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Liver Transplant

Donor Evaluation in LDLT

Medical Evaluation Phases

Phase 1

  • Clinical, CBC, Renal, Liver Function, Viral Serology
  • UPT (Urine Pregnancy Test)
  • Liver Attenuation Index (LAI) on NCCT
    • LAI < 0 leads to Phase 2 only after improvement following weight reduction

Phase 2

  • CT Angiography, Volumetry, and MRCP (Magnetic Resonance Cholangiopancreatography)
  • MR Fat Estimation and Liver Biopsy if >1 factor suggests Metabolic Syndrome

Phase 3

  • Detailed systemic evaluation including Cardio-pulmonary Tests and Consults
  • PAC (Pre-anesthetic Check-up)

Phase 4

  • Multidisciplinary Meeting
  • Authorization Committee Approval

Donor Evaluation - Contraindications

  • Age: Less than 18 years or more than 60 years
  • Steatosis: Greater than 30%
    • Right Lobe: Greater than 15%
    • Left Lobe: Greater than 20%
  • Donor Remnant Volume: Less than 30%
  • Psychiatric Illness
  • Coercion
  • BMI: Greater than 35 kg/m²
  • Hepatitis B Core Antigen Positive: Not a contraindication

Michels Classification of Hepatic Arterial Anatomy

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  • Type 1 (55%): Normal anatomy with right, middle, and left hepatic arteries originating from the proper hepatic artery.
  • Type 2 (10%): Replaced left hepatic artery originating from the left gastric artery.
  • Type 3 (11%): Replaced right hepatic artery originating from the superior mesenteric artery (SMA).
  • Type 4 (1%): Replaced right hepatic artery from SMA and replaced left hepatic artery from left gastric artery.
  • Type 5 (8%): Accessory left hepatic artery from the left gastric artery.
  • Type 6 (7%): Accessory right hepatic artery from the SMA.
  • Type 7 (1%): Accessory right hepatic artery from SMA and accessory left hepatic artery from left gastric artery.
  • Type 9 (4.5%): The common hepatic artery arises from the SMA.

Nakamura Classification

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  • Type 1:
    • RAPV, RPPV, and RPV are present.
    • n = 83 (86.4%)
  • Type 2:
    • RAPV branches out earlier, affecting the overall structure.
    • n = 6 (6.3%)
  • Type 3:
    • RAPV and RPPV are both distinct, but their branching pattern differs.
    • n = 7 (7.3%)

Undoable Portal Vein for RLLDLT

  • Type D:
    • Portal vein bifurcation with abnormal structure making it unusable for Right Lobe Living Donor Liver Transplantation (RLLDLT).
  • Type E:
    • Multiple branches (P4, P5, P8) and irregularities in portal vein anatomy render it unusable for RLLDLT.

Huang Classification of Right-Sided Biliary Anatomy

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  • Type A1:
    • RASD and RPSD join to form the right hepatic duct.
    • 62.6% occurrence.
  • Type A2:
    • RASD joins the LHD (Left Hepatic Duct), while RPSD joins the CHD.
    • 19% occurrence.
  • Type A3:
    • RPSD drains into the LHD.
    • 11% occurrence.
  • Type A4:
    • RASD drains into the LHD.
    • 5.8% occurrence.
  • Type A5:
    • RPSD drains directly into the CHD.
    • 1.6% occurrence.

Note: Variations in biliary anatomy are not a contraindication for donation.

Complications in Living Donor Liver Transplantation (LDLT)

  • 1-Year Survival Rate: 85%
  • 5-Year Survival Rate: 70%
  • Higher incidence of:
    • Hepatic Artery Thrombosis (HAT)
    • Bile Leak
    • Biliary Stricture
  • Early Allograft Dysfunction: [ Primary Non Function = less in case of LDLT]
    • Occurrence of Small-for-Size Syndrome in LDLT [ not seen in DDLT]

Procurement Injury in Liver Transplantation

  • Incidence: 20-30%
  • Most Common Injury: Ligation of an aberrant hepatic artery
  • High incidence of early Hepatic Artery Thrombosis (HAT)
  • Cold Ischemia Time (CIT) > 12 hours increases complications
  • Macrosteatosis > 30% is a risk factor for poor graft function

Primary Non-Function (PNF) in Liver Transplantation [ In DDLT setting]

  • Incidence: 2-6%
  • Donor Factors:
    • Age
    • Steatosis
    • Prolonged Cold Ischemia Time (CIT)
    • Prolonged Warm Ischemia Time (WIT) [ especially DCD patients]
  • Clinical Features:
    • Acidosis
    • Hypoglycemia
    • Coagulopathy
    • AST/ALT > 8000 within the first 24-48 hours ⇒ hepatic necrosis.
  • Most Reliable Predictor: Deranged INR indicating poor graft function
  • Requires Status 1 [above MELD listing] listing for retransplant
  • Diagnosis of exclusion [ after excluding HAT/ Septic Encephalopathy]
  • Management = Re Transplant

Early Allograft Dysfunction (EAD) [ In LDLT setting ⇒ Small for Size Sx]

  • Represents a spectrum of abnormalities in graft function
  • Graft-to-Recipient Weight Ratio (GRWR) < 0.8
  • Portal Systemic Gradient: Less than 15 mm Hg is required to tackle small for size syndrome
    • [ Inflow/Outflow Modulation]
    • Splenic Artery ligation , Shunt procedures etc
  • Risk Factors:
    • Increasing age of the donor
    • High BMI donor
    • Left liver grafts
    • Enlarged spleen

Hepatic Artery Thrombosis (HAT)

  • Most common arterial complication
  • Incidence:
    • 1.6% to 8% in adults
    • 15-26% in pediatric patients
  • Risk Factors:
    • CMV positive
    • Variant hepatic artery anatomy
    • Low surgical volume = Technical Problem is the most common cause
  • Early HAT (within 7 days): worst to manage
    • AST > 3000
    • INR > 2.5
    • Acidosis
    • Requires Status 1a listing
  • Late HAT:
    • Biliary complications such as Bilioma (most common presenting symptom)
    • Better prognosis than early HAT
  • Diagnosis:
    • Doppler within 1 week = if no flow ⇒
    • CT angiography = to confirm diagnosis
  • Management
    • Re anastomosis = gold standard
    • some patients may need re transplant also

Portal Vein Thrombosis (PVT)

  • Incidence: 5-25%
  • Earlier considered as a Contraindication for Transplant.
  • More pertinent in Preop Period.

Yerdel Classification:

  • Grade 1:
    • PVT < 50%
  • Grade 2:
    • PVT > 50% with SMV obstruction
  • Grade 3:
    • 100% PVT
  • Grade 4:
    • 100% PVT with SMV thrombosis

Management:

  • Grade 1 & 2 = Jump Graft from SMV to PV
  • Grade 3 & 4 = ??

Biliary Leak

  • Incidence: 10-50%
  • More common in LDLT than DDLT
  • Risk Factors:
    • Hepatic Artery Thrombosis (HAT)
    • Small bile ducts
  • Similar leak rates between:
    • Duct-to-duct anastomosis
    • Roux-en-Y Hepaticojejunostomy (RYHJ) = If patient has PSC or Pediatric patients RYHJ is done.
  • Management:
    • ERCP
    • Conservative treatment

Biliary Stricture

  • Incidence: 7-15% of liver transplants
  • Types:
    • Anastomotic
    • Non-anastomotic
  • Risk Factors:
    • Acute rejection
    • Hepatic Artery Thrombosis (HAT)
    • CMV infection
    • Recurrent disease
    • ABO incompatibility
    • Prolonged Cold Ischemia Time (CIT)
    • Infection and rejection
  • Most Common Site: Biliary anastomosis
  • Management:
    • Anastomotic = ERCP + Dilatation
    • NAS = In Marginal Grafts commonly & Chronic Rejection [ Ductopenia/Vanishing Duct]

Ischemic Cholangiopathy = NAS

  • Non-anastomotic Stricture:
    • Occurs at the hilar or intrahepatic regions
  • Risk Factors:
    • Hepatic Artery Thrombosis (HAT)
    • ABO incompatibility
    • Chronic rejection
    • Ischemia-reperfusion injury
    • Bile salt injury
    • Donation after Circulatory Death (DCD) donor
  • Prevention:
    • tPA (Tissue Plasminogen Activator) treatment in DCD donors reduces ischemic cholangiopathy
    • Machine perfusion decreases incidence of ischemic cholangiopathy

Acute Cellular Rejection (ACR)

  • Characteristics:
    • Acute deterioration of graft function with accompanying histological changes
  • Histology:
    • Lymphocyte infiltration in portal triads
    • Endothelitis
    • Disruption of the biliary, hepatic artery, and portal venous endothelium
  • Incidence: 24-80%
  • Impact:
    • No impact on mortality or long-term graft dysfunction
  • Earliest Laboratory Indicator:
    • Elevated bilirubin level
  • Diagnosis:
    • First doppler to exclude HAT
    • Liver Biopsy = Gold standard to diagnose ACR

Rejection Diagnosis and Treatment

  • Biopsy:
    • Gold standard for diagnosing rejection
  • Banff Score for Rejection:
    • Mild rejection: RAI < 4
      • Treatment: Increase Calcineurin Inhibitors (CNI)
    • Moderate to severe rejection:
      • Treatment: Pulse steroids

Banff Schema for Acute Hepatic Rejection (Rejection Activity Index - RAI)

  • Portal Inflammation:
    • Score 1: Mostly lymphatic inflammation involving a minority of triads
    • Score 2: Expansion of most triads by a mixed infiltrate (lymphocytes, neutrophils, eosinophils)
    • Score 3: Marked expansion of most or all triads with numerous blasts and spillover into perivenular parenchyma
  • Bile Duct Damage:
    • Score 1: Minor duct inflammation with mild reactive changes
    • Score 2: Duct inflammation with degenerative duct changes (nuclear pleomorphism, distortion)
    • Score 3: Most or all ducts show degenerative changes
  • Venous Endothelial Inflammation:
    • Score 1: Subendothelial lymphocytic infiltration of some portal/hepatic venules
    • Score 2: Subendothelial infiltration of most/all portal or hepatic venules
    • Score 3: Associated perivenular inflammation with hepatocyte necrosis

Chronic Rejection in Liver Transplantation

  • Effect: Significantly reduced graft survival
  • Ductopenic Rejection:
    • Loss of bile ducts in more than 50% of portal tracts
  • Arteriopathy:
    • Involves large and medium-sized arteries
    • Characterized by foamy infiltration of the intima
  • Vanishing Bile Duct Syndrome:
    • Progressive loss of intrahepatic bile ducts
  • Treatment:
    • Often requires retransplantation

Banff Schema for Chronic Hepatic Rejection

  • Small Bile Ducts (<60 μm):
    • Early: Degenerative changes in ducts with increased nuclear-to-cytoplasmic ratio, nuclear hyperchromasia
    • Late: Degenerative changes in remaining bile ducts
  • Terminal Hepatic Venules:
    • Early: Bile duct loss in less than 50% of portal tracts, inflammation
    • Late: Bile duct loss in more than 50%, severe fibrosis
  • Portal Tract Hepatic Arterioles:
    • Early: Focal lytic necrosis, inflammation
    • Late: Focal obliteration, bridging fibrosis
  • Large Peribiliary Hepatic Arteries:
    • Early: Inflammation damage, foam-cell deposition
    • Late: Luminal narrowing by subintimal foam cells and fibrointimal proliferation

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Antibody-Mediated Rejection (AMR) in Liver Transplantation

  • Incidence: 1% of all liver transplants
  • Very common in Kidney Transplantations
  • Diagnosis:
    • CRD positive staining on biopsy
    • Presence of positive donor-specific antigens (DSA)
  • Treatment:
    • Plasmapheresis
    • Intravenous Immunoglobulin (IVIG)

Infection in Liver Transplantation

  • Fungal, CMV, EBV all these can be seen.
  • Cytomegalovirus (CMV):
    • Most important infection in organ transplant
  • Onset:
    • Typically 30-50 days after transplant
  • CMV Disease:
    • Histologically evident invasive CMV infection confirmed through:
      • Tissue biopsy
      • Mucosal biopsy
      • Brushing for Owl's eye nucleus, hepatocyte necrosis, and microabscesses
  • Risk Factors:
    • Seropositive donor
    • Use of OKT3 (Orthoclone T3, a monoclonal antibody)
  • Treatment:
    • IV ganciclovir/ foscarnet
    • Oral valganciclovir - prophylaxis for 3-6 months

Post-Transplant Lymphoproliferative Disorder (PTLD)

  • Pathogenesis: Associated with Epstein-Barr Virus (EBV)
  • Characterized by unrestricted proliferation of B cells
  • Risk Factors:
    • Use of polyclonal antilymphocyte globulin or monoclonal OKT3

Management:

  • Polyclonal PTLD: PreLymphoma type.
    • Discontinuation of immunosuppression
  • Monoclonal PTLD: ⇒ tumor like lymphoma.
    • Rituximab (antibody against CD20)
    • Radiation
    • Chemotherapy
    • Surgical resection

Hyperacute Rejection

  • Cause: Presence of donor-specific antibodies before transplantation
  • Very common in Kidney Transplant
  • Onset: Occurs within minutes to hours post-transplant
  • Pathophysiology:
    • Graft thrombosis due to endothelitis and complement activation (C4d) deposition

Acute Rejection

  • Mediated by:
    • T cells (T-cell mediated rejection)
    • Antibody-mediated rejection involving memory B cells
  • Types:
    • Acute vascular rejection
    • Antibody-mediated rejection
  • Onset: Occurs within days to months post-transplant
  • Characteristics:
    • Reversible
    • Does not affect graft survival in liver transplantation
  • Treatment:
    • Steroids are the treatment of choice

Chronic Rejection

  • Mechanisms:
    • Immune and non-immune processes
  • Hallmark:
    • Fibrosis (mediated by TGF-β)
    • Involves macrophages, dendritic cells, few lymphocytes, and epithelial destruction through Epithelial-to-Mesenchymal Transition (EMT)
  • Associated Conditions:
    • Vanishing Bile Duct Syndrome (liver)
    • Coronary Vasculopathy (heart)
    • Interstitial Fibrosis (kidney)
  • Treatment:
    • No effective treatment
  • Prevention:
    • Prevention of Acute Cellular Rejection (ACR)
    • Managing donor-specific antibodies may help prevent chronic rejection

Immunosuppression Mechanism

  • T Cell Receptor (TCR): Key component in T-cell activation
  • CD4 T Cells:
    • Interact with MHC Class II molecules
  • Direct Pathway:
    • Donor Antigen-Presenting Cells (APC) present to recipient T cells
  • Cytokine Activation:
    • IL-2 and IFN-alpha produced by T cells
    • Stimulate APCs to secrete IL-12

Molecular Mechanisms of Immunosuppression in T-Cell Activation

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  • Signal 1:
    • Antigen is presented by the APC (Antigen-Presenting Cell) on MHC to the TCR/CD3 complex.
    • This triggers calcineurin activation, leading to dephosphorylation of NF-AT, which enters the nucleus and promotes transcription of cytokines like IL-2.
    • Cyclosporine and Tacrolimus inhibit calcineurin, preventing NF-AT activation.
  • Signal 2 (Costimulatory Signal):
    • CD28 interacts with CD80/86 on the APC.
    • The signal leads to activation of pathways like PI3K, IKK, and MAP kinases, promoting NF-κB and AP-1 to initiate transcription.
  • Signal 3:
    • IL-2 binds to its receptor CD25, triggering downstream signaling via JAK3 and PI3K, leading to activation of mTOR, which regulates the cell cycle (G1 to S phase transition).
    • Sirolimus and Everolimus inhibit mTOR, blocking IL-2 receptor signal transduction.
    • Anti-CD25 monoclonal antibodies inhibit IL-2 receptor interaction.
  • Medications and Targets:
    • Azathioprine and Mycophenolate (MMF/MPA): Disrupt nucleotide synthesis and inhibit cell cycle progression.
    • Anti-CD3 monoclonal antibodies: Inhibit TCR signal transduction by blocking the CD3 complex.
    • Anti-CD52 (Alemtuzumab): Leads to CD52 depletion and T-cell inactivation.
    • FTY720: Alters lymphocyte recirculation by affecting the S1-P receptor.
    • CTLA-4-Ig: Blocks CD28 costimulation by competing with CD80/86.

T-Cell Receptor (TCR) Signal Transduction Pathway and Immunosuppressants

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  • TCR Activation:
    • CD4 binds to MHC Class II.
    • Signal transduction is initiated through PLC and activation of PIP2 and DAG.
  • Calcium Pathway:
    • IP3 increases intracellular Ca²⁺, leading to the activation of calcineurin.
    • Calcineurin dephosphorylates NF-AT, allowing it to enter the nucleus and promote IL-2 transcription.
  • Cytokine Production:
    • IL-2 stimulates T-cell proliferation through the IL-2 receptor.
  • Key Immunosuppressants:
    • Cyclosporine and Tacrolimus (FK506): Inhibit calcineurin, preventing NF-AT dephosphorylation.
    • Sirolimus: Inhibits mTOR, blocking IL-2 receptor signal transduction.
    • Azathioprine and Mycophenolate (MMF): Inhibit cell cycle progression by altering nucleic acid metabolism.
    • Corticosteroids (GC): Upregulate Iκ-Bα, inhibiting NF-κB release.
    • Anti-CD25: Inhibits IL-2 receptor function.
    • OKT3: Targets CD3 on T-cells, blocking activation.

Calcineurin Inhibitors (Cyclosporine)

  • Origin: Derived from Tolypocladium inflatum Gans
  • Mechanism of Action:
    • Binds to cyclophilin, forming a complex that inhibits the calcineurin-calmodulin pathway.
    • Prevents the activation of NF-AT, which is necessary for T-cell activation.
    • Inhibits IL-2 gene transcription, thereby blocking T-cell proliferation.
    • Causes upregulation of TGF-alpha, contributing to nephrotoxicity.
  • Effects:
    • No effect on costimulatory signaling.
  • Clinical Use:
    • Used for maintenance immunosuppression.
    • No role in rescue therapy. [rescue therapy in IBD]
    • Not as potent as tacrolimus.

Tacrolimus

  • Origin: Derived from Streptomyces tsukabensis
  • Mechanism of Action:
    • Binds to FK-binding protein (FK-BP), inhibiting the calcineurin pathway.
    • Prevents activation of NF-AT, thereby inhibiting T-cell activation.
    • Increases TGF-alpha transcription, contributing to its effects.
  • Potency:
    • 100 times more potent than cyclosporine.
  • Clinical Use:
    • High doses can reverse liver rejection episodes.
    • Used to reduce acute cellular rejection (ACR) and treat steroid-resistant ACR.
  • Side Effects:
    • More neurotoxicity (headache and tremor).
    • Associated with Type 2 diabetes.
    • Fewer cosmetic side effects, such as hypertrichosis (compared to cyclosporine).

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Antiproliferative Agents: Azathioprine & Mycophenolate Mofetil (MMF)

  • Azathioprine:
    • Prevents DNA synthesis in all dividing cells.
    • Side effects:
      • Hepatotoxicity
      • Myelotoxicity
  • Mycophenolate Mofetil (MMF):
    • Inhibits IMP dehydrogenase, blocking GMP synthesis in lymphocytes. [ therefore no agranulocytosis or hepatotoxicity etc]
    • Side effects:
      • Leukopenia
      • Diarrhea
  • Common Features:
    • Both are lymphocyte-specific antiproliferative agents.
    • Do not cause nephrotoxicity or neurotoxicity.
    • Used for maintenance immunosuppression.

Mycophenolate Mofetil (MMF)

  • Mechanism of Action:
    • Non-competitive, reversible inhibitor of IMP dehydrogenase, preventing the synthesis of GMP.
    • Blocks a critical step in RNA and DNA synthesis.
    • Lymphocytes lack the salvage pathway found in other cells, making MMF lymphocyte-specific.
    • Inhibits the proliferation of both B cells and T cells.
  • Clinical Features:
    • Renal sparing effect (does not cause nephrotoxicity).
  • Side Effects:
    • Gastrointestinal: Diarrhea
    • Metabolic Syndrome: Includes diabetes mellitus (DM) and hypertriglyceridemia.

Co-Stimulation Blockade

  • Key Pathways:
    • CD154-CD40 and CD28-CD80/86 pathways involved in T-cell activation.
  • Medications:
    • Belatacept:
      • Targets the CD28 pathway.
      • Blocks co-stimulation, leading to the formation of immature T cells.
    • Alemtuzumab:
      • A CD52-specific antibody.
      • Depletes T cells by targeting CD52 on their surface.

Sirolimus / Everolimus

  • Class: Macrolide antibiotics derived from Streptomyces hygroscopicus
  • Mechanism of Action:
    • Binds to FKBP12, targeting the mTOR pathway.
    • Does not affect calcineurin activity.
    • Inhibits IL-2 receptor signal transduction, blocking T-cell proliferation.
  • Clinical Features:
    • Renal sparing effect, but may cause proteinuria.
    • Anti-tumor activity, particularly useful in Hepatocellular Carcinoma (HCC) post-transplant.
    • Prevents Post-Transplant Lymphoproliferative Disorder (PTLD).
    • Used in drug-eluting stents.
  • Side Effects:
    • Increased incidence of hypercholesterolemia.
    • Oral ulcers, lymphocele.
    • Proteinuria and thrombocytopenia.
    • Hepatic Artery Thrombosis (HAT) with sirolimus, particularly within 28 days post-transplant.

Summary of Immunosuppressive Drugs

Drug Description Mechanism Non-immune Toxicity and Comments
Prednisone Corticosteroid Binds nuclear receptor and enhances transcription of IL-1, inhibits NF-κB and T-cell activation Diabetes, weight gain, osteoporosis, hypertension, cataracts, skin thinning, insomnia, mood disturbances
Cyclosporine (CsA) 11-Amino acid cyclic peptide from Tolypocladium inflatum Binds to cyclophilin, inhibiting calcineurin phosphatase and T-cell activation Nephrotoxicity, hypertension, neurotoxicity, hyperlipidemia, hirsutism, gum hyperplasia
Tacrolimus (Prograf) Macrolide antibiotic from Streptomyces tsukubaensis Binds to FK-BP12, inhibiting calcineurin phosphatase and T-cell activation More neurotoxic than CsA, but fewer cosmetic side effects, hyperglycemia, diabetes, hyperlipidemia
Sirolimus (Rapamycin) Triene macrolide antibiotic from Streptomyces hygroscopicus from Easter Island Binds FK-BP12, inhibiting mTOR-dependent T-cell proliferation Hyperlipidemia, delayed wound healing, oral ulcers, thrombocytopenia, proteinuria, delayed lung disease, HAT (with sirolimus)
Everolimus (Zortress) Derivative of sirolimus Similar to sirolimus Similar to sirolimus but shorter half-life, reduced dosing frequency, increased proteinuria, hypercholesterolemia
Mycophenolate mofetil (CellCept) Mycophenolic acid from Penicillium stoloniferum Inhibits guanosine monophosphate nucleotides, preventing proliferation of T and B cells Gastrointestinal symptoms (diarrhea), leukopenia, neutropenia, metabolic syndrome (diabetes, hypertriglyceridemia)
Azathioprine (Imuran) Prodrug that undergoes hepatic metabolism to 6-mercaptopurine Converts to 6-mercaptopurine, blocking synthesis of thioguanine nucleotides that interfere with DNA/RNA synthesis Leukopenia, bone marrow suppression, liver toxicity (uncommon)
Antithymocyte globulin Polyclonal IgG from rabbits/horses immunized with human thymocytes Blocks T-cell membrane proteins (CD2, CD3, CD45), causing lymphocyte depletion Cytokine release syndrome, thrombocytopenia, leukopenia, serum sickness
OKT3 (Muromonab-CD3) Anti-CD3 murine monoclonal antibody Binds CD3 associated with TCR, leading to T-cell depletion Severe cytokine release syndrome, fever, pulmonary edema, central nervous system symptoms
Basiliximab Anti-CD25 chimeric monoclonal antibody Binds to IL-2 receptor (CD25) on activated T-cells, causing depletion Hypersensitivity reactions (rare), commonly used in initial stages of transplantation
Rituximab Anti-CD20 chimeric monoclonal antibody Binds CD20 on B cells and causes depletion Hypersensitivity, increased infection risk
Alemtuzumab Anti-CD52 humanized monoclonal antibody Binds to CD52 on most T and B cells, NK cells, macrophages, and leads to prolonged depletion Mild cytokine release, prolonged lymphopenia, neutropenia, anemia
FTY720 Sphingosine-1 receptor modulator from Fungus Isaria sinclairii Blocks lymphocyte egress by targeting sphingosine-1 receptors Reversible first-dose bradycardia, increased blood pressure
Belatacept (LEA29Y) High-affinity homologue of CTLA-4 Binds to CD80/86, preventing costimulation of T-cells Lower risk of nephrotoxicity than CsA, improved graft survival

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MCQs for Transplantation and Immunosuppression

  1. Acute rejection post-transplantation is mediated by:
    • A. T cells
    • B. B cells
    • C. Antibody mediated
    • D. All of the aboveAnswer: D
  2. Vanishing bile duct syndrome after liver transplantation (LT) is seen in:
    • A. Acute rejection
    • B. Chronic rejection
    • C. Acute on chronic rejection
    • D. Hyperacute rejectionAnswer: B
  3. Not true about chronic rejection after organ transplantation:
    • A. High dose immunosuppression is used for treatment of chronic rejection
    • B. Prevention of ACR can prevent chronic rejection
    • C. Prevention of donor-specific antibodies can prevent chronic rejection
    • D. Mediated by TGF-β causing fibrosisAnswer: A
  4. Diarrhea is a side effect of:
    • A. MMF
    • B. Cyclosporine
    • C. Tacrolimus
    • D. BasiliximabAnswer: A
  5. GRWR is defined as:
    • A. Graft weight by donor weight ratio
    • B. Graft volume by standard liver volume ratio
    • C. Graft weight by recipient body weight ratio
    • D. None of theseAnswer: C

MCQs for Transplantation and Post-Transplant Care

  1. All of the following are done to reduce the incidence of small-for-size syndrome except:
    • A. Splenic artery ligation
    • B. Portosystemic shunt
    • C. MHV reconstruction
    • D. Domino liver transplantAnswer: D
  2. A 50-year-old male underwent DDLT for alcoholic CLD. On POD2, he became delirious with hypotension. USG and Doppler are normal. Liver enzymes: SGOT-8000, SGPT-10000, Alk-550, Bil-2.5. TLC count is 12000. Probable diagnosis:
    • A. Primary non-function
    • B. Hepatic artery thrombosis
    • C. Portal vein thrombosis
    • D. Sepsis-related ALFAnswer: A
  3. Risk factors for Hepatic Artery Thrombosis (HAT) are all except:
    • A. Intimal dissection
    • B. Technical factors
    • C. Aberrant anatomy
    • D. Male donorAnswer: D (Female donor is a risk factor)
  4. Risk factors for non-anastomotic biliary stricture:
    • A. DCD donor
    • B. HAT
    • C. ABO incompatibility
    • D. All of the aboveAnswer: D
  5. Pathological findings in liver biopsy of acute cellular rejection are all except:
    • A. Endothelitis
    • B. Ductopenia
    • C. Portal triaditis
    • D. All of the aboveAnswer: B
  6. True about rejection in liver transplant:
    • A. ACR is mediated by preformed antibodies
    • B. Chronic rejection is manifested with ductopenia
    • C. Treatment of chronic rejection is pulse steroids
    • D. Frequent episodes of ACR lead to chronic rejectionAnswer: B and D
  7. Not true about acute cellular rejection in liver transplant:
    • A. MC laboratory finding is elevation of bilirubin
    • B. Banff criteria is used for severity grading
    • C. Leads to decreased graft survival
    • D. All of the aboveAnswer: C

  8. Not true about CMV infection post-liver transplant:

    • A. Liver biopsy establishes CMV disease
    • B. Owl’s eye appearance on biopsy
    • C. Oral valganciclovir is used in prophylaxis
    • D. Occurs during 1st month post-transplant

    Answer: D (Typically occurs 30-50 days post-transplant)

  9. True about PTLD:

    • A. Hodgkin’s lymphoma is the most common type
    • B. Mostly T-cell lymphoma
    • C. Polyclonal PTLD is treated with rituximab
    • D. Caused by EBV virus

    Answer: D

  10. Which of the following agents is not used as a rescue agent in the treatment of ACR:

    • A. Steroids
    • B. OKT3
    • C. Basiliximab
    • D. Cyclosporine

    Answer: D

  11. Not true about the use of MMF in liver transplant:

    • A. Reversible inhibitor of IMP
    • B. Gastrointestinal toxicity is a major adverse effect
    • C. Can cause severe agranulocytosis
    • D. Diabetes and hyperlipidemia are long-term side effects

    Answer: C (Agranulocytosis is more commonly associated with azathioprine)

MCQs for mTOR Inhibitors and Post-Transplant Care

  1. Not true regarding mTOR inhibitors:
    • A. Binds to FKBP and blocks IL-2 signal transduction
    • B. Used in transplant for HCC due to its antiproliferative effect
    • C. Nephrotoxicity as a major adverse effect
    • D. Sirolimus can cause hepatic artery thrombosisAnswer: C
  2. Management of encephalopathy and elevated ICP in Acute Liver Failure (ALF) includes all except:
    • A. Hyperventilation
    • B. Head elevation to 30 degrees
    • C. Hyperthermia
    • D. Maintaining CPP >60 mm HgAnswer: C (Hypothermia is preferred)
  3. Post reperfusion syndrome is defined by all except:
    • A. MAP <60 mm Hg within 5 minutes of liver perfusion
    • B. Decrease in MAP less than 70% of prereperfusion value
    • C. Administration of antifibrinolytics
    • D. TachycardiaAnswer: D (Bradycardia and asystole are more typical)
  4. Key points for post reperfusion syndrome:
    • MAP <60 mm Hg within 5 minutes of liver perfusion for at least 1 minute.
    • <70% of prereperfusion values.
    • Bradycardia and antifibrinolytics are common features.

MCQs for Liver Transplantation and Tacrolimus

  1. Domino liver transplant is used in all except:
    • A. Maple syrup disease
    • B. Familial Amyloid Polyneuropathy (FAP)
    • C. Familial hypercholesterolemia
    • D. Primary hyperoxaluriaAnswer: D
  2. Regarding the use of Tacrolimus in immunosuppression - Not true:
    • A. Binds to FK-BP
    • B. More neurotoxicity than cyclosporine
    • C. Decreased cosmetic side effects
    • D. Less potent than cyclosporineAnswer: D (Tacrolimus is 100 times more potent than cyclosporine)
  1. Absolute contraindication for liver transplant includes all except:
    • A. Active sepsis
    • B. Advanced cardiopulmonary disease
    • C. Active alcohol abuse
    • D. HIV infectionAnswer: D (AIDS with CD4 count <200 is a contraindication, not HIV itself)
  2. True about portopulmonary hypertension except:
    • A. PAP > 30 mm Hg during exercise
    • B. Orthodoxia (Orthodeoxia, seen in HPS, not portopulmonary hypertension)
    • C. Degree of PPH not related to degree of portal hypertension
    • D. Intrapulmonary vasoconstrictionAnswer: B
  3. Not true about hepatopulmonary syndrome (HPS):
    • A. PaO2 less than 50 mm Hg on room air is a contraindication to LT
    • B. Appearance of saline in left side four to six beats after appearance on the right side
    • C. Dyspnea on standing
    • D. Ventilation-perfusion mismatch due to pulmonary vasodilatationAnswer: A (PaO2 <50 mm Hg qualifies for MELD exception points, not a contraindication)
  4. Hydrothorax in cirrhosis:
    • Pleural effusion >500 mL without cardiac or pulmonary cause.
    • Management includes:
      • TIPS (Transjugular Intrahepatic Portosystemic Shunt)
      • Pleurodesis
      • Diaphragmatic repair
      • Avoidance of tube thoracostomy (pleural catheter can be placed instead).

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MCQs for Liver Transplantation Indications and Contraindications

  1. Indication for combined liver and kidney transplant are all except:
    • A. Cirrhosis with hepatorenal syndrome
    • B. Cirrhosis with CKD with GFR less than 30 mL/min
    • C. Cirrhosis with AKI with dialysis for more than 8 weeks
    • D. Cirrhosis with CKD with histology showing more than 30% fibrosisAnswer: A

  2. Superurgent indication for liver transplant for fulminant hepatic failure include all except:

    • A. HAT within 21 days of LT
    • B. Liver failure in live donor within 4 weeks of operation
    • C. Acute Budd-Chiari with encephalopathy

    • D. Cirrhosis with HPS

      Answer: D

    • Key Points:

      • Fulminant hepatic failure: Encephalopathy within 8 weeks of onset.
      • Active sepsis and fixed dilated pupils are contraindications for liver transplant.
      • Prothrombin time (PT) is the best guide to monitor disease progression for transplant.
      • Two-stage transplant and APOLT (Auxiliary Partial Orthotopic Liver Transplant) are possible strategies.
    • Genetic disorder which is an indication for liver transplant where the liver is not affected:
    • A. Protoporphyria
    • B. Byler disease
    • C. Primary hypercholesterolemia
    • D. Gaucher diseaseAnswer: C

Inborn Errors of Metabolism Treated by Liver Transplantation

Liver Affected:

  • α1-Antitrypsin deficiency
  • Wilson disease
  • Protoporphyria
  • Tyrosinosis
  • Tyrosinemia
  • Galactosemia
  • Glycogen storage disease types I and IV
  • Byler disease
  • Hemochromatosis (may recur after transplantation)
  • Cystic fibrosis
  • Gaucher disease (may recur after transplantation)
  • Urea cycle enzyme deficiencies

Other Organs Also Affected:

  • Primary hyperoxaluria
  • Crigler-Najjar syndrome
  • Primary hypercholesterolemia
  • Niemann-Pick disease
  • Sea-blue histiocyte disease (may recur after transplantation)
  • Hemophilia A and B
  • Protein C deficiency
  • Protein S deficiency

This table highlights various metabolic disorders that can be managed by liver transplantation, including those affecting both the liver and other organs. Some conditions may recur after the transplant, such as hemochromatosis and Gaucher disease.

MCQ for Indications of Liver Transplantation in Cirrhosis

Indications for liver transplantation in cirrhosis include all except:

  • A. Hepatic encephalopathy
  • B. Recurrent variceal bleeding
  • C. Muscle wasting
  • D. Jaundice (Bilirubin 2.5 mg/dL)Answer: D (Bilirubin of 2.5 mg/dL alone is not an indication for transplantation)

Indications for Liver Transplantation in Cirrhosis

  1. Symptoms:
    • Hepatic decompensation
    • Hepatic encephalopathy
    • Increasing ascites
    • Recurrent variceal bleeding
    • Spontaneous bacterial peritonitis
  2. Side Effects of Liver Disease:
    • Increasing osteopenia
    • Hepatopulmonary syndrome
    • Intractable symptoms (e.g., itching or lethargy)
    • Development of hepatocellular carcinoma
    • Muscle wasting
  3. Biochemical Markers:
    • Serum albumin <30 g/dL
    • Serum bilirubin >50 µmol/L for parenchymal disease
    • Serum bilirubin >100 µmol/L for cholestatic disease
    • MELD score >17

MCQs for Liver Transplantation in HCC and Hemostasis in ESLD

  1. Indication for liver transplantation in hepatocellular carcinoma (HCC) includes all except:
    • A. Single lesion less than 5 cm
    • B. Up to three lesions, none more than 3 cm
    • C. Single lesion less than 6.5 cm
    • D. AFP >1000 ng/mLAnswer: D
  2. Hemostasis abnormalities seen in End-Stage Liver Disease (ESLD) are all except:
    • A. Thrombocytopenia
    • B. Elevation in vWF factor
    • C. Decrease in factor VIII
    • D. Deficiency of Protein C and SAnswer: C (Factor VIII is actually increased in ESLD)

Explanation

  • Indications for Liver Transplantation in HCC follow Milan criteria, which include:
    • Single tumor ≤ 5 cm or up to three tumors ≤ 3 cm.
    • Alpha-fetoprotein (AFP) >1000 ng/mL is considered a poor prognostic factor and not a transplant criterion.
  • Hemostasis Abnormalities in ESLD:
    • Thrombocytopenia: Due to splenic sequestration.
    • Elevated von Willebrand Factor (vWF): Due to endothelial activation.
    • Factor VIII: Increased due to decreased hepatic clearance.
    • Protein C and S deficiency: Common in liver disease, leading to hypercoagulability.

Hemostatic Abnormalities in Liver Disease

Anticoagulant Factors:

  • Thrombocytopenia (reduced platelet count)
  • Impaired platelet function
  • Reduced hematocrit
  • Upregulated nitric oxide (NO) and prostacyclin (inhibit platelets)
  • Low levels of coagulation factors: II, V, VII, IX, X, XI
  • Vitamin K deficiency
  • Hypofibrinogenemia, dysfibrinogenemia
  • Decreased Factor XIII, TAFI (thrombin-activatable fibrinolysis inhibitor)
  • Elevated tPA, decreased PAI-1 (plasminogen activator inhibitor)

Procoagulant Factors:

  • Elevated Factor VIII and von Willebrand factor
  • Decreased proteins S and C and antithrombin III
  • Decreased plasminogen and α2-antiplasmin

This table summarizes the complex balance of procoagulant and anticoagulant factors in liver disease, leading to both bleeding and thrombotic risks.

MCQ for Hepatorenal Syndrome (HRS)

  1. Not true about Hepatorenal Syndrome (HRS):

    • A. RRT longer than 6 weeks is an indication for transplant (RRT > 8 weeks is the actual indication)
    • B. Splanchnic vasodilation with renal vasoconstriction
    • C. HRS 1 has the worst prognosis
    • D. Terlipressin with albumin is given

    Answer: A

Key Points about Hepatorenal Syndrome (HRS)

  • HRS 1: Rapid decline in kidney function, associated with worst prognosis.
  • HRS 2: Slower progression, with a better prognosis.
  • Histologically normal kidneys despite functional decline.
  • Pathophysiology: Intrarenal vasoconstriction with splanchnic vasodilatation.
  • Refractory ascites is commonly present.
  • Treatment: Combination of Albumin + Terlipressin; TIPS can be considered.
  • Liver Transplant Indication: If RRT is required for more than 8 weeks.

MCQ for Acute Liver Failure (ALF)

  1. Which of the following has the worst prognosis in Acute Liver Failure?
    • A. Acetaminophen
    • B. Hepatitis A
    • C. Idiosyncratic drug reaction
    • D. Hepatitis BAnswer: C

Key Points about Acute Liver Failure (ALF)

  • Hyperacute liver failure (onset of encephalopathy within 7 days of jaundice) has the best prognosis.
  • Prognosis order (best to worst):
    • Hepatitis A
    • Acetaminophen toxicity
    • Hepatitis B
    • Intermediate origin
    • Drug-induced (Idiosyncratic drug reaction), which has the worst prognosis.
  • Subacute liver failure (onset of encephalopathy between 28 days to 3 months) has a poorer prognosis.
  • Hepatitis C does not cause Acute Liver Failure.

MCQs for Management of Raised ICP in ALF and King's College Criteria

  1. Management of raised ICP in Acute Liver Failure includes all except:
    • A. Hypothermia
    • B. Hypertonic saline
    • C. Hepatectomy
    • D. HypoventilationAnswer: D (Hyperventilation is used, not hypoventilation)
  2. King's College Criteria for Acetaminophen-induced ALF include all except:
    • A. Arterial pH
    • B. Serum creatinine
    • C. Presence of encephalopathy
    • D. Serum bilirubinAnswer: D

Key Points for Management of Raised ICP in ALF

  • Management includes:
    • Hypothermia: Helps reduce metabolic demand and ICP.
    • Hypertonic saline: Used to reduce cerebral edema.
    • Hepatectomy: May be considered in preparation for liver transplant.
    • Hyperventilation: Reduces ICP by causing cerebral vasoconstriction.

King's College Criteria for Acetaminophen-induced ALF

  • Key parameters include:

    • Arterial pH < 7.3 after fluid resuscitation.
    • Serum creatinine > 3.4 mg/dL (300 µmol/L).
    • Presence of encephalopathy (grade III or IV).

    Serum bilirubin is not included in King's College Criteria for acetaminophen-induced ALF.

The King's College Criteria for poor prognosis in Acute Liver Failure (ALF) are as follows:

Non-Acetaminophen-Induced ALF:

  • INR > 6.5OR
  • Three of the following five criteria:
    • Patient age <11 or >40 years
    • Serum bilirubin > 300 µmol/L
    • Time from onset of jaundice to development of coma > 7 days
    • INR > 3.5
    • Drug toxicity, regardless of whether it caused ALF

Acetaminophen-Induced ALF:

  • Arterial pH < 7.3OR
  • All three of the following:
    • INR > 6.5
    • Serum creatinine > 300 µmol/L
    • Presence of encephalopathy (Grade III or IV)

This criterion is used to assess the severity of ALF and guide liver transplantation decisions.

MCQs for Acute Liver Failure and Liver Transplantation

  1. Clichy prognostic model for Acute Liver Failure (ALF) includes:
    • A. Serum Factor V
    • B. Encephalopathy
    • C. Age
    • D. All of the aboveAnswer: A (The Clichy model is based on Serum Factor V levels and encephalopathy, not age)
  2. All of the following are done in liver transplantation for acute liver failure except:
    • A. Plasmapheresis
    • B. Portal vein clamping
    • C. Piggyback technique
    • D. Two-stage hepatectomyAnswer: B (Portal vein clamping is not typically part of the LT procedure in ALF)

Key Points

  • Clichy Prognostic Model: Uses Serum Factor V levels and degree of encephalopathy to determine prognosis in acute liver failure.

  • Liver Transplantation in ALF: Common procedures include plasmapheresis, Piggyback technique, and sometimes two-stage hepatectomy. Portal vein clamping is not typically involved.

    Key Points for Liver Transplantation Procedures in ALF

    1. INR Correction:
      • In the absence of active bleeding, INR correction is not required for liver transplant patients.
    2. Surgical Techniques:
      • Avoid IVC (Inferior Vena Cava) and portal vein clamping: Typically, during liver transplantation, modern techniques like the piggyback technique avoid clamping the IVC to maintain hemodynamic stability.
      • Two-stage hepatectomy: In cases of large liver tumors or staged liver resection, a two-stage approach may be adopted.
    3. Portacaval Shunt:
      • A portacaval shunt is a surgical procedure to divert blood flow from the portal vein directly to the IVC, bypassing the liver, often used in conditions of severe portal hypertension.
    4. ABO Incompatible Liver Transplantation:
      • Rituximab: A monoclonal antibody used to deplete B cells, which are responsible for antibody production in ABO-incompatible transplants.
      • IVIg (Intravenous Immunoglobulin): Administered to neutralize antibodies and reduce the risk of rejection in ABO-incompatible transplants.

    These points outline the advanced surgical and immunosuppressive strategies in liver transplantation, particularly in complex cases like ABO incompatibility.

MCQ for APOLT (Auxiliary Partial Orthotopic Liver Transplantation)

  1. Not true about APOLT:
    • A. Liver is placed in orthotopic position
    • B. Used in hyperacute liver failure
    • C. Removal of auxiliary graft is done after clinical recovery (This is incorrect, as graft hepatectomy should never be done)
    • D. AWOLT involves subtotal hepatectomyAnswer: C

Key Points about APOLT

  • APOLT is used in hyperacute liver failure, especially in cases caused by Acetaminophen, HAV, HBV.
  • It requires absence of fibrosis in the liver.
  • A reduced liver graft is used and placed in the orthotopic position.
  • AWOLT (Auxiliary Whole Orthotopic Liver Transplantation) involves subtotal hepatectomy of the native liver.
  • Immunosuppression is withdrawn after clinical recovery.
  • Graft hepatectomy should never be done after recovery, as the auxiliary liver functions to support recovery.

MCQ for Post-Transplant Immunosuppression in HCC

  1. Post-transplant immunosuppression for HCC includes all except:
    • A. Maintaining tacrolimus level more than 10 ng/ml (High levels increase recurrence risk)
    • B. Use of sirolimus
    • C. Low cyclosporine trough level (less than 300 ng/ml)
    • D. None of the aboveAnswer: A

Key Points

  • High calcineurin inhibitor (CNI) levels, such as tacrolimus or cyclosporine, are associated with a higher recurrence rate of HCC after transplant.
  • Sirolimus (an mTOR inhibitor) is preferred due to its anti-tumor effect in HCC patients.
  • Low cyclosporine trough levels (below 300 ng/ml) are typically maintained to reduce tumor recurrence risk.

Immunosuppression regimens post-transplant aim to balance preventing rejection while minimizing cancer recurrence, especially in HCC cases.

MCQ for Tumor Downstaging in HCC (Outside Milan Criteria)

  1. Which of the following is not true about tumor downstaging for HCC outside Milan criteria:
    • A. Minimum follow-up period of 3 months is required
    • B. Tumor should be downstaged to UNOS T2 stage
    • C. Presence of microvascular invasion after resection is a contraindication for transplant
    • D. LDLT is contraindicatedAnswer: D

Key Points

  • A minimum follow-up period of 3 months is required after downstaging before considering the patient for liver transplantation.
  • The tumor should be downstaged to UNOS T2 stage, which aligns with Milan criteria (one tumor ≤ 5 cm or up to three tumors ≤ 3 cm).
  • Microvascular invasion after resection is a contraindication for transplantation due to the increased risk of recurrence.
  • Living donor liver transplantation (LDLT) is not contraindicated and can be considered in downstaged HCC cases that meet the criteria.