Above what BMI value is considered obese?
As an individual gains weight, the risk of any of the consequences rises dramatically.
There is a near exponential positive relationship between BMI and diabetes risk. Though this only occurs once our body reaches a certain weight; it seems that we have a threshold and once it is passed our risk factors dramatically increase.
Define non-alcoholic fatty liver disease (NAFLD).
Give alcohol intake values for the disease to be considered caused by factors other than drinking.
Liver disease that has nothing to do with alcohol consumption.
By Definition, a women may not drink more than 20g of alcohol a day (2 units) and a man may not drink more than 30g a day (3 units).
State and define the progressive stages of NAFLD.
The different stages of the condition = Steatosis --> NASH --> Cirrhosis
Steatosis = Fat in the liver
NASH = Fat and inflammation in the liver
Cirrhosis = bad scarring of the liver
Steatosis --> NASH = __1__% of individuals progress.
NASH --> Cirrhosis = __1__% of individuals progress.
Virtually every population that NAFLD has been examined in, between 20%-__1__% of the population have some degree of NAFLD.
Examinations are primarily done by ____2____.
The main predictor of long term NAFLD outcome is not the presentation of the biopsy, but the amount of ______ that is present in the biopsy.
The movement between steatosis and NASH is ______, in that individuals are likely to be moving back and forth between the 2.
State the 2 ways fat content in the liver can increase.
Can import fatty acids into the liver (either from diet or fat stores in adipose tissue).
Can synthesize fatty acids from carbohydrates from the diet.
State the 2 ways to decrese fat content in the liver.
Can esterify the fat into triglycerides and export it as VLDL (cholesterol).
Can burn it within the liver for energy (different types of oxidation).
In diabetics/insulin resistance there is a disconnect between peripheral tissues (muscles and adipose tissues) in that they ignore the ____1____ from the insulin. What happens is that HSL (hormone sensitive lipase) is dis-inhibited causing the flooding of fatty acids into the liver.
But the liver itself remains relatively sensitive to insulin signalling. So as the peripheral insulin resistance causes an influx of FFA’s into the liver, the ____2____ insulin and glucose levels in the blood are driving further ____3____ of fatty acids. = perfect storm of more fatty acids flowing to the liver and more fatty acids being made in the liver.
The liver tries to deal with the fatty acids and it starts to partition them towards ____4____. This is the fat we see when we look down the microscope.
It has been suggested that it is a simple 2-headed hypothesis for NAFLD.
- Fat build-up in the liver
- Inflammation and scarring in the liver
It would therefore be tempting to think that if we could inhibit this transfer of fatty acids to triglycerides, we would stop the fat accumulation and cure NAFLD.
But scientists have tried this: They used a diet called the MCD diet, to induce fat accumulation in the liver. They then used ____1____ (so RNA silencing) to inhibit the enzyme DGAT2 (the key enzyme in the fatty acid esterification step). What they found was that by doing this they reduced the fat levels in the liver but they saw that the serum ALT levels (which are a ____2____ for liver damage, and are 20-30 in a healthy individual) shot up to 1800 in the mice. Also they saw lots of lipid oxidation so in other words, ______ 3 ______ damage to the liver cells. They saw this damage again when they measure TBars (another marker for oxidative stress in the liver).
So what has happened?
Well if you inhibit the synthesis of triglycerides, the fatty acids are pushed towards fatty acid oxidation. And it is this oxidation that releases lots of the chemicals that actually damage the cells. This ______ 3 ______ combined with lipotoxicity, ER stress, neutrophil recruitment, necrosis and apoptosis drives the formation of ____4____ in the liver.
3. Oxidative stress
Fatty liver disease is also a marker of an increased chance of ____1____ and ____2____.
In fact more people with NAFLD will die of ____1____ and a ____2____ than liver failure or liver cancer.
NAFLD is a marker for the increased risk of HCC, which is what?
Hepatocarcinoma (liver cancer)
List the 3 gene alleles linked to increased NAFLD risk by GWAS studies.
The standard medical blood tests we can do are not particularly good at determining how bad the fatty liver disease is.
I.e. the ALT values (which the doctor will check) will be the same regardless if you have a slightly fatty liver or ______ (and everything in between).
Doctors can however look at the ratio of 2 blood markers, ALT & AST, to determine disease state.
Sufferers of fatty liver disease start with a high ALT and a lower AST. As the disease progresses toward ______ this ratio reverses. So this change in ratio can be used to track disease state and progression.
Which blood tests can be used to diagnose NASH?
All tests are too variable so none are in widespread clinical use.
The NAFLD Fibrosis score is used worldwide. What does its value tell us?
Not only does it tell you how scarred the liver is right now, it is also useful to predict whether individuals are going to die of liver disease or not.
What is the single best treatment for NAFLD?
Weight loss (diet and exercise).
Describe a liver biopsy.
A liver biopsy is a procedure in which a small needle is inserted into theliver to collect a tissue sample. The tissue is then analyzed in a laboratory to help doctors diagnose a variety of disorders and diseases in the liver.
Rank in order of prognostic value for NAFLD, from high to low:
- Portal inflammation
- Portal inflammation
What is the most commonly used technique for imaging a fatty liver?
What is the primary limitation using imaging techniques for diagnosis and prognosis of NAFLD and ALD?
Imaging can not diﬀerentiate between steatosis and steatohepatitis or identify ﬁbrosis in the absence of advanced cirrhosis.
Imaging based modalities can help us look at the liver but they are not particularly sensitive for viewing ____1____, with exception of the FibroScan.
The FibroScan measures the stiffness of the liver. The idea being that the stiffer the liver, the more ____2____ it is.
What is Metformins effect on steatosis, inflammation or fibrosis?
It has no effect.
Taking metformin reduces the risk of ______ cancer.
Data suggests that Glitazones may be beneficial for reducing ____1____, inflammation and possibly fibrosis within the liver.
The reason Glitazones only ‘possibly’ reduce fibrosis in the liver is because in the PIVENS trial Pioglitazone failed to reach its defined ____2____ therefore it was concluded to not work against fibrosis.
PIVENS trial suggests Vitamin __3__ is better at reducing liver fibrosis, so for e.g. in the U.S. it is prescribed at 800 IU (international units) per day (amount the PIVENS trial suggests). But this is ignoring other data that demonstrated that at 400 IU the risk of death by other causes is increased.
Name a promising drug for the future of NAFLD treatment.