Intestinal and liver inflammatory diseases Flashcards
What are the main functions of the liver? (3)
- Synthesis
- Detoxification
- Metabolism
Explain the process of detoxification in the liver (2)
- Oxygen-rich blood from the hepatic artery and food- and bacteria-rich blood from the portal vein enter the liver
- Substances from the blood (such as drugs and endoxenous and exogenous toxins) and bacteria from the intestines are broken down
What does the liver store?
Hepatocytes store glycogen, fat-soluble vitamins (A, D, E and K), and minorals (copper and iron) that are taken up from the blood.
What does the liver synthesize?
Bile, amino acids, acute phase proteins and other plasma proteins
What does the liver metabolize?
Medications to lower toxicity and glucose (gluconeogenesis) from glycogen
Explain the structure of the basic liver components (or draw it).
The liver is organized into hepatic lobules, each with a central vein and surrounded by portal triads (hepatic artery, portal vein, bile duct). Hepatocytes form plates radiating from the central vein, with sinusoids (capillary-like spaces) in between. Sinusoids are lined by endothelial cells, Kupffer cells (macrophages), and stellate cells (store vitamin A). The Space of Disse lies between hepatocytes and sinusoids for nutrient exchange. Bile flows from bile canaliculi (between hepatocytes) to bile ducts in the portal triads.
What is the acute phase response, and what is the role of the liver?
The production of proteins involved in the initial systemic innate response to pathogens, inflammation and damage.
During this phase, the liver produces acute phase proteins such as C-reactive protein, fibrin, and complement proteins.
Why is it important to have a tight balance between liver tolerance and liver immunity?
There needs to be a response to pathogens in the blood, but there is also a lot of food and bacteria present from the intestines to which the liver should not react.
What are 3 liver-resident cells important for liver immunity?
Kupffer cells
LSECs
Dendritic cells
Bonus: Hepatocytes
What is the role of Kupffer cells in liver immunity? (4)
- Phagocytosis (food, bacteria, toxins)
- Antigen presentation to T cells
-Supression and activation of T cells (Tregs) - IgA production (IL-10 and TGF-ß production supports B cell class switching to IgA)
What is the role of LSECs in liver immunity and homeostasis? (5)
- Immune tolerance: Low T cell activation levels by presenting antigens but with low levels of co-stimulatory molecules, also IL-10, TGF-ß and PD-L1 production
- Immune surveillance: PRRs (and thus cytokine release)
- Endocytosis: through scavenger receptors
- (Permeable) barrier
- Fibrosis regulation
What is the role of hepatocytes in liver immunity?
Production of acute phase proteins and antigen presentation
What cells can shift liver tolerance to more pro-inflammatory?
Liver dendritic cells, which are usually more tolerogenic
What are the most common transmission routes for hepatitis B and C?
B: vertical transmission
C: needle sharing
Do hepatitis B and C have vaccines?
B yes, C no, however hepatitis C can be cured and B can not
What is a main difference in innate responses to HBV and HCV?
HBV does not induce a type I IFN response by lowering transcription due to suporession of signals downstream of PRRs, while HCV does. However, HCV inhibits the function of Type I interferons.
What is the main difference in T cell responses to HBV and HCV
T cell response to HCV correlates with viral clearance, but they disappear or become exhausted in chronic patients.
In HBV patients, there is insufficient or tolerogenic antigen presentation in the acute phase, and prolonged antigen exposure leads to exhaustion in chronic patients.
How do HCV and HBV infections lead to hepatocellular carcinoma (HCC)? (3)
- The proinflammatory environment leads to tumors
- HBV integrates into host genome which leads to oncogenic DNA strands
-HBX protein leads to mitochondrial stress which leads to ROS and DNA strand breakage
What is the main transmission route for hepatitis C?
Intravenous drug use
What are the differences in chronic infection rates between adults and children with HBV?
90% of children compared to 10% of adults develop chronic hepatitis from HBV
How do nucleos(t)ide analougues work in treating HBV?
They cause chain termination and suppress HBV replication. They do not eliminate the virus and need to be taken lifelong. It works by incorporating a faulty nucleotide during reverse transcriptase in replication. This does not affect the host genome because it specifically works only during reverse transcriptase.
Are nucleos(t)ide analogues specific for HBV?
No, they work during reverse transcriptase phase of viral infections in general. FOr exmaple, Tenofovir is also used in HIV.
What happens when the use of nucleos(t)ide analogues is stopped in patients with HBV and why?
cccDNA, which is the transcriptional template for all HBV RNAs, that is integrated in the host genome is used as a template to produce new virions, so replication is no longer supressed.
What is the diagnostic role of HBsAg?
It is HBV surface antigen and one of the earliest markers to appear in HBV infection. It’s presence in the blood indicates active HBV infection in acute and chronic HBV infection.
How can HBsAg be used to monitor HBV infections?
Persistent presence in the blood inficates chronic infection. Loss of HBsAg is considered a key indicator of a functional cute in HBV treatment.
What is the role of HBsAg in monitoring immune responses in HBV infections?
The immune system produced anti-HBs. The presence of anti-HBs often indicates immunity, either through recovery or vaccination.
In what forms can a person be cured of HBV? (3)
Sterilizing cure: Complete elimination of the virus and its cccDNA. It is considered unattainable with current treatments and extremely rare.
Functional cure: Loss of HBsAg with or without seroconversion (anti-HBs). This is the most plausible goal, and most treatments aim for this.
Partial cure: Certain markers are suppressed or eliminated, others persist. DNA becomes undetectable in the bloodstream. HBeAG is lost (low levels of viral activity), but HBsAg remains detectable.
What are the main barriers to curing HBV?
cccDNA integration, high levels of viral proteins and impaired immune control
What medications have been shown to have extremely high efficacy with minimal side effects and no virus adaptation or tolerance in HCV infections, even in patients with cirrhosis?
Protease and polymerase inhibitors
What are four biomarkers used for treatment initiation and monitoring in HBV patients?
DNA, viral protein (HBeAg/HBsAg), antibodies (anti-HBe/antiHBs), and liver transaminases (AST/ALT)
What is effectivity of PEG-IFN against viral hepatitis in HCV largely dependent on?
Virus genotype
What are TLR8 agonists and their role in HBV treatment?
They are agonists for endosomal TLR8, stimulating NK cell activity, enhancing antibody-dependent cytotoxicity, and inducing the production of IFN-γ to aide in a functional cure.
What is autoimmune hepatitis (AIH)?
AIH is an immune-mediated liver disease characterized by inflammation, circulating autoantibodies, increased IgG concentrations, and distinctive histological features.
What is the presence of auto-antibodies in AIH based on?
Serological subtype
What are the types of Autoimmune Hepatitis (AIH)?
AIH can be classified into three types: Type 1 (ANA+ and anti-SMA+), Type 2 (anti-LKM1 and anti-LC-1), and Type 3 (anti-SLA/LP). Type 1 is the most common and has a good response to therapy.
What AIH type has the worst prognosis and why?
Type 2, characterized by anti-LM1 and anti LC-1 antibodies. It is predominantly in children, has a poor treatment response and cirrhosis is often already present at diagnosis.
Why is there often already cirrhosis when type 2 AIH is diagnosed?
It has an aggressive disease course and delayed recognition due to presentation of AIH before cirrhosis often being asymptomatic or atypical/aspecific.
What are histopathological features of AIH? (3)
Interface hepatitis - accumulation of lymphocytes infiltrated throughout the liver (patchy)
Hepatocyte ballooning
Necrosis
What are the main treatment goals in AIH? What is usually used as treatment?
The main goals are to reduce inflammation, decrease cholestasis, and prevent fibrosis progression. Immunosuppressive therapy (e.g., prednisone and azathioprine) is often used.
What is cholestasis?
The slowing or stalling of bile flow through your biliary system. This can cause backup of bile, inflammation and leakage into the bloodstream.
What are common triggers for AIH? (2)
Molecular mimicry (hepatitis viruses and EBV) and drugs such as anti-TNF
What role do CD4+ and CD8+ T cells play in the pathogenesis of AIH?
CD4+ T cells mediate the immune response by targeting specific epitopes on hepatocytes, while CD8+ T cells contribute to cytotoxic damage, leading to hepatocyte destruction.
What is the role of Th17 cells in Autoimmune Hepatitis (AIH)?
Th17 cells are implicated in AIH pathogenesis by producing IL-17, which induces hepatic IL-6 expression and promotes inflammation by stimulating hepatocytes to produce acute phase proteins, inhibiting Treg differentiaton, recruiting neutrophils, and activating fibroblasts (leading to fibrosis)
What is Primary Biliary Cholangitis (PBC)?
PBC is a chronic, autoimmune disease that involves destruction of small intrahepatic bile ducts, leading to cholestasis, inflammation, and cirrhosis.
What is the pathogenesis of Primary Biliary Cholangitis, and what determines severity?
Anti-mitochondrial antibodies (AMAs) bind to mitochondrial protein PDC-E2, leading CD4 and CD8 T cells to attack. T cells also recruit macropphages and NK cells.
When defects in the AE2 protein disrupts the protective bicarbonate layer that shields bile ducts, bile accumulates and injure duct cells, leading to the release of PDC-E2 in apoptotic bodies and thus more antigen to drive inflammation.
What is the main treatment for Primary Biliary Cholangitis and how does it work?
Ursodeoxycholic acid (UDCA). It replaces toxic bile, increases bile secretion, and modulates the immune system.
What is Primary Sclerosing Cholangitis (PSC)?
PSC is a chronic cholestatic liver disease characterized by fibrosis and strictures of intrahepatic and extrahepatic bile ducts, causing damage due to bile accumulation, leading to fibrosis and cirrhosis.
What autoimmune liver disease of often associated with IBD?
Primary Sclerosing Cholangitis
How does Primary Sclerosing Cholangitis relate to IBD? (4)
There is a co-occurence of 60-80% in PSC patients. Increased intestinal permeability allows bacterial product to reach the liver, triggering bile duct inflammation. There is also microbiota dysbiosis which modulated bile acid metabolism and worsens inflammation in both organs. There are also shared immune pathways.
How might microbiota influence the pathogenesis of Primary Sclerosing Cholangitis (PSC)?
Altered microbiota in PSC patients can influence bile acid metabolism and modulate immune responses, potentially contributing to disease progression.
What are risk factors for end-stage liver disease? (4)
Genetics, viral infections, alcohol and obesity.
Why are alternatives needed for liver transplantation? (2)
Donor livers are in short supply, and the quality of available livers is declining due to obesity, alcohol use, and aging populations.
What are alternatives to traditional liver transplantation? (4)
Living donor liver transplantation, reviving non-transplantable livers, tissue engineering, and (stem) cell therapy.
What is organ decellularization?
A process to remove all cells from an organ, leaving behind the extracellular matrix (ECM) as a scaffold for tissue engineering.
What are the key steps in liver decellularization?
- Heparin to remove blood
- Soap wash with Triton X-100
- 0,9% NaCl rinse
- DNAse treatment to remove DNA
- Freeze-thaw cycles to remove cells while preserving ECM
- Freeze for storage
What is essential for successful decellularization? (3)
No cells, ECM proteins must be unaffected and the liver architecture must remain intact
What is machine perfusion, and how is it used?
A technique to preserve or repair donor livers by circulating fluids through them. It allows therapeutic interventions like gene therapy or stem cell delivery.
What are organoids?
Three-dimensional structures derived from stem or progenitor cells that mimic the architecture and function of native tissues in vitro.
What are some applications of liver organoids? (4)
Toxicological studies, drug testing, disease modeling, and potentially clinical transplantation.
What challenges exist in using organoids for liver tissue engineering? (3)
Obtaining enough cells, maintaining cell viability, and ensuring successful integration into host tissues.
How can machine perfusion improve donor livers? (4)
It can de-fat steatotic livers, remove debris, deliver gene-corrected or stem cells, and reduce ischemia-related damage.
What is the role of organ scaffolds in tissue engineering?
Scaffolds, like decellularized ECM, provide a structural framework for recellularization and tissue regeneration.
What are the potential future uses of liver tissue engineering? (2)
Creating functional liver tissue for transplantation, disease-specific models.
What are microRNAs?
Small, non-coding RNAs that regulate gene expression post-transcriptionally by binding to complementary mRNA sequences, leading to mRNA degradation or translational inhibition.
What is the role of RNA interference (RNAi) in miRNA function?
RNAi is the process where miRNAs, via Dicer and RISC complexes, mediate the silencing of specific mRNA targets, blocking protein synthesis.
What is miR-122 and how does it contribute to disease?
miR-122 is a liver-specific miRNA that regulates lipid metabolism (leading to steatosis or fatty liver, fibrosis and HCC), promotes hepatitis C virus (HCV) replication (by binding to the 5’ UTR of HCV genome, thereby stabilizing it).
In what way can miR-122 be used as a biomarker? (3)
It is abundantly expressed in the liver, and release in the bloodstream sensitively indicates hepatocellular damage.
It can serve as an early indicator of graft injury or rejection following transplant.
Altered expression is associated with HCC.
Why is miR-122 a more reliable biomarker for liver injury than ALT? (3)
It is highly specific and measurably released even in minor liver damage, making it more sensitive than ALT for early detection or mild injury.
ALT is present in other tissues, reducing specificity.
It is much more stable in the blood and during sample processing than ALT.
How do miRNAs contribute to liver disease?
miRNAs like miR-122 and others regulate liver functions, and their dysregulation can lead to liver injury, fibrosis, cancer, and impaired regeneration.
How are miRNAs targeted therapeutically?
Antisense oligonucleotides (e.g., LNA anti-miRs) are used to inhibit specific miRNAs, such as miR-122, reducing HCV replication or modulating liver injury.
What are the challenges in miRNA-based therapies? (3)
Off-target effects, efficient delivery to liver cells, and potential disruption of normal gene regulation.
Why are miRNAs considered ideal biomarkers for liver disease? (4)
miRNAs are highly stable, specific to cell types, easily detectable in biological samples, and more sensitive than traditional markers like ALT.
How are miRNAs used as biomarkers in liver transplantation?
Circulating miRNAs can indicate hepatic injury or early rejection after transplantation, providing real-time monitoring.
What is the relationship between miRNAs and liver cancer?
miRNAs regulate key pathways in liver cancer, acting as oncogenes or tumor suppressors, making them targets for both diagnosis and therapy.
What are food-derived miRNAs, and how do they influence liver health?
Food-derived miRNAs may regulate liver gene expression, but their clinical significance is still under investigation.
