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Bench to bedside and beyond > Liver transplant case study > Flashcards

Liver transplant case study Flashcards

1
Q

What are the key symptoms of primary biliary cholangitis?

A
  1. extreme tiredness
  2. itchy skin
  3. dry eyes and mouth
  4. diarrhoea
  5. weight loss
  6. pain in the right abdomen
  7. oedema of the feet and ankles
  8. jaundice
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2
Q

What causes the itchy skin?

A

The liver disease degrades the bile ducts making it harder to flow so it enters the blood and causes histamine to be produced and the itchy skin

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3
Q

What causes diarrhoea and weight loss?

A

fat malabsorption due to the lack of bile in the bile duct

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4
Q

What are the symptoms of the secondary cytomegalovirus infection?

A
  1. fever
  2. malaise
  3. anorexia
  4. night sweats
  5. swollen liver
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5
Q

What does a full family history comprise of?

A
  1. relevant health conditions and diseases of your family
  2. family age
  3. disease onset, treatment given and outcomes
  4. Biological relationship with the patient
  5. ethnicity and ancestry information
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6
Q

What is a full medical history?

A
  1. personal info like age, gender and ethnicity
  2. current diagnosis of disease and info about duration and severity
  3. info about past medications
  4. allergy and adverse reactions
  5. vaccinations
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7
Q

What is involved in an abdominal exam and what is the doctor looking for?

A
  1. inspect the abdomen for differences in space/size/rashes/scars
  2. they may use a stethoscope to listen to bowel sounds
  3. apply pressure to assess for tenderness and superficial masses
  4. heavy pressure used for detection of enlarged organs or abnormal masses
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8
Q

Blood tests: Complete blood count

A

evaluates RBC, WBC and platelets

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9
Q

Blood tests: metabolic panel

A

measures electrolytes, glucose, kidney function and liver enzymes.
abnormal liver enzymes = liver dysfunction and graft rejection

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10
Q

Blood tests: lipid panel

A

assess cholesterol and triglyceride levels. Checks for risk of CVD

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11
Q

Blood tests: thyroid panel

A

measure thyroid hormone levels to asses thyroid dysfunction

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12
Q

Blood tests: Coagulation panel

A

Evaluates blood clotting functions. Assesses bleeding or thrombosis

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13
Q

Blood tests: DHEA sulphate serum test

A

check for adrenal gland dysfunction

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14
Q

Blood tests: C reactive protein

A

measures inflammation levels

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15
Q

Blood tests: antimitochondrial antibody test

A

detects antibodies associated with autoimmune liver disease

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16
Q

What are liver biopsies and why are they used?

A
  1. Microscopically examine a sample of liver tissue to assess structure function and signs of damage/disease
  2. look at liver architecture, structure and organisation
  3. cellular morphology - the appearance/size/shape/damage of hepatocytes
  4. look for presence of pro inflammatory cells
  5. look for fibrosis
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17
Q

What is biliary cholangitis?

A
  1. autoimmune disease
  2. bile ducts are inflamed and slowly destroyed
  3. can be characterised by high titres of serum anti-mitochondrial antibodies
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18
Q

What are the stages of primary biliary cholangitis?

A

Stage 1: medium-sized bile ducts are affected and there is slight inflammation and damage
Stage 2: small-sized bile ducts are beginning to form blockages
Stage 3: scarring begins in the liver
Stage 4: the liver has been permanently damaged by cirrhosis. This is irreversible.

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19
Q

What are the causes of biliary cholangitis?

A
  1. autoimmune disease
  2. the body attacks healthy cells believing they’re foreign invaders
  3. the antibodies target the mitochondria (AMAs)
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20
Q

What is the role of the immune system in primary biliary cholangitis?

A
  1. Inflammation in the liver can lead to bile duct inflammation and damage known as cholangitis
  2. This degrades the bile duct causing it to be harder for bile to flow through
  3. bile back up inside the liver damaging the tissue.
  4. The immune system attempts to repair the scarring resulting to scar tissue formation - fibrosis
  5. this leads to cirrhosis or permanent scarring and then liver failure
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21
Q

What is the role of the immune cells in primary biliary cholangitis?

A
  1. CD4 T cells activate other immune cells like autoreactive CD8 T cells and B cells
  2. the CD8 T cells causes the epithelial cell injury
  3. The B cells produce large quanities of AMAs
  4. Dendritic cells, NK cells, monocytes and macrophages are activated. This perpetuates bile duct damage.
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22
Q

Are there sex differences in the incidence of biliary cholangitis? Who is most at risk?

A
  1. Mostly affects women. ~ 90%
  2. Mostly occurs between 30-60 years old.
  3. most people have a family member that has it
  4. most common in people of Northern European descent but affect all ethnicities
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23
Q

What causes primary biliary cholangitis?

A
  1. combination of genetic and environmental factors
  2. infections such as UTIs
  3. Smoking over long periods
  4. exposure to toxic chemcials
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24
Q

Treatments for biliary cholangitis: UDCA

A
  1. Ursodeoxycholic acid
  2. the primary therapy
  3. helps delay liver damage in the early stages
  4. helps move bile through the liver
  5. not a cure
  6. Improves liver function test and reduce scarring
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25
Q

Treatments for biliary cholangitis: Obeticholic acid

A
  1. helps liver function and slows fibrosis
  2. improves bile flow and reduce inflammation
  3. can be taken with UDCA
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26
Q

Treatments for biliary cholangitis: Fibrates (Tricor)

A
  1. can help ease symptoms
  2. when taken with UDCA it can reduce liver inflammation and itching in some people.
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27
Q

Treatments for biliary cholangitis: liver transplantation

A

For advanced disease.
70% survival after 10 years

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28
Q

What does CMV seronegative mean?

A

No IgG antibodies found for CMV in the blood.

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29
Q

What is the importance of CMV seronegative blood donors?

A
  1. Their blood is in high demand due to high prevalence of CMV in the population.
  2. Important for transplant patients, neonates, and immunocompromised people.
  3. Still a small risk of transmission.
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30
Q

What is CMV?

A
  1. Cytomegalovirus
  2. The most common opportunistic infection for liver transplant patients.
  3. 29% of liver transplant patients will get CMV with in 3 months. Most of these are CMV seronegative patients.
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31
Q

What can CMV infection affect?

A

Graft survival and mortality

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32
Q

What are the risk factors for developing a CMV infection post transplant?

A
  1. CMV seronegative patient
  2. high levels of immunosuppression
  3. treatment with lymphocyte-depleting antibodies
  4. confection with another herpes virus
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33
Q

Why does CMV attack the graft?

A
  1. Not really sure why
  2. It could be due to the organ being a reservoir for latent CMV.
  3. Reactivation after transplantation is not detected by an impaired immune system.
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34
Q

How is CMV linked to graft rejection?

A
  1. causes inflammation in the liver.
  2. the symptoms are similar to those of rejection causing confusion and incorrect treatment.
  3. causes a 4 fold increase of chronic and acute rejection.
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35
Q

How does CMV infection effect post transplant treatment?

A
  1. Reduction of immunosuppression leading to increased risk of rejection.
  2. Oral valganciclovir as prophylaxis.
  3. IV (val)ganciclovir as treatment.
  4. For resistant CMV combination therapy of Foscarnet and cidofovir.
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36
Q

Who can refer someone for a liver transplant?

A

A hepatologist or gastroenterologist

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37
Q

What is involved in transplant assessment?

A
  1. Done in 1 of 7 liver transplant centres therefore travel costs.
  2. 5 days of tests as an in or out patient depending on health and travel distance.
  3. Asked about symptoms, medical history, alcohol and drug habits.
  4. Tests include blood tests, X-rays, other scans, ECG, spirometry, endoscopy.
38
Q

What must be the odds of survival to be accepted for a transplant?

A

50 in 100 after 5 years

39
Q

When might you not get put on the transplant wait list?

A

If you are suitable for one but you are still too well and your current organs is functioning above a certain level.

40
Q

What is the liver transplant wait times?

A

65 days for adults.
77 days for children.
Less if you have a living donor.

41
Q

What does a patient need to do while on the waiting list?

A
  1. Eat healthily and exercise if you can.
  2. No smoking.
  3. Stay up to date on vaccinations.
  4. Be on contraception if you are a woman.
  5. Prepare and make arrangements with family.
  6. Provided with mental health support.
42
Q

How are recipients of organs chosen?

A

Based on suitability determined by the assessments done during referral.
Done to give the organs and person the best 2nd chance.

43
Q

What makes a patient not suitable for an organ transplant?

A
  1. There is a low chance of it being successful.
  2. The patient is too ill.
  3. The patient has a recent heart attack, stroke or metastatic cancer.
44
Q

What patients need specialist assessment?

A
  1. patients using or with a history of using intravenous drugs.
  2. Patients with excessive alcohol consumption.
  3. This is due to these patients being less likely to follow mediation and follow up schedules and increasing the chance of rejection.
45
Q

Why do re-transplant patients need specialist care?

A

due to them having a higher risk of rejection

46
Q

How is a liver transplant carried out from the patient POV?

A
  1. Recipient called into hospital.
  2. Recipient under general anaesthetic during operation.
  3. Surgery lasts 5-8 hours.
  4. 2-stage operation: removal of the damaged liver and transplant of the donor liver.
  5. Recipient receives 1/2 drains into the abdomen to drain fluid and blood.
47
Q

How is the damaged liver removed?

A
  1. Y-shaped incision over upper abdomen.
  2. Caval replacement which includes removal of the inferior vena cava.
  3. OR side-to-side cava-cavostomy which retains the recipient’s inferior vena cava and attaching it to the new liver.
  4. Blood vessels in and out of the liver and the bile duct are cut.
48
Q

How is the donor liver transplanted?

A
  1. Blood vessels into and out of the new liver are connected to the recipient’s blood vessels.
  2. The gallbladder of the donor liver is removed.
  3. Donor bile duct connected to recipient’s bile duct
49
Q

What is a split liver transplant?

A

The extended right lobe (right lobe and the upper left lobe) is transplanted into the adult.
The smaller left part is used for a child recipient.

50
Q

What are the benefits of using a live donor?

A
  1. Able to plan ahead and find a match and get the compatibility as close as it can be.
  2. Better organ preservation.
  3. Live donor organs tend to be viable for longer and give the recipient better quality of life.
  4. Transplant occur sooner then waiting on the wait list.
51
Q

What are the risks of using a live donor?

A
  1. Limited as only live whole organ transplants can be kidneys and partial liver.
  2. Some recipients can’t wait to find a live donor match.
  3. The donor has to be in good health.
  4. Extensive regulation assessing health, psychological, and motivational.
  5. Ensuring consent is freely given.
52
Q

What are the benefits of using a cadaveric donor?

A
  1. More options as most organs can be obtained from these donors.
  2. Deemed consent system.
  3. There are less rigorous regulations than for live donation.
53
Q

What are the risks of using a cadaveric donor?

A
  1. There is less time to test for compatibility due to organ viability time. For heart and liver no HLA matching is done.
  2. Type of death increases risks for different organs. (DCD= heart/liver risk, DBD= lung risk).
  3. Cannot plan ahead.
  4. Family consent affects availability of organs.
54
Q

How does valganciclovir work?

A
  1. It is a nucleoside analogue to guanine.
  2. Gets broken down into active ganciclovir.
  3. Ganciclovir is phosphorylated 3 times to form ganciclovir triphosphate.
  4. This acts as a competitive inhibitor to viral DNA polymerase as it doesn’t have a 3’ phosphate.
  5. Inhibits viral replication.
55
Q

What barrier does the immune system pose to tranplantation?

A
  1. HLA function in antigen presentation and self recognition.
  2. identification of mismatches initiated an immune response and results in transplant rejection.
  3. Blood grouping is important for immune tolerance due to the presence of antibodies against the antigens not present.
  4. Also consider RhD +/-
56
Q

What matching is usually performed between donors and recipients of liver transplants?

A
  1. Based on the transplant benefit score.
  2. categories like age, health conditions, blood group, and matching body size.
  3. Microbiological screening for CMV and EBV.
  4. Ethnic background matching is not required.
  5. HLA matching is not considered for heart and liver transplants due to problems with organ preservation and immunosuppression can overcome this.
57
Q

What donor and recipient factors affect the success of organ transplantation?

A
  1. Recipient factors: age, comorbidity, disease considerations, time after diagnosis, race.
  2. Prior chemotherapy regimens and IL-10 promoter polymorphisms.
  3. Donor risk factors: HLA mismatch, gender, relation, age, organ quality (fat, scar tissue, ischemic time), killer cell immunoglobulin-like receptor genotype.
58
Q

What measures can be taken to improve organ preservation during transportation?

A
  1. Normothermic perfusion and subnormothermic perfusion to deliver nutrients and oxygen whilst removing waste.
  2. Freezing of non-living tissue.
  3. cryopreservation of living tissue.
  4. Storage of living tissues above freezing.
  5. Storage in a tissue bank.
  6. Hypothermic storage.
59
Q

What can be preserved with freezing of non-living tissue?

A

At -40 - -80
1. bone
2. cartilage
3. amniotic membrane

60
Q

What can be preserved with cryopreservation of living tissue?

A

At -135
1. heart valves
2. arteries
3. skin

61
Q

What is hypothermic storage?

A
  1. At 0-4
  2. reduces metabolism and bacterial growth.
  3. increases tolerance of ischemia
  4. limits protein synthesis and intracellular ionic imbalance
62
Q

What is a biliary anastomosis?

A
  1. a surgical connection between the bile ducts and either the small intestine or another part of the biliary system.
  2. this creates a roux limb and a hepatobiliary limb that are joined at the mid jejunum
  3. can also be used to treat bile obstructions.
63
Q

What is a hepaticojejunostomy?

A
  1. an anastomosis between the bile ducts of the liver and the jejunum.
  2. This reroutes the bile ducts to the jejunum allowing the bile to bypass the obstructed area and flow directly into the small intestine.
  3. This restores bile flow
64
Q

What is a unit of donor blood?

A

The standard quantity of blood collected from a single donation.
This is around 450ml and ensure the RBC component meets the specification.

65
Q

What happens to blood after it is donated?

A
  1. Processed and kept as whole blood
  2. OR separated into components such as red blood cells, plasma and platelets.
66
Q

What is a unit of processed blood?

A

A unit of blood is more versatile with a specific amount of red blood cells, plasma and platelets allowing for targeted treatments.

67
Q

What are transfusion-transmitted infections?

A
  1. an infection that a recipient acquires through the transfusion of blood or blood products.
  2. these can be caused by viruses, bacteria, parasites and prions that could be present in blood.
  3. This includes hepatitis B and C, HIV and malaria.
68
Q

How is microbiological screening done?

A
  1. Nucleic acid amplification test to detect viral genetic material for early diagnosis.
  2. Serological testing to detect antibodies and antigens in the blood to indicate the presence of infectious diseases. HIV, syphilis, hepatitis B/C.
  3. Bacterial contamination screening for platelet donations which are more susceptible to bacterial growth
69
Q

Why is immune suppression used post transplant?

A
  1. the recipient’s immune system can perceive the new organ as a threat.
  2. to prevent rejection, immune-suppressing medications are used to balance suppressing the immune response while maintaining infection defence.
70
Q

Immune suppression medicine: Antilymphocyte globulin

A
  1. Antibodies that specifically target antigens on the surface of lymphocytes.
  2. Binding triggers cell death by complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.
  3. reduces ability to mount an immune response reducing acute rejection risk
71
Q

Immune suppression medicine: Tacrolimus

A
  1. Binds immunophilin FK506-binding protein 12.
  2. This complex then inhibits the phosphatase activity of the calcineurin.
  3. This prevents the activations of the NFAT transcription factor.
  4. This prevents the activation of genes that are critical for T-cell activation and proliferation like IL-2.
72
Q

Immune suppression medicine: Mycophenolate

A
  1. Inhibits inosine monophosphate dehydrogenase which is important for making guanosine nucleotides.
  2. lymphocytes heavily rely on this for proliferation.
  3. inhibiting this pathway blocks the proliferation of T and B lymphocytes.
  4. Quite specific to lymphocytes so other cells are spared.
73
Q

Immune suppression medicine: Prednisone

A
  1. converted in the liver to active form = prednisolone.
  2. This binds cytoplasmic glucocorticoid receptors, forms a complex, and enters the nucleus.
  3. This can activate and repress the transcription of a wide range of genes associated with immunity and inflammation.
  4. Suppress genes coding for pro-inflammatory cytokines like IL-2.
  5. Activate genes for anti-inflammatory proteins like IL-10
  6. It can also inhibit the expression of adhesion molecules on endothelial cells and leukocytes reducing immune cell trafficking to sites of inflammation.
74
Q

Why is antimicrobial prophylaxis used post transplant?

A

To prevent the occurrence of infections in patients who are at high risk due weakened immune system.

75
Q

Antimicrobial prophylaxis: Trimethoprim-sulfamethoxazole

A
  1. combination antibiotic
  2. inhibits bacterial synthesis of nucleic acids and proteins.
  3. trimethoprim inhibits dihydrofolate reductase.
  4. Sulfamethoxazole inhibits dihydropteroate synthesis.
  5. Together this blocks tetrahydrofolic acid production which is essential for the synthesis of bacterial purines, thymidine, and amino acids.
76
Q

Antimicrobial prophylaxis: Acyclovir

A
  1. Used against herpes simplex
  2. mimics guanine and gets incorporated into the viral DNA.
  3. It is a chain terminator so inhibits replication.
  4. However it requires activation by phosphorylation to produce acyclovir triphosphate.
  5. Doesn’t cause significant toxicity to host cells
77
Q

Antimicrobial prophylaxis: Fluconazole

A
  1. Anti-fungal
  2. inhibits cytochrome P450 enzyme 14a-demethylase which is important for making the fungal cell membrane.
  3. This leads to cell death.
  4. effective against candida and cryptococcus neoformans
78
Q

Antimicrobial prophylaxis: Foscarnet

A
  1. Broad spectrum anti-viral agent
  2. directly inhibits viral DNA polymerase, RNA polymerase and reverse transcriptase.
  3. Doesn’t need activation by phosphorylation.
  4. It binds the pyrophosphate binding site which blocks the cleavage of pyrophosphate from dNTPs, an essential step of nucleic acid synthesis.
  5. Mostly used against CMV and acyclovir-resistant HSV infections
79
Q

What does a low haematocrit blood test result mean?

A

indicates potential anaemia due to decreased RBC production or blood loss due to bleeding.

80
Q

What does a low WBC blood test result mean?

A

A weakened immune system or the presence of an infection.

81
Q

What does a low platelet blood test result mean?

A

Thrombocytopenia which reduces clotting potential and means a higher risk of bleeding.

82
Q

What does a high AST blood test result mean?

A

Indicates damage to liver cells so the enzymes are leaking into the bloodstream.
Also a sign of inflammation.

83
Q

What does a high ALT blood test result mean?

A

Indicates high levels of liver damage or inflammation.
ALT is more specific to the liver the AST.

84
Q

What does a high bilirubin blood test result mean?

A

indicates jaundice or the liver’s reduced ability to process bilirubin possibly due to blockage or liver cell damage.

85
Q

What can cause the diagnosis of probable rejection?

A
  1. Worsening liver function tests.
  2. Clinical symptoms despite ongoing treatment for CMV
  3. suggests the patient’s immune system may be attacking the graft.
86
Q

What does increased CMV antigenemia indicate?

A

active viral replication and infection severity.

87
Q

What does high AST indicate in terms of graft rejection?

A

severe liver damage often associated with rejection or severe infection.

88
Q

How could the CMV infection become ganciclovir-resistant?

A
  1. Mutations in CMV leading to resistance or suboptimal treatment.
  2. Inadequate drug absorption leading to lower than needed drug levels to effectively fight the infection.
  3. Previous antiviral exposure could lead to selection for resistant CMV strains.
89
Q

How long would a liver transplant be expected to last?

A

At least 5 years.
- 72% of patients are alive after 5 years
- 53% or patients are alive after 20 years
It depends on age and gender.

90
Q

Will primary biliary cholangitis reoccur in the new liver?

A

Unlikely but more likely in older patients

91
Q

What are the causes of liver rejection?

A
  1. graft dysfunction due to infection or ischemia.
  2. incorrect HLA matching causing alloantibodies or antibodies causing rejection.
  3. recurrence of the initial disease.
92
Q

How can you detect liver graft rejection?

A
  1. acute or chronic
  2. detected by elevated hepatic enzymes like bilirubin.
  3. confirmed by a liver biopsy.

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