Flashcards in Alcoholic liver disease Deck (25):
Why is alcohol a toxin?
It is an indirect toxin where alcohol is metabolised to acetaldehyde by alcohol dehydrogenase using NAD as a cofactor
However this enzyme is readily saturable driving ethanol metabolism by CYP2E1 which uses NADPH as a cofactor, this enzyme can lead to the generation of the alpha-hydroxyethyl free radical potentially leading to membrane damage and other free radical associated damage
Why do alcoholics have rapid metabolism of alcohol?
They have induction of CYP2E1, which leads to increased alcohol metabolic degradation through this pathway leading to increased formation of the alkpha-hydroxyethyl radical in alcoholics
How does alcohol consumption lead to alteration of a cells biochemistry?
High activity of alcohol dehydrogenase can alter the cells biochemistry due high production of NADH which can be used directly by the mitochondria preventing the need for TCA causing decreased beta oxidation leading to ketosis as well as causing altered conversion of pyruvate to lactic acid leading to acidosis, affecting glucose metabolism leading to hypoglycemia
What are the toxic effects of acetaldehyde?
It is an electrophilic metabolite that depletes glutathione and binds to lysine residues in proteins such as tubulin, actin, calmodulin and collagen
It can also interfere with lipoprotein secretion and microtubule formation causing cytoskeletal damage
It induces lipoprotein damage and increased likelihood of steatosis
What is mallory’s hyaline?
An inclusion body made of damaged, ubiquitinated protein often seen in alcoholic liver disease
Why are some people more at risk of acetaldehyde toxicity?
There are also genetic variants in the alcohol dehydrogenase enzyme which converts alcohol to acetaldehyde with high and low activity variants as well as in the acetaldehyde dehydrogenase enzyme which detoxifies acetaldehyde with low activity variants
This means that some people may have combinations where there is a rapid activity alcohol dehydrogenase enzyme and a low activity acetaldehyde dehydrogenase enzyme leading to high levels of acetaldehyde
What are the effects of excess blood acetaldehyde?
Facial flushing, Tachycardia, reduced blood pressure, headache, nausea and vomiting
What is one of the earliest signs of cellular toxicity?
Steatosis which is observed following even a non-intoxicating dose of alcohol
However this is rapidly reversible and does not appear to be clinically significant
What zone of the liver lobule is most affected by alcohol toxicity?
Zone 3 as this is where the highest level of CYP2E1 and Alcohol dehydrogenase is expressed
What are the ultra structural changes that will be observed in zone 3 of the liver with steatosis?
Abnormal inclusions such as fat droplets, proliferation of endoplasmic reticulum leading to glassy cytoplasm due to CYP induction
Giant mitochondria due to dysfunctional TCA cycle and beta-oxidation
What is steatohepatisis?
This may occur after continued insult with ethanol and the combination of release of reactive oxygen and nitrogen species from inflammatory cells
This is an intermediate stage between benign fatty liver disease and hepatisis as it does not revert back to normal physiology
What may bethe rate limiting step to cirrhosis?
The risk of fibrosis
How does chronic alcohol damage lead to steatohepatitis?
Chronic alcohol use can cause necrotic damage to hepatocytes leading to an inflammatory response from neutorphils and kupffer cells which release TNFalpha, NO and superoxide which directly damage stellate cells
What are the distinguishing features of steatohepatisis?
Hepatocyte necrosis and neutrophil infiltration
Enlarged hepatocytes with ballooning degeneration that can lead to prtal hypertension
Mallory’s hyaline deposition due to microtubule damage
Damage to stellate cells
What are stellate cells?
Cells which sort fat and vitamin A located in the space of disse, they control the size of the fenestrations into the sinusoids acting as part of the liver sieve
If damaged they undergo metaplasia to myofibroblasts which produce large amounts of collagen leading to loss of fenestrations and limited access to plasma sourced nutrients and blood as a waste exit mechanism
What is the irreversible damage caused to the liver?
If there is continued damage to hepatocytes this tissue may become replaced with fibrotic material
This more commonly occurs in zone 3 due to the metabolic gradient of the liver lobule
This leads to vasculature changes in the liver with destruction of sinusoidal blood flow increasing portal hypertension and leading to occlusion of the central vein
What occurs with lymphocyte infiltration of the central vein wall?
Perivenular fibrosis and obliteration of the lumen as well as obliteration of the lumen and fibrointimal hyperplasia and occlusion of the lumen
What is typical of cirrhosis?
Conitnues cycles of necrosis, fibrosis and regeneration leading to large areas of fibrosis devoid of hepatocytes causing the typical cirrhotic nodules
What is the result of abstinence from alcohol?
Proliferation of hepatocytes in the nodule and micronodular cirrhosis can become macronodular, this hyperplasia can lead to regeneration of functioning liver lobule as liver stem cells form heaptocytes and sinusoidal cells however it often an embryonic phenotype of two cells thick rather than just 1 cell thick
What is the link between alcohol and cancer?
Ethanol can act as tumour promoter possibly though ROS effects on the genome or increasing the metabolism of procarcinogens by CYP2E1
The vitamin A deficiency also promotes neoplasia
Hepatocellular carcinoma occurs in 5-10% of patients with alcoholic cirrhosis observed as haptocytes that are 3 plates thick and have local invasion
What are some of the manifestations of a damaged liver?
Spider angiomas, testicular atrophy and gynecomastia, loss of pubic hair due to estrogen excess, fibrosis and erythema of the palms, jaundice, Caput medusa due to portal hypertension, fetor hepaticus, asterixis, encephalopathy
Why does portal hypertension occur in liver disease?
A rise in vascular resistence due to a rise in blood pressure in the sinusoids leading to gastro esophageal varices and umbilical caput medusa
Why does ascites occur?
Increased exudate of fluid from the portal vein into the abdominal cavity
Why does coagulopathy occur in liver failure?
Loss of protein synthesis leads to hypoalbminaemia and coagulopathy causing an increased bleeding tendency