

A

alpha-one-antitrypsin

50
Q

what is the inheritance pattern of alpha-one-antitrypsin

A

autosomal co-dominant

51
Q

what are the 3 allele variations seen in alpha-one-antitrypsin

A
  1. Wild type
  2. null allelle (homozygous mutated, no protein produced)
  3. suboptimal (less protein produced)
52
Q

what does a heterozygous alpha-one-antitrypsin mutation lead to (liver)

A

accelarated NAFLD with faster cirrhosis risk

53
Q

what type of molecule is alpha-one-antitrypsin

A

serpins - molecules that inhibit other enzymes

54
Q

why does alpha-one-antitrypsin deficency result in early emphysema

A

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
Q

how else can alpha-one-antitrypsin be inhibted

A

smoking -> leads to emphysema

56
Q

what is a potential treatment for alpha-one-antitrypsin deficency

A

targeting mRNA

57
Q

how can alpha-one-antitrypsin polymerisation cause damage

A

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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