metabolic liver disease Flashcards
what 2 conditions are encompased withing NAFLD
- non alcoholic fatty liver (75%)
- non alcoholic steaoto-hepatitis (25%)
other causes of liver steatosis (not NAFLD - 6)
- hep C
- alcohol excess
- genetic disorders
- medications
- hypothyroidism
- metabolic dysfunction
what is the principle cause of NAFL
matabolic associated dysfunction i.e. insulin resistance -> liver and adipose insulin resistance
how does metabolic associated dysfunction result in NAFL
too many calories intake -> increased visceral fat -> insulin resistance -> fat spills into portal circulation -> taken up by liver cells
what tests can be done to look for metabolic associated dysfunction
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)
what are key histological features seen in NASH (4)
- steatosis (build up of fat)
- ballooning (hallmark of liver cell injury)
- inflammation
- fibrosis
at what stage does bridging occur in NAFLD
stage 3
what are the fibrosis stages of NALFD
0 - no fibrosis
1a - mild perisinusoidal
1b - moderate perisinusoidal
1c - portal-periportal fibrosis
2 - perisinusoidal and portal fibrosis
3 - bridging fibrosis
4 - cirrhosis
what cancer are ppl w NALFD at a higher risk of
hepatocellular carcinoma (HCC)
what happens to the AST:ALT ratio with increased scarring
the ratio increases
ferrous vs ferric
ferrous is iron (II) compounds;
ferric is iron (III) compounds
what is haemachromatosis
a common autosomal recessive condition with a mutation in the iron sensititvity proteins leading to accumulation in the tissue
role of hepcidin
decreases the level of iron by reducing dietary absorption and inhibiting iron release from cellular storage
what are the 2 mutations commonly seen in haemachromatosis !
- cystine 282 tyrosine
- H63D
what are the mutation combinations seen in haemachromatosis
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!
what gene is affected in haemachormatosis
HFE -> this is found in the HLA region
what is ferroportin
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)
what forms does iron exist in in the body (6)
- Hb
- myoglobin
- enzymes (Fe/S clusters)
- haem containing cytochromes
- stored as ferratin/haemosiderin
- plasma transferrin bound iron
3 ways to lose iron
- menstruation
- intestinal shedding into bowel
- skin shedding
i.e. it is hard to lose iron, so absorption must be regulated
what enzyme is responsible for the reduction of Fe3+ to Fe2+ in the body
duodenal cytochrome b (a ferrireducatase)
what vitamin is essential for the functioning of ferrireducatse enzymes
vit C -> the enzyme os dependent on vit C so the presence of vit C enhances absorption
how does Fe3+ enter enterocytes from the gut lumen
Fe3+ –(dcytB8)–> Fe2+ –(DMT1)–> enters enterocyte
how does Fe2+ enter the blood from the enterocyte
fe2+ –(ferroportin)–> blood –(hephastin)–> Fe3+ -> binds to transferrin
what is the transporter responsible for transporting organic iron (e.g. in heme) into the enterocyte
HCP1
what does a saturated transferrin % indicate
iron overload
iron overload criteria
- Serum ferritin raised (>300 ng/ml in males and >150 -200 ng/ml in menstruating females)
- transferrin saturation
what aretransferrins
iron binding blood plasma glycoprotein that control the level of free iron in biological fluids
what is the cellular storage protein for iron
ferratin
what does raised ferratin indicate
inflammation - it is an APP
or iron overload
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
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
what is hypotransferrinemia
a very rare inherited and life-threatening disorder characterized by low transferrin levels, systemic iron overload and anemia
how do iron stores affect hepcidin expression
low iron stores - hepcidin expression reduced
high iron stores -hepcidin expression increased
what is the target of hepcidin
ferroportin -> inhibits ferroportin expression
function of ferroportin
transport of Fe from cells to blood
how does iron overload cause damage
iron enters tissues -> free iron caauses oxidative stress, tissue injury and cellular apoptosis -> wound healing response -> fibrosis
consequences of iron overload (6 organs + its effect on them)
- pituitary gland - impaired growth, infertility
- thyroid gland - hypo(para?)thyroidism
- heart - dilated cardiomyopathy, cardiac failure
- liver - hepatic cirrhosis, increased risk of liver cancer
- pancreas - T1DM (beta cells damaged)
- gomads - hypogonadism
what does the HFE mutation result in (haemachromatosis)
increased duodenal absoprtion of iron leading to iron overload
what chromosome is the HFE gene located on
chromasome 6
what are the 3 phases of haemachromotosis T1
- latency
- biochemical expression - increase of iron parameter levels
- clinical expression - clinical picture w fatigue, arthritis (build up of iron in 2nd/3rd MCPs), hepatomegaly, skin pigmentation
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
what gene is mutated in wilsons
ATP7B on chromosome 13
where does copper removal normally happen in the body
via the liver -> removed in bile
what is ceruloplasmin
a protein made by the liver that stores and carries the mineral copper around your body
Cu + aceruloplasmia = ceruloplasmin
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
what can Cu build up in the brain lead to
early parkinsonian tremor
what can Cu build up present as in the eyes
Kayser-Fleischer Rings
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
what is a common cause of paediatric liver disease
alpha-one-antitrypsin
what is the inheritance pattern of alpha-one-antitrypsin
autosomal co-dominant
what are the 3 allele variations seen in alpha-one-antitrypsin
- Wild type
- null allelle (homozygous mutated, no protein produced)
- suboptimal (less protein produced)
what does a heterozygous alpha-one-antitrypsin mutation lead to (liver)
accelarated NAFLD with faster cirrhosis risk
what type of molecule is alpha-one-antitrypsin
serpins - molecules that inhibit other enzymes
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)
how else can alpha-one-antitrypsin be inhibted
smoking -> leads to emphysema
what is a potential treatment for alpha-one-antitrypsin deficency
targeting mRNA
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
