Case 15 Flashcards
(124 cards)
1
Q
What does bile consist of
A
- Bile Acids
- Bilirubin
- Phospholipids
- Cholesterol
- Xenobiotics (foreigns substances)
- H20 (water)
- Electrolytes (Na+, Ca2+ and HCO3-)
- Glutathione (anti-oxidant)
2
Q
What are the two primary Bile acids found in bile
A
The two bile acids are:
- Chenodeoxycholic acid
- Cholic acid
3
Q
What is the enterohepatic circulation
A
A recycling process where bile acids, bilirubin, drugs, and other substances are circulated between the liver, gallbladder, intestines, and back to the liver. (So from liver through bile duct into the duodenum, through the intestines and back to the liver through hepatic portal vein)
Liver → Gallbladder → Small Intestine (digestion/absorption) → Portal Vein → Liver (recycling).
4
Q
How are the two primary bile salts formed
A
Chenodeoxycholic acid and cholic acid are both synthesised from cholesterol. They are formed by cholesterol entering the smooth endoplasmic reticulum.
Chenodeoxycholic acid is formed when cholesterol is acted on by 7-alpha-hydroxylase in the smooth ER
Cholic acid is formed when some of the chenodeoxycholic acid gets acted on by 12-alpha hydroxylase in the smooth ER
5
Q
How do primary bile acids get turned into secondary bile acids after being released into the biliary system and through the enterohepatic circulation and what are they called
A
After Chenodeoxycholic acid and cholic acid are released into the duodenum they go to the ileum where bacteria further metabolism them via their 7 alpha-dehydroxylase
enzyme into secondary bile acids.
7 alpha-dehydroxylase turns:
- Cholic acid into Deoxycholic acid
- Chenodeoxycholic acid into Lithocholic acid
6
Q
What can happen to primary bile acids in the liver and what do they form
A
They can undergo conjugation by adding either a glycine or taurine molecule to make them more soluble, this creates bile salts known as:
- Glycochenodeoxycholic acid
- Taurochenodeoxycholic acid
- Glycocholic acid
- Taurocholic acid
7
Q
What can happen to secondary bile acids in the liver and what do they form
A
After coming back to the liver via the enterohepatic circulation they can undergo conjugation by adding either a glycine or taurine molecule to make them more soluble, this creates bile salts known as:
- Glycolithocholic acid
- Taurolithocholic acid
- Glycodeoxycholic acid
- Taurodeoxycholic acid
8
Q
What effect does chenodeoxycholic acid and cholic acid have on bile production when in high volumes
A
When in high volumes it can inhibit the action of 7-alpha-hydroxylase which is the rate limiting step of the production of bile acids, so bile acid levels decrease
9
Q
Just to recap what enzymes are used to turn cholesterol into primary bile acids
A
7-alpha-HYDROXYLASE (creates chenodeoxycholic acid)
and
12-alpha-HYDROXYLASE (creates cholic acid)
10
Q
What enzyme, produced by bacteria in the ileum, turn primary bile acids into secondary bile acids
A
7-alpha-DEHYDROXYLASE
11
Q
How do bile salts help with fat digestion
A
Mechanism:
Emulsification:
Bile salts have both hydrophilic (water-attracting) (the amino acid) and hydrophobic (fat-attracting) sides.
This amphipathic nature allows them to break large fat droplets into smaller ones, increasing surface area for enzymes.
Micelle Formation:
Bile salts surround fat digestion products (monoglycerides, fatty acids, cholesterol) to form micelles.
Micelles are water-soluble and transport fats to the intestinal epithelium for absorption.
12
Q
How long do RBCs approximately live for
A
120 days
13
Q
What happens to old RBCs what are the products of its breaking down
A
Old red blood cells enter the reticuloendothelial system in the liver and spleen, here they are engulfed by macrophages and broken down into heme and globin
14
Q
What happens to heme and globin
A
Heme gets further broken down by heme oxygenase and
which turns it into biliverdin and iron, and then biliverdin is further reduced by biliverdin reductase to form bilirubin
Globin and iron are recycled to form new RBCs
15
Q
Describe the journey of unconjugated bilirubin up until it conjugates
A
Unconjugated bilirubin (UCB) is lipid soluble and so can’t travel in the blood by itself, and so albumin transports it in the blood and takes it into the liver, the UCB undergoes facilitated diffusion and enters the liver. Once in the liver the enzyme UGT (Uridine Diphosphate Glucuronosyltransferase) adds glucuronic acid to UCB to turn it into conjugated bilirubin in a process called Glucuronidation
16
Q
What is the enzyme that conjugates unconjugated bilirubin
A
UGT (Uridine Diphosphate Glucuronosyltransferase) specifically UGT1A1 and it adds a glucuronic acid to the unconjugated bilirubin to conjugate it
17
Q
What happens to conjugated bilirubin
A
conjugated bilirubin goes into the gall bladder and into the bile where it gets secreted into the duodenum. The gut flora then metabolises conjugated bilirubin into Urobilinogen, if urobilinogen stays in the bowel it get further turned into Stercobilinogen and into stercobilin which is what makes faeces brown (85% of your bilirubin gets pooped out)
Some urobilinogen gets absorbed into the bloodstream and goes to the kidneys and turns into urobilin and excreted into the urine (which is what turns your urine yellow) which accounts for about 5% of urobilinogen, and the rest goes back to the liver and goes through the cycle again.
18
Q
What does urobilinogen turn into
A
85% turns into stercobilin and excreted and 5% gets turned into urobilin and peed out. The rest goes back to the liver
19
Q
What is Jaundice
A
A condition characterized by yellowing of the skin and or sclerae due to elevated bilirubin levels in the blood (hyperbilirubinemia).
20
Q
What is ALT (Alanine Aminotransferase)
A
Location: Primarily found in the liver, but also in smaller amounts in the kidneys, heart, and muscles.
Function: Converts alanine (an amino acid) to pyruvate during the process of amino acid metabolism.
Clinical Relevance:
- ALT is more liver-specific than AST. (remember aLt, for liver, it is more liver specific)
- Elevated ALT levels often indicate liver damage (e.g., hepatitis, cirrhosis, alcoholic liver disease).
21
Q
What is AST (Aspartate Aminotransferase)
A
Location: Found in many tissues, including the liver, heart, muscles, and kidneys.
Function: Converts aspartate (another amino acid) to oxaloacetate in the process of amino acid metabolism.
Clinical Relevance:
- AST is less liver-specific than ALT, as it is also present in the heart and muscles.
- Elevated AST levels may indicate liver damage, but can also be seen in heart conditions (e.g., myocardial infarction) or muscle injuries.
22
Q
What is ALP (Alkaline Phosphatase)
A
Location: Found in liver, bone, kidneys, intestines, and biliary tree
Function: Plays a role in breaking down proteins and is involved in phosphate transport in various tissues.
Clinical Relevance:
- Elevated ALP levels can indicate issues in the liver, bone (e.g., osteomalacia, Paget’s disease), or biliary system (e.g., bile duct obstruction, cholestasis).
- ALP is often elevated in extrahepatic jaundice (e.g., gallstones or pancreatic cancer obstructing bile ducts).
23
Q
What is GGT (Gamma-Glutamyl Transferase)
A
Location: Found in liver, kidneys, pancreas, and spleen. Mostly located in the biliary epithelial cells.
Function: Plays a role in transferring amino acids across cell membranes and in the metabolism of glutathione.
Clinical Relevance:
- Elevated GGT levels are commonly seen in liver diseases, especially those affecting the bile ducts (e.g., cholestasis, biliary obstruction).
- GGT is highly sensitive to alcohol use or drug-induced liver injury, making it a useful marker in diagnosing alcohol-related liver damage.
24
Q
Why do you usually test for both ALP and GGT
A
ALP is produced in other parts in the bodies, like the bones, meaning that it being elevated doesn’t necessarily mean that the liver is affected. GGT can be used to confirm that the liver/biliary tree is affected.
If ALP levels are high by GGT levels are low the liver is most likely not affected. If both ALP and GGT are high then it indicates Cholestasis (flow of bile from the liver is slowed or blocked) so can indicate diseases like gallstones, biliary tumor etc.
25
What are the 3 types of causes for jaundice
- Hemolytic (RBC breakdown)
- Hepatocellular (Liver breakdown / damage)
- Cholestatic (impaired bile production or flow)
26
What are some things that could cause hemolytic jaundice and what would their lab results look like
Causes:
- Mismatch blood transfusion
- Certain venoms
Lab results:
Blood:
- Low hematocrit (the percentage of red blood cells in your blood.)
- Low haemoglobin
- Free Haptoglobin levels will be low (Haptoglobin is a protein that binds to free floating haemoglobin which prevents it from doing damage)
Bilirubin:
- Conjugated bilirubin (direct bilirubin): levels will be normal
- Unconjugated bilirubin (indirect bilirubin): levels will be high as there will be lots of RBC lysis
- Urobilin: slightly elevated (may have darker faeces and urine)
Liver:
- AST / ALT levels: normal
- ALP / GGT levels: normal
- Might have hemoglobinuria (haemoglobin in urine)
27
What are some things that could cause Hepatocellular jaundice and what would their lab results look like
Causes:
- Alcohol induced liver injury
- Infectious liver injury (viral, bacterial or parasitic) (Hep can cause this, its viral)
- Autoimmune hepatitis
- Metabolic hepatitis ( Iron [haemochromatosis], Copper [wilson's disease] )
Lab results:
Bilirubin:
- Conjugated bilirubin: elevated
- Unconjugated bilirubin : elevated
- Urobilinogen: might have small decrease as liver cant put as much conjugated bilirubin into the biliary tree
Liver:
- AST and ALT levels: Very elevated (ALT is liver specific, AST not so much, HOWEVER, if ALT levels are two times higher than AST levels it is indicative of alcohol induced liver damage)
- If the liver damage is chronic you might have elevated ALP and GGT as it might lead to constricted biliary ducts and so increased levels. You will also have decreased albumin, and since albumin helps with osmotic gradient this will cause oedema
- For acute liver injury like in hepatitis you will have elevated prothrombin time as the liver produces clotting factors
28
What are some things that could cause Cholestatic jaundice and what would their lab results look like
Cholestatic refers to impaired bile formation or impaired bile flow
Causes:
- Biliary fibrosis
- Gallstones
- Biliary tumor
- Pancreatic tumor (obstructing bile flow)
Lab results:
Bilirubin:
- Conjugated bilirubin: elevated
- Unconjugated bilirubin: elevated
- Urobilinogen: very low or absent (because it cannot be excreted because of obstruction)
(Very pale / clay faeces)
Liver:
ALT / AST : Can be elevated as biliary obstruction can cause backflow of bile and damage liver cells
ALP / GGT : Levels will be very high
29
What does Hepatitis mean and what can cause it
Hepatitis is the inflammation of the liver, it can be caused by Infectious or Non-Infectious ways
Infectious:
- Viral (HEP A,B, C, D and E)
- Bacterial
- Fungal
- Parasitic
Non-Infectious:
- Alcohol
- Drugs (paracetamol)
- Autoimmune
- Metabolic (fatty liver disease)
- Ischemic
30
What Hepatitis viruses can be transmitted via faecal oral transmission
Hep A and E
31
What Hepatitis viruses can be transmitted via blood or bodily fluids
Hep B, C, D and E
32
What infections can lead to chronic infection (>6 months)
All except Hep A can lead to chronic infection
33
What hepatitis viruses are single strand RNA
Hep A, Hep C, Hep D and Hep E
34
What hepatitis virus has double stranded DNA
Hep B
35
In the case of viral hepatitis how is hepatocyte damage done
The hepatitis virus infects cells and causes it to produce viral proteins which act as antigens, these proteins then get expressed on the surface of the hepatocyte. The immune system (cytotoxic T-cells) then recognises these cells as foreign and causes hepatocyte apoptosis
Depending on strength of immune response it can cause Mild inflammation to
Massive necrosis of liver ('fulminant' hepatitis, acute liver failure)
36
How do you assess liver inflammation
ALT and AST are enzymes found within hepatocytes, Hepatocytes damage causes them to leak out into the bloodstream
injury to hepatocyte causes increased ALT and AST, injuring to bile canaliculi causes increased ALP and bilirubin (And GGT)
The liver also produces clotting factors so you can also assess liver function by measuring INR (International Normalized Ratio) which is a blood test that measures how long it takes for blood to clot) and Albumin levels
37
How can Acute viral hepatitis present
Acute viral hepatitis can present in a variety of ways, it depends on age and the immune status when you get it.
It can range from being Asymptomatic, Mild, non-specific or Fulminant (a severe condition characterized by rapid liver damage and failure, potentially leading to encephalopathy (brain dysfunction). It can be a life-threatening emergency)
38
Acute viral hepatitis present symptoms
Prodrome symptoms (early symptoms) can be:
- Nausea
- Fatigue,
- Malaise (Malaise is a general feeling of discomfort, illness, or unease)
- Fever
You can also get:
- Jaundice
- Dark urine
- Pale stools
(Because of Cholestasis) (dark urine is because conjugated bilirubin leaks into the blood because of cholestasis which gets filtered out by the kidneys in large amount make the urine dark)
And also
- Steatorrhea
- Right upper quadrant tenderness because of Hepatomegaly
39
What would blood test results for acute viral hepatitis show
Elevated ALT and AST. Bilirubin and ALP not as elevated as ALT and AST
- You should do a full blood count and INR (international normalized ratio) and a liver ultrasound to rule out obstruction
40
What type of screen do you do when testing for hepatitis and what does it include aswell as what antibodies do u see
You do a viral screen which includes:
Hepatitis A antibody
Hepatitis B surface antigen
Hepatitis C antibody
consider Hepatitis E IgM
IgM is produced in early infection
IgG produced later on
You see IgM first
41
What is chronic viral hepatitis and what does it lead to
Chronic viral hepatitis is when you have ongoing inflammation in due to immune response but it comes in cycles, so the liver tries to heal but it replaces the damaged liver cell with fibrotic tissue (fibrosis) that obviously cant do the function of the liver. FIbrosis can then progress to cirrhosis where so much of the liver tissue has
been replaced and you begin to get bridging and nodules forming.
The progression of fibrosis to cirrhosis usually takes about 20-30 years after first infection but factors like alcohol, HIV, diabetes and steatohepatitis can speed up this progression
Cirrhosis can be asymptomatic but it can get to a stage where there is so little liver function left that you start to develop jaundice or ascites and this is called liver decompensation
42
What is the gold standard in diagnosing liver cirrhosis and what other tools can u use for diagnosing
Liver biopsy is the gold standard for diagnosis
but it can also be diagnosed with non-invasive methods such as ultrasound elastography/FIbroscan which involves a probe that sends ultrasound waves through the liver which are then reflected back. Waves are reflected more quickly as the liver “stiffness” increases as the liver becomes more fibrotic
43
What are the complications of Cirrhosis
- Progression to decompensated liver disease and Hepatocellular carcinoma
- Complications of portal hypertension
ascites
- variceal bleeding (dilated veins that rupture)
- encephalopathy
- subacute bacterial peritonitis
- Acute on chronic liver failure
Need to screen and diagnose before onset of irreversible liver damage
44
What are hepatitis A and E, and how are they transmitted?
Hepatitis A and E are RNA viruses causing acute liver inflammation, transmitted via the fecal-oral route through contaminated food, water, or surfaces.
45
What are the families of hepatitis A and E viruses?
Hepatitis A belongs to the Picornavirus family, and Hepatitis E belongs to the Hepevirus family.
46
What is the structure of hepatitis A and E viruses?
Both are naked, single-stranded RNA viruses with a protein capsid but no lipid membrane.
47
How do hepatitis A and E viruses reach the liver?
After ingestion, the viruses travel via the hepatic portal venous system to the liver, where they infect hepatocytes and Kupffer cells.
48
What immune cells respond to hepatitis A and E infections?
CD4+ T cells, CD8+ cytotoxic T cells, and natural killer (NK) cells respond to infection by limiting replication and destroying infected liver cells.
49
What antibodies are produced during hepatitis A and E infections, and what do they indicate?
- IgM antibodies: Indicate acute infection.
- IgG antibodies: Indicate immunity (lifelong for hepatitis A, uncertain for hepatitis E). (post infection)
50
What are the main symptoms of hepatitis A and E?
Can be often be asymptomatic, but
Non-specific: Fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain.
Specific: Jaundice, dark urine, pale stools, itching.
51
What complications can arise from hepatitis A and E?
Fulminant Hepatitis: Rare, causes liver failure.
Chronic Hepatitis E: Occurs in immunocompromised individuals.
Pregnancy Risks with Hepatitis E: High mortality (~20%), stillbirth, and preterm delivery.
52
How is hepatitis A or E diagnosed?
Elevated liver enzymes (ALT, AST).
Detection of IgM anti-HAV (For Hep A) or anti-HEV antibodies (for Hep E) for acute infection.
IgG anti-HAV antibodies for immunity or vaccination. Anti-HEV IgG (after Hep E resolution)
53
How can hepatitis A and E infections be prevented?
Avoid contaminated food, water, and maintain good hygiene.
Hepatitis A vaccine: Inactivated vaccine (2 doses, protects for ~20 years).
Hepatitis E vaccine only available in China
54
How is hepatitis B transmitted?
Hepatitis B is transmitted through blood-borne routes (IV drug use, unsterile needles/tattoos), sexual contact, and vertical transmission (mother-to-child) (most important globally).
55
What is unique about the hepatitis B virus compared to other hepatitis viruses?
Hepatitis B is the only hepatitis virus with a DNA genome, which integrates into the host's DNA, increasing the risk of hepatocellular carcinoma (HCC).
56
What are the clinical presentations of acute hepatitis B? And its hallmark symptom
Acute hepatitis B presents with serum sickness-like symptoms, including fever, arthralgias, and rash.
Its hallmark symptom are: sickness-like symptoms which include fever, rashes and arthralgias (joint pain)
57
What are the symptoms of chronic hepatitis B?
Often asymptomatic but may progress to liver disease, including cirrhosis or HCC.
(Because Hep B integrates into into the host DNA causing increased oncogenuc potential it’s more likely to lead to Hepatocellular carcinoma)
58
What are the key viral proteins and antibodies used in hepatitis B diagnosis?
You have:
Viral proteins
- Hepatitis B surface antigen (HBsAg)(infection marker).
- Hepatitis B e antigen (HBeAg) (Envelope antigen) (active replication, high infectivity).
Host antibodies against the virus:
- Hepatitis B surface antibody (Anti-HBs)
- Hepatitis B core antibody (Anti-HBc)
- Hepatitis B e antibody (Anti-HBe)
During a Hep B infection you cannot detect Hep b core antigens only the antibodies make against it
59
What serologic marker that defines chronic hepatitis B?
Presence of Hepatitis B surface antigen (Anti-Hbs) to be present for more than 6 months.
60
What antibody would be in the blood for people that are vaccinated for Hep B
Hepatitis B surface antibody (Anti-Hbs) ONLY
61
What antibody is produced first IgM or IgG
IgM is produced first and then it dies down (found in acute) then IgG is produced after and it stays in chronic HEP B
62
What type of antigen is found first in Hep B infection and whats next and why
After 4 weeks you get Hep B surface antigens first then you have the Hep B e antigen because the E antigen is produced when the virus is replicating
63
Explain the serology you would see in acute infection of Hep B
HBsAg: Positive (indicates active infection)
Anti-HBc IgM: Positive (indicates recent infection)
Anti-HBc IgG: Negative or low (IgG will appear later as the infection resolves)
HBeAg: Positive (suggests active replication and high infectivity)
Anti-HBs: Negative (not yet developed, immunity will develop once infection clears)
64
When screening for someone for Chronic Hepatitis B what two tests do you do and why and what will their results look like
You test for HBC surface antigen and core antibody (mainly IgG).
You do this because HBC surface antigen tells you if the infection is currently active or not and core antibodies (IgG) tells you how long the infection has been going on because in acute infection you only have IgM antibodies against the core antigens but in chronic u now have IgG against the core antigens
You only produce IgG and IgM antibodies against core antigens
65
What are the stages for someone infected with Hep B at birth and explain them (HBV DNA to ALT)
First you have the Immune tolerant phase:
The HBV replicates a lot so u have high HBC DNA but ALT is low because the immune system is still immature and because damage in hepatitis is caused by the immune response ALT is low
Then you have the Immune Clearance phase where the immune system matures and starts attacking infected cells so you have increased ALT and decreased HBV DNA because the immune cells are killing the viruses
Eventually at around the 40s you have the Inactive carrier phase where the immune system calms damn and ALT drops but at this point you'd have fibrosis and cirrhosis
FInally the last phase is Reactivation and it can happen if you become immunosuppressant for whatever reason causing the virus to again reactivate leading to a spike in HBV DNA and ALT
66
Current therapies for chronic HBV and the mechanisms of the drugs used
Hep B takes its DNA and puts it into it into our DNA in the cells called cccDNA (Covalently Closed Circular DNA), this is difficult to remove with current therapies meaning it stays there forever. However Tenofovir & Entecavir stop DNA polymerase from synthesising the virus's DNA but they don't get rid of the cccDNA in the nucleus meaning they have to take this medication for the rest of their lives.
Another medication you can take is Pegylated Interferon which involves taking weekly injections which stimulates the immune response to recognize that the hepatocytes
contain a virus and will destroy the cell.
67
What is unique about Hepatitis D (HDV)?
HDV is a defective RNA virus that requires HBV coinfection and uses HBsAg for replication.
68
How is Hepatitis D transmitted?
Same as HBV—blood, sexual contact, and vertical transmission.
69
What serological markers are used to diagnose HDV?
Anti-HDV IgM for acute infection, Anti-HDV IgG for chronic infection, and HDV RNA for active viral replication.
70
What is the difference between simultaneous infection and superinfection in HDV?
Simultaneous: Both HBV and HDV infections occur together.
Superinfection: You're infected with HBV first then u get infected HDV
71
What are the clinical features of HDV infection?
Severe hepatitis with high ALT.
70% progress to cirrhosis.
2x increased risk of hepatocellular carcinoma (HCC).
HDV causes faster progression to cirrhosis and a higher risk of HCC by exacerbating liver damage in HBV-infected individuals.
72
What is the primary goal of HDV treatment?
Eradication of HBsAg to clear HDV infection, as HDV cannot replicate without HBV.
73
How can HDV infection be prevented?
Through Hepatitis B vaccination, as HDV cannot infect without HBV.
74
What is the impact of HDV superinfection compared to HBV alone?
Superinfection causes more severe liver injury, higher ALT levels, and accelerated progression to cirrhosis and HCC.
75
Give a general description of the Hepatitis C
- Belongs to the Flavivirus family
- Incubation period is 2 weeks to 6 months
- Acute infection is often asymptomatic so some people won't even know they have it, 75% of people infected develop chronic infection of Hep C,
- There is no vaccine for Hep C
76
How is Hep C transmitted
Blood exposure (IV drug use, unsafe medical practices, tattoos etc), sexual (higher risk in HIV + Male with male sex) (rare in mother to baby and heterosexual intercourse)
77
How do you diagnose Hepatitis C
You check for HCV antibody and HCV RNA
if both are negative u have no exposure
if HCV AB is positive but HCV RNA is negative then u had prior exposure
If HCV AB and HCV RNA is positive you have active infection (HCV RNA is indicative of active infection) based on history u can tell if its acute or chronic
78
Treatment for Hep C
Direct-acting antivirals (DAAs):
- Protease inhibitors (-previr), (Glecaprevir)
- NS5A inhibitors (-asvir), (Ledipasvir)
- NS5B polymerase inhibitors (-buvir). (Sofosbuvir)
* Legacy agents: Pegylated interferon +
ribavirin (now rarely used).
79
Hep C prevention
No vaccine but u can prevent it by harm reduction (sterile needles, safe sex, etc.).
80
What does ALT stand for
Alanine aminotransferase
81
What does AST stand for
Aspartate Aminotransferase
82
What does ALP stand for
Alkaline Phosphatase
83
What is non-alcoholic fatty liver disease (NAFLD)
NAFLD refers to fat accumulation in the liver not caused by excessive alcohol consumption.
84
What are common symptoms of early stage NAFLD?
Most people are asymptomatic, but some may experience fatigue, malaise, or upper right abdominal pain.
85
What are the stages of NAFLD
1. Simple steatosis (fat accumulation) (Fatty liver),
2. Non-alcoholic steatohepatitis (NASH - inflammation + fat),
3. Fibrosis,
4. Cirrhosis.
86
What is the main risk factor for NAFLD?
Metabolic syndrome, including obesity, insulin resistance, type 2 diabetes, hyperlipidemia, and hypertension.
87
How is NAFLD different from alcoholic liver disease?
NAFLD occurs without significant alcohol intake (<20g/day), whereas alcoholic liver disease is due to excessive alcohol consumption.
88
How is NAFLD diagnosed?
- First indication is often raised ALT
- Liver ultrasound can be used to diagnose hepatic steatosis (fatty liver) because fat has a higher echogenicity
- Enhanced liver fibrosis (ELF) test can be used to assess fibrosis, Fibroscan can also be done
- Liver biopsy is gold standard but isnt always done
89
Can liver cirrhosis or late stages of fibrosis cause portal hypertension and what can that cause
Cirrhosis of the liver can cause portal hypertension which can lead to complications like:
- Abdominal distension
- Enlarged spleen
- Varices (which can rupture and bleed)
- Bypass of blood around the liver, causing toxin buildup and hepatic encephalopathy.
90
Can NAFLD be treated?
There is no specific treatment, but it can be prevented or reversed through:
- Weight loss
- Healthy eating
- Physical exercise
91
Q: What is Alcoholic Liver disease?
Liver damage caused by alcohol abuse. Risk increases with amount and duration of alcohol use, daily drinking, gender, genetics, and obesity.
92
What are the stages of alcoholic liver disease?
Alcoholic Fatty Liver: Reversible fat accumulation in the liver. Often asymptomatic.
Alcoholic Hepatitis: Liver inflammation with symptoms like fever, jaundice, fatigue, and tender liver.
Fibrosis: Accumulation of fibrous tissue in the liver
Cirrhosis: Irreversible scarring of the liver leading to end-stage liver disease.
93
What are the two main alcohol metabolism pathways?
- Alcohol dehydrogenase (ADH) Pathway:
Alcohol is converted into Acetaldehyde by alcohol dehydrogenase, acetaldehyde is then converted into acetate by Aldehyde dehydrogenase (Both reactions convert NAD+ into NADH) (Acetaldehyde is what causes the negative effects of alcohol like Facial flushing, nause, headache, increased heart rate etc.)
- CYP-2E1 (Cytochrome P450 2E1) is the other pathway and it metabolizes alcohol into acetaldehyde, similar to the ADH pathway. However, it becomes more active during chronic alcohol use.
94
What pathway is upregulated in heavy drinkers
Chronic Use Effects:
Chronic alcohol consumption upregulates CYP-2E1 activity, increasing its expression in the liver. This makes the pathway more prominent in heavy drinkers.
Reactive Oxygen Species (ROS):
Unlike the ADH pathway, CYP-2E1 produces harmful reactive oxygen species (ROS) as by-products.
These ROS cause oxidative stress, leading to cellular damage, including to proteins, lipids, and DNA.
95
How does alcohol lead to fatty liver?
Increased NADH/NAD+ ratio inhibits fatty acid oxidation and promotes synthesis.
Acetaldehyde enhances fat synthesis and inhibits fat oxidation.
Fat export from the liver is reduced.
96
How does chronic alcohol exposure promote inflammation?
Activates macrophages, triggering inflammation.
Acetaldehyde binds proteins, forming adducts seen as antigens by the immune system.
97
How is alcoholic liver disease diagnosed?
Based on signs of liver dysfunction, alcohol use history, liver function tests, and complete blood count.
98
What is the best treatment for alcoholic liver disease?
Abstinence from alcohol, supportive care (nutrition, vitamin supplements), and corticosteroids (effectiveness debated). Liver transplantation is an option for severe damage in abstinent patients.
99
What condition, caused by compromised liver function can affect cognitive function
A condition called hepatic encephalopathy, where toxins bypass the liver, affecting the brain, causing confusion, tremor, drowsiness, or coma.
100
Where is pain from the liver typically referred, and why?
Liver pain is referred to the right upper quadrant, right shoulder/scapular area, or epigastrium. This occurs due to the liver's innervation by the PHRENIC nerve (C3-C5) (irritating the diaphragm) and shared pathways through the celiac plexus.
101
Difference between Pharmacodynamics and Pharmacokinetics
Pharmacodynamics is what the drug does to the body
Pharmacokinetics is what the body does to the drug
102
What does volume of distribution mean and what it being high or low mean
Vd is a measure of how extensively a drug distributes into the body's tissues compared to staying in the bloodstream. A high Vd means more distribution into tissues, while a low Vd means the drug stays mostly in plasma.
Low Vd (Stays in Bloodstream):
The drug doesn’t like to leave the blood because:
- It dissolves better in water (hydrophilic).
- It binds tightly to plasma proteins like albumin.
Example: A drug that treats blood infections might stay in the bloodstream to work effectively.
High Vd (Spreads to Tissues):
The drug moves out of the bloodstream because:
- It dissolves better in fat (lipophilic).
- It binds to tissues (like fat or muscle) rather than staying in the blood.
Example: A sedative might go to the brain or fat tissue, so it has a higher Vd.
103
How can liver disease affect pharmokinetics
If the liver is damaged you have less blood proteins like albumin in the blood, drugs can bind to proteins like albumin in the blood, these bound drugs don't exert its effect since its bound to albumin and cant enter target cells, and so free drugs are those that can exert its function.
If liver function is impaired causing less albumin to be produced it means that there will be more free drugs available and so the drug will have a greater effect, this can be bad for drugs that have a narrow therapeutic window like warfarin and phenytoin
Since bilirubin is transported via albumin, high levels of bilirubin can displace drugs bound to albumin increasing the drug's effect
104
What's the problem with lipophilic drugs and how do we deal with this problem
Most drugs are lipophilic, the problem is since they're lipophilic they can re-circulate after going through the glomerulus and so we need to find a way to eliminate them. To do this it must undergo drug metabolism which is the enzyme-mediated conversion of a lipophilic compound into a more hydrophilic compound. And these drug metabolism reactions occur mostly in the liver
105
Drug metabolism is done by Drug Metabolising Enzyme reactions (DME reactions) and is divided into two phases, what are they and what do they generally do
Phase 1 reactions:
- Involve oxidation, reduction, or hydrolysis
- Make drugs more polar (water-soluble)
- Preparation for phase 2
- Mainly carried out by Cytochrome P450 enzymes (genereally CYP1-3)
- Can produce both active and inactive metabolites
Phase 2 reactions:
- Involve conjugation reactions (adding molecules like glucuronic acid, sulfate, or glutathione)
- Generally produce inactive, more water-soluble compounds (it inactivates the drug)
- Increases molecular weight
- Make drugs easier to excrete through urine or bile
- Examples include glucuronidation, sulfation, and acetylation
106
What are pro drugs and how do they work
Pro drugs are drugs that when first administered has no effect on its own but when it is metabolised it turns it into an active drug (usually in phase 1) e.g.
e.g. Prednisone (pro-drug) gets turned into Prednisolone (active drug)
107
What are some Conjugation reactions
- Glucuronidation * - most
widespread
- Sulphation *
- Methylation
- Acetylation
- Amino acid
Typically with glycine and
glutamine, which are
typically reduced in liver
dysfunction (can cause
an issue with drugs that
are typically conjugated
with amino acids)
- Glutathione
- Fatty acid
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Describe a drug's journey in the enterohepatic circulation
Glucuronides are effective in increasing amount of some drugs present in the body
Image describes the following process
- Drug absorbed from GI tract into the blood
- Reaches the liver where is undergoes glucuronidation.
- The drug-glucoride gets mixed with bile and in the GI tract, gets either excreted into the faeces or hydrolysed by B-glucuronidase into the
drug to be reabsorbed
109
What are some internal factors (factors we have no control over) that affect drug metabolism
Age:
- DMEs may be immature at birth
- As we age we naturally have reduced liver mass and decreased blood flow
- Drug inactivation is slower (mostly Phase 1 oxidation)
- Decreased first-pass metabolism
Sex (to a lesser extent):
- Some differences in certain enzymes
Pregnancy:
- Increased hepatic metabolism (increased blood flow, increased activity of some DMEs)
Disease (hepatic)
Genetics:
- DNA insertions, deletions, disparity in the number of repeated sequences, and Single Nucleotide Polymorphisms or SNPs (e.g.
TAGC - TACC) all lead to polymorphisms. SNPs are especially important as they can help with personalised medicine
110
What are some external factors (factors we have control over) that affect drug metabolism
- Drug-induced (more on this late, these are drugs that can damage the liver e.g. paracetamol)
- Lifestyle: cigarette smoking induces metabolism of: Theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide, estradiol, etc.
- Environment, e.g. arsenic, toluene, fluorine
diet (BBQed meat, Brussels sprouts increase drug metabolism, grapefruit juice decrease drug metabolism)
Inducers or Inhibitors (increase or decrease drug metabolism)
111
Explain what Type A and Type B adverse drug reactions mean
Type A (Augmented) ADRs:
- Description: These reactions are predictable, dose-dependent, and related to the pharmacological action of the drug.
- Cause: Due to an exaggerated or excessive response to the drug's normal mechanism of action.
Characteristics:
- Common
- Occur at therapeutic doses
- Can often be avoided by adjusting the dose or monitoring the patient more closely.
Examples:
- Hypoglycemia with insulin (caused by its glucose-lowering effect).
- Bleeding with anticoagulants like warfarin (due to its blood-thinning mechanism).
- Sedation with antihistamines (related to their CNS effects).
Type B (Bizarre) ADRs
Description: These reactions are unpredictable, not dose-dependent, and not related to the drug’s known pharmacological action.
Cause: Often due to idiosyncratic reactions, immune-mediated effects, or genetic predispositions.
Characteristics:
- Rare
- Serious and potentially life-threatening
- Not preventable through dose adjustments or routine monitoring.
Examples:
- Anaphylaxis to penicillin (a hypersensitivity reaction).
- Stevens-Johnson syndrome with certain antibiotics or anticonvulsants (a severe immune-mediated skin reaction).
- Hemolytic anemia in patients with G6PD deficiency after taking certain drugs (like sulfonamides).
112
Explain paracetamol drug-induced liver toxicity
Paracetamol can be broken down into two ways, approx 85% of the paracetamol is converted into an inactive form and excreted in the urine, but in the other pathway paracetamol is turned not another compound first (NAPQI, ends in imine) which has to be conjugated and if not it can cause hepatotoxicity, this toxic compound has to undergo glutathione conjugation and be converted into an inactive metabolite and excreted
In liver damage glutathione concentrations can be reduced so the compound is not broken down and can cause hepatotoxicity and cell death and so that is why paracetamol is contraindicated in patients with liver damage,
113
What are some Inducers or Inhibitors of drug metabolism
Inducers:
- Carbamazepine
- Alcohol
- St. John's wort
Inhibitors:
- Fluoxetine
- Erythromycin
- Ketoconazole
- Grape juice (it can inhibit CYP3A4 enzyme which metabolises 30% of all drugs (statins, verapamil, nifedipine etc.) this will mean the drug will stay in blood plasma for longer meaning it will have a prolonged effect
114
What are the patterns of drug-induced liver injury (3 categories)
115
How can genetic polymorphisms affect drug metabolism
The image above displays how metabolism can differ between individuals depending on their genetics. The more functional genes you have for drug metabolism, the less plasma drug will be present and the more metabolites produced and vice versa.
For example if someone has more functional genes for the CYP protein they will metabolise a druge faster, decreasing the time the drug spends in their blood plasma meaning it'll have less of an effect of them.
116
Can you give an example of where individualised therapy can be used because of SNPs
For liver transplants some immunosuppressants e.g. tacrolimus, has a very narrow therapeutic window, CYP3А4 and CYP3A5 are major enzymes responsible for metabolising tacrolimus, if you have a SNP in both enzymes it can cause it to not be able to carry out its metabolising function, this will lead to tacrolimus to be in the blood for longer which increases risk of nephrotoxicity. To prevent this sometimes we will screen for the allele before the transplantation to ensure the correct dose of tacrolimus is given,
117
What are the best indicators for liver function
(These are the best according to the lecture)
- Serum Albumin
- Prothrombin time
(But)
- Measuring liver enzymes like AST, ALT, ALP and GGT can also be useful to measure
- CYP450 is also reduced in liver disease but its hard to measure
118
What happens to blood flow through the liver, first pass metabolism, drug half-life and drug clearance ability during liver disease
- Decreased blood flow through liver
- Decreased first-pass metabolism which increases plasma concentration of certain drug
- Increase half-life of drugs since drug metabolism is impaired
- Decreased clearance since drug metabolism is impaired
So if we are unaware someone has liver damage and we give them a normal dose of a drug it can cause toxic side effects
119
What is Liver Fibrosis
Progressive deposition of type I collagen-rich ECM in response to iterative (repeated) liver injury, it is the final pathway to most chronic liver injuries and leads to cirrhosis
Fibrosis is done by Hepatic Stellate Cells in response to injuries and by the inflammatory cascade
120
What is the liver fibrosis staging
IS0 (No Fibrosis):
- No significant scarring in the liver.
- Normal liver architecture and function.
IS1 (Mild Fibrosis):
- Minimal scarring, typically around portal areas (fibrosis confined to small regions near blood vessels).
- Function is largely preserved.
IS2 (Moderate Fibrosis):
- Fibrosis extends beyond portal areas but does not form significant bridging between regions.
- Early changes in liver structure may start to appear.
IS3 (Severe Fibrosis Without Bridging):
- More extensive scarring that may be approaching the formation of bridges between portal and central veins.
- Liver function begins to be affected.
IS4 (Bridging Fibrosis):
- Fibrous bands connect different regions (portal to portal or portal to central areas).
- Significant alteration of liver structure.
- Increased risk of progressing to cirrhosis.
IS5 (Cirrhosis Without Nodularity):
- Extensive scarring disrupts liver architecture, but the liver tissue is not yet nodular.
- Function is significantly compromised.
IS6 (Cirrhosis With Nodularity):
- Complete disruption of liver architecture with nodular regeneration.
- This is end-stage liver disease, associated with complications like portal hypertension, varices, and liver failure.
121
Liver cirrhosis treatment
TDF stands for Tenofovir Disoproxil Fumarate, which is an antiviral medication used to treat chronic hepatitis B infection. According to
the context, it has been shown to help reverse liver fibrosis and cirrhosis when used as a treatment for 5 years.
122
What is the Childs-Pugh Score
- Originally designed as a surgical risk score.
- Expanded as prognostic score for people with cirrhosis.
- Weirdly goes from 5-15 and divided into 3 stages.
123
What does a ratio of AST:ALT >2 and <1 usually indicate
A ratio of >2 strongly suggests alcoholic liver disease
A ratio of <1 is more common in viral hepatitis and non-alcoholic fatty liver disease
124
How does liver pain present differently in conditions like hepatitis vs. gallbladder disease?
Hepatitis: Diffuse, dull pain in the RUQ, sometimes accompanied by systemic symptoms.
Gallbladder disease: Sharper, intermittent RUQ pain, potentially radiating to the back or right shoulder.
