L9: Toxins - Liver Flashcards
Alcoholic liver disease
Direct result of CHRONIC alcohol abuse. The end result of the disease is cirrhosis which culminates in a dysfunctional and diffusely scarred liver
Types of alcoholic liver disease
- Fatty liver
- Alcoholic hepatitis
- Cirrhosis
Acute effects of alcohol in the CNS
Powerful depressant, inhibitory control centres depressed (excitatory pathways released) in the cortex first then the limbic system (emotions), followed by cerebellum (motor control) and lower brain stem (BP/breathing)
Acute effects of alcohol in the liver
Fatty liver - rapid response
Accumulation of small (microvesicular) lipid droplets in hepatocytes
Reversible
Acute effects of alcohol in the stomach
Acute gastritis - acute, transient mucosal inflammatory process of the lining of the stomach + haemorrhage and/or sloughing of mucosa
Major diseases due to chronic alcohol abuse
Peptic ulcer (stomach)
Abscess (lung)
Tissue remodeling (liver - fatty acid syndrome, cirrhosis, hepatitis)
Cancer (alcohol not a direct carcinogen)
Risk factors for serious liver damage in heavy drinkers
Polymorphisms in EtOH-metabolising genes
Obesity
Exposure to other hepatotoxins (high doses of analgesics e.g. paracetamol, antibiotics e.g. penicillin)
Infection with hepatitis C
Glisson capsule
The protective covering of the liver
Primary cell of the liver and their function
Primary cell - hepatocytes, which are responsible for adjusting secretion and absorption levels of nutrients within the liver and comprise 70-80% of the liver mass
True or false: hepatocytes can participate in regenerating damaged hepatic tissue
True
Blood enters the lobules of the kidney through a) ___ then flows through small channels called b) ___
a) branches of the portal vein and venules (80%) from the intestine carrying digested food materials and hepatic artery (20%) carrying oxygenated blood from the heart
b) sinusoids
The portal vein and venule carry
digested food materials from the intestine
Hepatic artery carries
oxygenated blood to the liver and arteriole
Most of the alcohol metabolism occurs in the
cytoplasm
Mechanism of cytosolic metabolism of ethanol
ADH (alcohol dehydrogenase) converts ethanol to acetyldehyde, one of the most toxic metabolites formed in the body, which is then broken down to acetic acid in the mitochondria.
Microsomes
Membrane-bound vesicle enriched on ER in hepatocytes contains CYP2E1/P450 oxidase enzyme system, secondary breakdown system of ethanol when EtOH is high
Mechanism of alcohol metabolism in peroxisomes
H2O2 is converted to H2O by catalase
Fatty liver - mechanisms of FA metabolism alteration
- Increase in fatty acids from diet to liver cell in cytoplasm
- Increased conversion of acetate to FA
- Increased FA conversion to ketone bodies (subsequent decrease in pH)
- Increased FA conversion to triglycerides (TG)
- Decrease in TGs linked to apoproteins (releasing more free FA)
- Decrease in lipoproteins (more free FA)
Fatty Liver
Reversible condition.
Fat accumulation in cells due to increased FA synthesis, production of triglycerides, decreased mitochondrial oxidation of FA, and impaired release of lipoproteins.
Key morphologic features of alcohol-induced liver diseases
- Steatosis/fatty liver - fatty change, perivenular fibrosis. Rapid onset, and reversible with abstinence. Severe prolonged exposure can lead to …
- Hepatitis - liver cell necroris, inflammation, Mallory bodies, fatty change
- Repeated attacks and continued exposure can lead to cirrhosis - remodeling due to fibrosis and hyperplastic nodules
Pathogenesis and histopathology of alcoholic hepatitis
Visible disruption to sinusoid channels
Infiltration of immune cells e.g. neutrophils
Inflammatory disease cytokines from Kupffer cells (resident macrophages)
Characterised by necrosis of hepatocytes
Cytoplasmic hyaline inclusions (Mallory bodies - intermediate filaments = cytokeratin)
Cirrhosis
Necrosis + inflammation + fibrosis + regeneration = cirrhosis
Irreversible scarring leads to portal hypertension
Define: sinusoids
Gaps between liver cells
Anatomy of liver and blood flow
Blood enters lobules through branches of the portal vein and hepatic artery, then flows through small channels called sinusoids that are lined with primary liver cells (hepatocytes) which remove toxic substances, including alcohol from the blood which then exits the lobule through the central vein/hepatic venule.
Clinical liver function assessment tests include testing for which proteins
Alanine aminotransferase
Aspartate aminotransferase
Alkaline phosphatase
Bilirubin - byproduct of Hb breakdown - jaundice
Albumin - produced in liver and major plasma protein
Total protein
Pathogenesis of cirrhosis
Fatty liver and/or hepatitis usual precursor but not always
Induction of p450 leads to toxic products and O2 radicals
Microtubular and mitochondrial function affected
Through remodeling and formation of hyaline membranes/Mallory bodies new epitopes can be developed which activate immune response leading to repeated cycles of inflammation-regeneration
Hepatic failure occurs when ___ % of hepatic function is lost due to cirrhosis
80-90%
Mechanisms that support a protective effect of coffee in liver
Anti-inflammatory activity - inhibition of NFkB, as well as IL-6, TNF-α, IFN-γ and TGF-β
Detoxification - various compounds in coffee induce endogenous Phase II enzyme system
Portal hypertension
Elevation of BP within the portal venous system. It develops as a result of the resistance to normal blood flow to the liver via the main portal vein. Portal hypertension is the earliest and most important complication of cirrhosis because most of the physical problems associated with cirrhosis are attributable to it. Leads to gastroesophageal varices, found in 65% of patients with advanced cirrhosis. These are fragile vessels which can rupture and lead to acute haemorrhage and death in about half of patients
Hepatic encephalopathy
A brain abnormality caused by the liver’s inability to remove toxins, specifically ammonia, from the blood
Patients can suffer from a wide range of CNS abnormalities that include day-night reversal, mild intellectual impairment, and even coma
Alcohol toxicity & pregnancy
Alcohol is able to cross the placenta-foetal
barrier. Brain develops from the third week
Alcohol use in first trimester ‐ morphologic abnormalities, second trimester ‐ spontaneous abortion, third trimester ‐ poor foetal growth
Protective effects of moderate drinking
blood vessels - decreases atherosclerosis, decreased AMI
blood - inhibits platelet aggregation, decreased thrombosis
gall bladder - decreased risk of gall stones
bone - decreased osteoporosis
Narcosis typically occurs at which concentration of alcohol?
0.1 gm/dl
Coma/fatal respiratory arrest typically occurs at which concentration of alcohol?
0.3-0.4 gm/dl
Liver contains how many lobes?
3
Blood from the liver re-enters circulation via the
hepatic vein
