Hepatology Practice Questions, Edition 1

This patient has intrahepatic cholestasis of pregnancy, which is diagnosed with a combination of clinical findings of new onset pruritus in the 2nd/3rd trimesters, elevated serum bile acids, and negative serologies for other causes of abnormal liver chemistries. No further diagnostics are needed (Choices A and B). While there is no risk to the mother with intrahepatic cholestasis of pregnancy (ICP), there is an increased risk of fetal demise with ICP. However, this is typically with much higher bile acid levels (> 100 micromol/L). Even with higher bile acids, delivery is often delayed until after 36 weeks gestation to allow for further fetal development. Ursodiol is routinely prescribed at 10-15mg/kg maternal body weight and can reduce pruritus. However, evidence regarding effectiveness in preventing adverse fetal outcomes is controversial. This patient does not have any pregnancy-related liver disease that necessitates emergent delivery (e.g. HELLP, acute fatty liver of pregnancy, or preeclampsia with severe features).

KEY POINT: Intrahepatic cholestasis of pregnancy should be managed with a trial of ursodiol for symptoms and close, serial monitoring of serum bile acids. High serum bile acid levels pose a risk to the developing fetus and therefore help determine optimal delivery timing, which should be a conversation with OB/Gyn.

AUTHOR, TOPIC: MO, liver disease in pregnancy

Patient has compensated cirrhosis with preserved liver function, and good performance status, but has multinodular disease and therefore is BCLC stage B. Although his tumor burden is outside Milan criteria (Single tumor =<5cm, or up to 3 tumors, none >3cm), however he meets OPTN downstaging criteria:

1) single tumor >5cm and =<8

2) up to 3 tumors, each >3 cm and =<5 cm, with total diameter of all lesions =< 8.

3) up to 5 lesions, each <3 cm, with total diameter of all lesions =< 8.

His tumor burden can be down staged via locoregional treatment, and if his post treatment disease is within OPTN T2 criteria (1 lesion between 2-5 cm, or up to 3 lesions each between 1-3 cm), he can be listed for transplant with HCC exception points. Liver transplant is curative and gives him the best chance of long term survival. Answer A is incorrect as the tumor burden is outside Milan criteria, and therefore resection or ablation carries a very high risk of liver insufficiency, and subsequent decompensation. Answer B is incorrect as the patient is still within UCSF or OPTN down staging criteria, and once treated with locoregional therapy, could still be considered for liver transplant. Answer D is incorrect as if down staging is achieved, he will have better survival with liver transplant.

KEY POINT: Locoregional therapy followed by liver transplant provides the best survival benefit in patients in BCLC stage B who meet OPTN or UNOS downstaging criteria. Patients must meet T2 criteria after downstaging to be eligible for transplant

AUTHOR, TOPIC: AR, liver tumors

References:

1.     Journal of Hepatology 2022 76681-693DOI: (10.1016/j.jhep.2021.11.018); Organ Procurement and Transplantation Network (OPTN) policies; Lingiah et al. J Clin Transl Heptaol 2020
 

The Grocott Methenamine Silver (GMS) stain illustrates Pneumocystis jiroveci cysts, and the patient in the vignette has Pneumocystis jiroveci pneumonia (PJP). She was at risk for this fungal infection due to her recent treatment for graft rejection.  The first-line treatment for PJP is Trimethoprim-Sulfamethoxazole (TMP-SMX) due to superior outcomes when compared to all other antimicrobials.  Answer B) is incorrect as atovaquone is a treatment option for PJP but is not the first line treatment.  Answer E) is incorrect as Dapsone is used as a prophylactic agent against PJP, but it has not been used alone to treat PJP. Answers A) and C) are incorrect as azithromycin and caspofungin are not used alone to treat PJP.

KEY POINT: Post-transplant patients on high-dose corticosteroids are at risk for Pneumocystis jiroveci pneumonia which presents with hypoxia, fever, cough and positive Gomori methenamine-silver (GMS) stain on bronchoalveolar lavage.  The first-line treatment is high-dose trimethoprim-sulfamethoxazole.

AUTHOR, TOPIC: LC, infectious complications

References:

1.         Fishman JA, Gans H; on behalf of the AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33:e13587. https://doi.org/10.1111/ctr.13587

2.         Wilkin A, Feinberg J. Pneumocystis carinii pneumonia: a clinical review. Am Fam Phys 1999;60:1699–1708, 1713–1694.

Risk factors for the development of anastomotic strictures in patients undergoing transplant include DCD or LDLT, peri-operative ischemia, post-operative bile leak and hepatic artery stenosis or thrombosis.

KEY POINT: Receipt of DCD donor, living donor, peri-operative ischemia and hepatic artery thromboses are all risk factors for biliary complications post-liver transplant. 

AUTHOR, TOPIC: DA, non-immune complications post-LT

Reference: Ryu CH, Lee SK. Biliary strictures after liver transplantation. Gut Liver. 2011;5(2):133-142. doi:10.5009/gnl.2011.5.2.133

Arthropathy and hypogonadism do not improve with iron depletion whereas reduction of fibrosis, reduced insulin requirements, improved cardiac function and reduced appearance of varices can all be seen with iron depletion.

KEY POINT: Arthropathy and hypogonadism do not improve with iron depletion whereas reduction of fibrosis, reduced insulin requirements, improved cardiac function and reduced appearance of varices can all be seen with iron depletion.

AUTHOR, TOPIC: JPED, genetic liver diseases

This young patient has aggressive post-transplant lymphoproliferative disorder (PTLD), and initial management includes 1) reducing immunosuppression to the lowest possible dose, 2) surgical excision if feasible, and 3) systemic chemotherapy (typically with R-CHOP regimen of cyclophosphamide, doxorubicin, prednisone, rituximab and vincristine).  There is no effective antiviral for EBV (Answer A). Surgery (Answer D) is indicated for patients with localized PTLD; however, this patient has diffuse disease, so excision is not feasible. She already has confirmed widespread EBV+ DLBCL, so a CT-PET (Choice E) will not change management. 

 KEY POINT: Management of PTLD includes 1) reducing immunosuppression to the lowest possible dose, 2) surgical excision if feasible, and 3) systemic chemotherapy (typically with R-CHOP).  Reduction of immunosuppression is the first step in PTLD mgmt.

 AUTHOR, TOPIC: MO, post-transplant malignancy

This patient has evidence of calcineurin inhibitor (CNI) toxicity as evidenced by AKI and tremors. The pathophysiology of the AKI with CNI toxicity is endothelial dysfunction secondary to inhibition of nitric oxide synthesis and free radical formation leading to vasoconstriction and activation of the renin-angiotensin system (RAS). The exact mechanism of tacrolimus-induced neurotoxicity is unknown, however, it is postulated that the increased production of endothelin and free radicals may play a role. This likely occurred in the setting of initiation of anti-infectious agents; fluconazole is a cytochrome P450 inhibitor and ciprofloxacin a weak CYP3A4 inhibitor.  Both agents increase calcineurin inhibitor concentrations.

Option A is incorrect as her biliary drain has continued significant output. Option B is incorrect because this is not the first step in evaluating a patient with CNI toxicity, initial management includes holding the CNI and monitoring levels and renal function and restarting the drug at a lower dose once the trough is below the goal. Option D is incorrect because adjustment of tacrolimus levels may allow for continued tacrolimus usage.

KEY POINT: CNI toxicity can occur in the setting of concomitant P450 inhibitor/CYP3A4 inhibitor usage. Signs and symptoms include kidney injury, nausea and neurologic symptoms, most commonly tremors.

AUTHOR, TOPIC: DA, short-term immune and nonimmune toxicity of immunosuppressive medications

Reference:  Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;4(2):481-508. doi:10.2215/CJN.04800908

Both fluconazole and nifedipine are CYP450 3A inhibitors. However, given that he has been on fluconazole since calcineurin inhibitor initiation the antihypertensive agent is most likely responsible for increased tacrolimus level.  Answer B is incorrect as carbamazepine is a CYP450 3A inducer so in fact lowers calcineurin inhibitor level.

KEY POINT: CYP450 3A inhibitors (macrolides, azoles, ca channel blockers (not amlodipine), metoclopramide, grapefruit, danazole, protease inhibitors) increase calcineurin inhibitor levels.  CYP450 3A inducers (rifampin, anti-epileptic drugs, including phenytoin, phenobarb, carbamazepine, st john’s wort) reduce calcineurin inhibitor levels.

AUTHOR, TOPIC: JPED, mechanism and pharmacokinetic of immunosuppressive medications

This history and imaging are consistent with hepatoblastoma.  The best survival occurs with surgical resection with perioperative (aka neoadjuvant) chemotherapy.  If patients are unresectable, liver transplant can be considered.  Answer A) is incorrect as hepatoblastomas are highly vascular so needle biopsy is not recommended; if required open surgical biopsy is preferred.

KEY POINT: Hepatoblastomas classically present as asymptomatic right upper quadrant mass in child <3 years old. Hepatoblastomas are more common in males and Caucasians.  AFP may be 100,000-300,000.  Needle biopsy should be avoided given lesions can be highly vascular.

AUTHOR, TOPIC: JPED, genetic liver diseases

Answer B) is the correct answer.  Answer C) and E) are incorrect as tests for β-D-Glucan are non-specific because this polysaccharide is found in the cell wall of multiple fungal species (including Candida and Pneumocystis) so while consistent with invasive pulmonary aspergillosis, positive β-D-Glucan test is not specific.  Answer A) is incorrect as while sputum cultures can be positive in the setting of invasive pulmonary aspergillosis, this typically occurs in later stages of infection; it would therefore not be the next best test due to low overall sensitivity. Bronchoalveolar lavage galactomannan is the recommended test for diagnosis, in combination with another testing modality (such as CT chest).

KEY POINT: Invasive pulmonary aspergillosis presents classically with high fever, cough, pulmonary nodules in an immunosuppressed patient.  Diagnosis is made with bronchoalveolar galactomannan and imaging.

AUTHOR, TOPIC: LC, infectious complications of transplant

Reference:

1.         Husain S, Camargo JF, on behalf of the AST Infectious Diseases Community of Practice. Invasive Aspergillosis in solid‐organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33:e13544.https://doi.org/10.1111/ctr.13544

Split liver transplantation was pioneered in the late 1980s as a technique for transplantation of small pediatric patients. Classically, split liver transplantation consists of dividing the liver into a left lateral lobe (segments II and III) for a child recipient and an extended right lobe (ERL, segments I + IV-VIII) for an adult, though modifications of this technique can be utilized to split the liver between two adult recipients. Though early studies suggested worse outcomes for adult recipients of ERL grafts compared to whole liver grafts, increased experience and more careful donor and recipient selection have led to more recent analyses demonstrating similar outcomes. Factors that have been associated with worse outcomes among ERL graft recipients include: donor age >50 years (Answer choice A), ex situ splitting, recipient MELD score >30 (Answer choice C), donor-recipient weight ratio <1.0 (Answer choice D), use of the graft for retransplantation (Answer choice E), and use in recipients with UNOS status I-IIa. In situ liver splitting (Answer B) is associated with improved outcomes in transplant recipients due to decreased cold ischemia time.

KEY POINT: Split liver transplantation is a safe and effective option for expanding the donor pool, but donors/ recipients must be carefully selected for the best outcomes.

AUTHOR, TOPIC: LC, split liver graft

References:

1.         Vilca-Melendez H, Heaton ND. Split Liver Transplantation for Pediatric and Adult Recipients. In: Busuttil RW, Klintmalm GBG. Eds. Transplantation of the Liver. 3rd ed. Elsevier Saunders; 2015: Chapter 52. Accessed April 30, 2023. https://www.clinicalkey.es/#!/browse/book/3-s2.0-C20100663474.

2.         Hackl C, Schmidt KM, Süsal C, Döhler B, Zidek M, Schlitt HJ. Split liver transplantation: Current developments. World J Gastroenterol. 2018;24(47):5312-5321. doi:10.3748/wjg.v24.i47.5312.

New classification divides Hepatic Adenomas (HA) into 4 groups, based on histologic features and immunohistochemical markers. These 4 subtypes are (1) HAs with inactivating mutations of hepatocyte nuclear factor 1α (HNF1A; HA-H), (2) HAs with activating mutations of β-catenin gene (HA-B), (3) HAs with inflammatory features (HA-I), and (4) unclassified HAs that have no specific gene mutations or unique morphologic features (HA-U). The HA-B subtype is morphologically characterized by pseudoacinar formation and mild cytologic atypia and are difficult to distinguish from well-differentiated HCC. Immunostaining with β-catenin shows a heterogenous pattern of nuclear and cytoplasmic reactivity and diffuse/strong cytoplasmic glutamine synthetase reactivity. Glutamine synthetase staining results are negative in other HAs. Answer A is incorrect, although hepatic adenomas are more common in women, the risk for malignant transformation is much higher in men. Answer C is incorrect as the biopsy has typical features of HA, especially the β-catenin subtype. Answer D is incorrect, as the small size of the lesion, makes rupture and massive bleeding less likely. The risk of rupture is increased in patients with tumor larger than 7 cm and associated oral contraceptive use.

KEY POINT:  Hepatic adenomas are classified based on histological features. The β-catenin subtype has high risk for malignant transformation.           

AUTHOR, TOPIC: AR, liver tumors

References: Arch Pathol Lab Med. 2014 Aug;138(8):1090-7. doi: 10.5858/arpa.2013-0183-RA

This patient has impaired arterial inflow from his atherosclerotic celiac plaque that can lead to both acute and chronic biliary ischemia.  Post-transplant, the celiac axis provides the sole arterial flow to the hepatic artery which in turn provides the sole blood supply to the biliary tree. The new graft does not have arterial collaterals as the gastroduodenal artery (GDA), which can provide flow from the superior mesenteric artery (SMA) prior to transplant, is ligated during transplant to prevent steal syndrome.  This patient had a celiac axis plaque that became clinically significant once the patient lost the collateral inflow to the hepatic artery after clamping of the GDA during surgery.

Answer A is incorrect as IV heparin would be treatment for hepatic artery thrombosis (HAT) however typically HAT would show absent Doppler or very low resistive index <4.   . Answer B is incorrect as the Organ Procurement and Transplantation Network (OPTN) defines primary non-function (PNF) as AST ≥3,000 U/L and at least one additional criterion: INR ≥2.5, arterial blood pH ≤7.3, and lactate ≥4 mmol/L within 7 days after transplantation. This is a fatal complication unless the patient receives a liver transplant, however the patient currently does not meet these criteria. Answer C is incorrect as the median arcuate ligament compresses the celiac axis not the portal vein. Answer E is incorrect as the GDA provides collateral blood flow from the SMA, so preserving it during surgery could have potentially prevented this complication.

KEY POINT: Pre-operative compression of the celiac axis by the median arcuate ligament of the diaphragm or from an atherosclerotic celiac axis plaque can cause clinically significant hepatic artery inflow limitations post-transplant even if not clinically significant prior to transplant due to loss of collateral flow.  Hepatic artery inflow compromise should be suspected when Doppler shows low resistive indices and cholestasis is present.  GDA preservation intra-operatively may reduce risk of this complication. 

References:

1. Horrow et al; 2020; Complications after Liver Transplant Related to Preexisting Conditions: Diagnosis, Treatment, and Prevention

2. Sannananja et al; 2018; Tricky Findings in Liver Transplant Imaging: A Review of Pitfalls With Solutions

AUTHOR, TOPIC: AR, surgical complications

Post-transplant blood pressure goals are <140/90 in patients without proteinuria and <130/80 in patients with proteinuria.  If proteinuria is present, angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) are preferred first-line therapy.  If there is no proteinuria present, dihydropyridine calcium channel blocker (e.g. amlodipine) is the preferred first-line therapy.

KEY POINT: In the absence of proteinuria, goal blood pressure in post-LT patients is <140/90 and dihydropyridine calcium channel blockers (e.g., amlodipine) are first line therapy.  In the presence of proteinuria, goal blood pressure is <130/80 and preferred first-line agent is ACE-I/ARB.

AUTHOR, TOPIC: JPED, non-immune complications post-transplant

Biliary cast syndrome is the development of hard, dark material that takes the shape of the bile ducts and can occur in up to 18% of liver transplant recipients. The hard casts are composed of bilirubin and bile and are thought to occur due to ischemia during transplant. It typically presents in the first 6 months after transplant with signs and symptoms of biliary obstruction and infection. Risk factors include hepatic artery stenosis, biliary strictures and ischemia.  The first step in management after stabilizing the patient is ERCP to remove the casts and place a stent. If this is unsuccessful, interventional radiology may place a percutaneous biliary drain. If this fails or the condition becomes recurrent, surgical options such as revision of hepaticojejunostomy or re-transplantation may be considered. Option C is correct. Options D and E can be considered if ERCP is not feasible, for example in the setting of Roux-en-Y anatomy. Option B is wrong because this patient has signs and symptoms of infection and high dose steroids would be harmful in this setting.

KEY POINT:  The initial management of biliary cast syndrome is ERCP with duct clearance and stenting.  If ERCP is unsuccessful can consider surgical revision and ultimately retransplantation.

AUTHOR, TOPIC: DA, non-immune complications post-transplantation

Reference:

1. Gor NV, Levy RM, Ahn J, Kogan D, Dodson SF, Cohen SM. Biliary cast syndrome following liver transplantation: Predictive factors and clinical outcomes. Liver Transpl. 2008;14(10):1466-1472. doi:10.1002/lt.21492

Perform ERCP to evaluate for suspected biliary stricture given worsening cholestasis. The likelihood of HAT or HAS is low in the setting of a normal doppler US.  Individuals who undergo LDLT are at increased risk of biliary stricture (30%-40% vs 10-15% in DDLT) and ultrasound does not reliably demonstrate biliary dilation in post-transplant setting.   MRCP may or may not be helpful. Even in the setting of a negative MRCP, given the clinical context and lab pattern, ERCP would be indicated.

He has adequate levels of immunosuppression, so rejection is less likely.

KEY POINT: US does not reliably demonstrate biliary dilation following liver transplantation.

AUTHOR, TOPIC: JPED, perioperative complications

Minocycline and nitrofurantoin can cause an AIH-like presentation which can be associated with positive autoantibodies (although ASMA most often negative in minocycline-induced AIH).   This is more common in women and older patients.   If severe disease is seen, the best treatment is to stop the offending agent and start corticosteroids.  Upon liver enzyme normalization steroid withdrawal can be attempted; if no relapse of disease occurs drug related AIH is likely diagnosis.   Answer A) is incorrect as biopsy is not required to establish diagnosis and there is no clinical evidence of advanced liver disease. Answer B) is incorrect as minocycline needs to be stopped given the high risk of DILI.  Answer D) is incorrect - while statins can cause hepatocellular injury, they are not commonly associated with AIH-type presentation, and unlikely to respond to steroid therapy

KEY POINT: minocycline and nitrofurantoin can cause AIH-like disease that if severe should be treated with steroids and drug discontinuation.

AUTHOR, TOPIC: JPED, Drug Induced Liver Disease

In recipients who are not HBcAb+ and HBsAb+ that receive isolated HBcAb+ donor organs, prophylaxis with antiviral therapy should be given for at least one year.  Answer A) and C) are incorrect as hepatitis B immune globulin is no longer needed in the setting of availability of effective antiviral therapy.  Answer B) is incorrect as antiviral prophylaxis is recommended in all recipients who are not naturally immune to hepatitis B (HBsAb positive and HBcAb positive). Answer E) is incorrect as the only setting in which prophylaxis is not needed for the recipient of an isolated HBcAb+ donor is if they have natural immunity to hepatitis B – HBcAb positive and HBsAb positive.  The recommended interval to monitor HBV DNA as well as HBsAg is every 3 months during the first year after transplant then every 6 months thereafter.

KEY POINT: Antiviral prophylaxis is recommended for recipients of organs from isolated HbcAb positive donors unless they have natural immunity to hepatitis B (i.e. HBsAb+, HBcAb+).

AUTHOR, TOPIC: DA, donor transmission of disease

Reference: Huprikar S, et. al. Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management. Am J Transplant. 2015 May;15(5):1162-72. doi: 10.1111/ajt.13187.

Early acute TCMR is a result of direct antigen presentation of donor antigens by donor APC cells to recipient T cells.  Answer B) is incorrect; this is the pathway for chronic rejection or later (>3 months post-transplant) T cell-mediated rejection.  Answers C) and D) are incorrect as presentation of recipient antigens would not cause rejection.

KEY POINT: acute TCMR is mediated by donor APCs presenting to recipient T cells; chronic rejection is mediated by recipient APCs presenting to recipient T cells.

AUTHOR, TOPIC: JPED, basic immunology

This presentation is consistent with PFIC1.  All progressive familial intrahepatic cholestasis (PFIC) disorders are autosomal recessive.  PFIC1 and PFIC2 are associated with low GGT; PFIC 3 is associated with high GGT.  PFIC1 is characterized by extrahepatic manifestations including pancreatitis, diarrhea, sensorineural deafness and short stature.  PFIC2 and PFIC3 have no extrahepatic manifestations.  On histology, PFIC1 has bland cholestasis, PFIC2 has giant cell hepatitis and PFIC 3 bile duct proliferation.  PFIC2 is associated with high risk of HCC and patients should begin undergoing HCC screening at 12 months of age. Genetic mutations shown in the answers are correct.

KEY POINT: PFIC1 is associated with elevated liver enzymes, low GGT and extrahepatic manifestations including diarrhea, pancreatitis, deafness and short status.

AUTHOR, TOPIC: JPED, genetic liver diseases

A “step-up” therapy strategy – from less invasive to more invasive – is typically recommended. Systemic anticoagulation (Answer A) has already been attempted, but the patient has continued symptoms of outflow obstruction.  Thrombolysis can be considered in acute Budd-Chiari syndrome but is avoided when clot burden is extensive. Thrombectomy (Answer B) will remove the outflow obstruction, but in a hypercoagulable patient is unlikely to provide prolonged benefit. Transjugular intra-hepatic portosystemic shunt (TIPS) alone (Answer C) is aimed at maintaining hepatic vascular patency and relieving signs of portal hypertension after the outflow obstruction is managed.

Liver transplant (Answer E) is reserved for patients in whom medical and endovascular management fail to control symptoms. It is reasonable to start the transplant evaluation process but liver transplant without a trial of a vascular shunt would be inappropriate.

KEY POINT: Patients with acute Budd-Chiari syndrome should undergo a step-up management in therapy with systemic anticoagulation followed by TIPS/ direct intrahepatic portocaval shunt with thrombectomy and then transplant if more conservative management fails to control the disease.

AUTHOR, TOPIC: MO, Budd Chiari

HEV presents with portal hepatitis on liver biopsy and can become chronic in patients on significant immunosuppression.  It is more common in patients transplanted outside the US.  Answer A) is incorrect as HEV should be ruled out first.  Answer B) is incorrect as HEV should be ruled out and this patient has not received high-dose corticosteroids to be considered truly corticosteroid-refractory.  Answer C) is incorrect as negative C4d staining and DSAs argue against antibody-mediated rejection.

KEY POINT: Chronic HEV is a reason for elevated liver enzymes in patients following OLT on significant immunosuppression and histology may appear similar to acute cellular rejection.

AUTHOR, TOPIC: JPED, post transplant infectious complications

This patient should be started on a balanced diuretic regimen and meets criteria for primary SBP prophylaxis (Fluid protein < 1.5, Na < 130, and serum creatinine > 1.2).  Ceftriaxone (Answer A) would treat spontaneous bacterial peritonitis (SBP), but the patient’s initial ascites fluid studies are not consistent with SBP (60 PMNs, negative gram stain). Albumin-assisted IV diuresis (Answer B) can be helpful, but this patient has symptomatic relief after a large volume paracentesis (LVP) and no other signs of volume overload. Transjugular intrahepatic portosystemic shunt (Answer C) should be reserved for diuretic resistant and diuretic intolerant ascites in select patients, and this patient has never been on diuretics. Performing as-needed LVP (Answer D) without a trial of diuretics is inappropriate.

KEY POINT: Primary SBP prophylaxis should be started in patients with low fluid protein (< 1.5) and either Na < 130, Cr > 1.2, BUN > 35, or CP > 9 with Bilirubin > 3. Typical regimens include ciprofloxacin 500mg daily (first choice) or second line with Bactrim 1 DS tab daily. Both should be renally dosed.

AUTHOR, TOPIC: MO, portal hypertension

This patient is in the highest risk group for CMV post-transplant (donor CMV-seropositive/ recipient CMV-seronegative). Both antiviral prophylaxis and preemptive therapy approaches are similarly efficacious (though limited studies have been done) and each approach has its own possible advantages and disadvantages. The American Society of Transplantation recommends several different approaches to prevent CMV in the liver transplant patient. For patients such as the one in this question (donor positive/ recipient negative), anti-viral prophylaxis with either PO valganciclovir 900mg daily or IV ganciclovir (5mg/kg) daily is recommended to be administered for 3-6 months post-transplant (Answer choices C and E). For the preemptive approach, weekly CMV nucleic acid amplification test (NAT) should be done for 12 weeks, and if a threshold CMV level is reached, treatment with PO valganciclovir (answer choice A) or IV ganciclovir (answer choice B) should be administered until testing is negative. PO valacyclovir (Answer choice D) is not recommended as prophylaxis for any solid organ transplant recipient; treatment of CMV with valacyclovir is only recommended in kidney transplant recipients.

KEY POINT: There are multiple recommended approaches to the prevention of CMV infection after liver transplantation, especially for those who are serodiscordant.

AUTHOR, TOPIC: LC, infectious complications

Reference:  Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients— Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33:e13512. doi:10.1111/ctr.13512

The patient has liver stiffness of < 20kPa and a platelet count > 150 and therefore meets Baveno VI criteria as low risk for having esophageal varices. She can therefore safely forego an upper endoscopy (Choice A). Starting a non-selective beta-blocker without evidence of clinically significant portal hypertension (Choice B) is not recommended. Non-invasive measures have been shown to estimate risk of EV development, and the likelihood of clinically significant portal hypertension is low in this patient with platelet >150.  HVPG (Choice D) is therefore not needed. TIPS placement (Choice E) is recommended in select patients who have had variceal bleeding.

KEY POINT: Patients with compensated cirrhosis who meet Baveno VI criteria for low risk of EV (stiffness < 20 kPa and platelets > 150) can forego screening endoscopy. With ongoing risk factors for disease progression, it is important to repeat this testing periodically to ensure that they have not become higher risk for clinically significant portal hypertension.

AUTHOR, TOPIC: MO, portal hypertension

Small for size syndrome risk is increased by both small grafts (graft:recipient body weight ratio <0.8 and graft volume:calculated standard liver volume <30%) and portal hypertension with portal pressures >15mm Hg at closure associated with mortality and SFSS.   Answers A) and B) are incorrect as these are acceptable ratios for LDLT.   Answer D) is incorrect as reduced remnant donor liver volume increases donor morbidity and mortality but does not negatively impact recipient outcomes.

KEY POINT: Portal hypertension defined as portal pressure >15 mmHg at abdominal closure increases risk of small for size syndrome.

AUTHOR, TOPIC: JPED, surgical complications

REFERENCES: Ogura Y, et. al. Portal pressure <15 mm Hg is a key for successful adult living donor liver transplantation utilizing smaller grafts than before. Liver Transpl. 2010 Jun;16(6):718-28. doi: 10.1002/lt.22059. PMID: 20517905.

Lee SG. A complete treatment of adult living donor liver transplantation: a review of surgical technique and current challenges to expand indication of patients. Am J Transplant. 2015 Jan;15(1):17-38. doi: 10.1111/ajt.12907. Epub 2014 Oct 30. PMID: 25358749

mTOR inhibitors can worsen proteinuria and may have to be discontinued in patients with significant proteinuria.  mTORi have been shown to have anti-tumor properties in vitro and are associated with reduced risk of HCC recurrence and improved overall survival for the first 5 years after transplant in low-risk patients, such as this patient who is within Milan criteria. In the early post-operative period, mTOR inhibitors are associated with impaired wound healing and higher risk of vascular complications and are contra-indicated.  Lipids should be monitored periodically as mTORi can worsen hyperlipidemia.

KEY POINT: mTOR inhibitors are associated with reduced risk of HCC recurrence in patients who are within Milan criteria, but they have high risk of early post-operative complications. mTOR initiation should therefore be delayed 4-6 weeks post-transplant.

AUTHOR, TOPIC: MO, post-transplant malignancy

UNOS criteria for primary non-function are as follows: within 7 days, AST ≥ 3000* and INR ≥  2.5 OR arterial pH ≤ 7.3 or venous pH ≤ 7.25 or lactate  ≥  4

*No AST requirement for LDLT segmental grafts.  Answer B is incorrect because AST <3,000.  Answer C is incorrect because INR, arterial pH and lactate all do not meet thresholds.  Answer D is incorrect because labs are from POD9 (need to be within 7 days).  Answer E is incorrect because INR, venous pH and lactate all do not meet thresholds.

KEY POINT: Segmental LDLT grafts do not have an AST threshold as part of criteria for relisting for primary non-function.

AUTHOR, TOPIC: JPED, indications for retransplantation

Answer A) would be correct if she did not have PSC however patients with PSC have better outcomes with transplant vs resection as the risk of multifocal disease is high.  Answer B) is incorrect as you already have tissue diagnosis and risk of seeding of peritoneum is high and would actually be a contraindication to transplant if this was performed.  Answer C) is incorrect as patients who have neoadjuvant chemotherapy prior to LT for cholangiocarcinoma have improved outcomes.

KEY POINT: Patients with PSC and/or unresectable hilar cholangiocarcinoma should be referred for consideration of OLT after neoadjuvant chemotherapy.

AUTHOR, TOPIC: JPED, liver tumors

Endoscopic methods have shown excellent success in the management of bile leaks, with a reported resolution rate of 82%-92%. Answer A is incorrect as despite shorter cold ischemic time, the risk of biliary complications which are twice as common as seen with DDLT. Answer C is incorrect as there are two main types of bile leak after LDLT, anastomotic leaks, and cut surface leaks. Cut surface bile leaks usually originate from small bile ducts that are transected during surgery, and usually heal spontaneously. Answer D is incorrect as anastomotic leaks occur more frequently with Roux-en-Y anastomoses than with duct-to-duct anastomoses. Answer E is incorrect a there is no evidence that PBC puts her at increased risk of early biliary leak post transplant

KEY POINT: Bile leak is more common in living donor transplant compared to DDLT. ERCP with sphincterotomy +/- stent placement have shown excellent success in the management of bile leaks, with a reported resolution rate of 82%-92%

References:

1. Simoes et al; 2015; Spectrum of biliary complications following live donor liver transplantation

AUTHOR, TOPIC: AR, surgical complication

This patient presents with hemolysis, elevated liver enzymes, and a low platelet count and the diagnosis is HELLP syndrome. She already has evidence of end-organ damage with acute kidney injury (AKI) and fetal heart rate abnormalities and the management is ultimately emergent delivery. Indications for emergent delivery in patients with HELLP syndrome include: gestational age >34 weeks, fetal demise, placental abruption, hepatic bleeding, AKI, disseminated intravascular coagulation, pulmonary edema and abnormal fetal heart rate.

Options A and D are incorrect, there is no role for IVIG or plasma exchange in the management of HELLP syndrome. Option B is incorrect because this should only be done in cases where the patient and the fetus are stable and the gestational age is less than 34 weeks.

KEY POINT: Patients with HELLP who have gestational age greater than 34 weeks should proceed to emergent delivery.

AUTHOR, TOPIC: DA, liver diseases of pregnancy

REFERENCE:

Stone JH. HELLP syndrome: hemolysis, elevated liver enzymes, and low platelets. JAMA. 1998;280(6):559-562. doi:10.1001/jama.280.6.559l
 

While LDLT comprises over 80% of liver transplants in some Eastern countries, in Western countries like the United States, less than 5% of all liver transplants are from living donors. Transplant centers performing LDLT have a learning curve, after which, outcomes are comparable to those after DDLT. Though earlier reports indicated that HCC recurred more commonly among LDLT recipients (likely due to less time to observe how aggressive the tumor was prior to transplant), more recent studies with better matched populations have found that the recurrence of liver diseases (including HCC) after LDLT are no different than recurrence after DDLT (Answer choice A). Similarly, earlier studies indicated that hepatic artery thrombosis (HAT) occurred more frequently in LDLT recipients; however, a recent meta-analysis did not find any difference in the rate of HAT when comparing DDLT and LDLT (Answer choice E).

Rejection rates among DDLT and LDLT recipients are equivalent (Answer choice C), with some studies actually demonstrating less rejection among LDLT recipients (perhaps related to less cold ischemia time and/or the fact that living donors are more likely to be biologically related to recipients). Primary graft non-function (Answer choice D) is actually more commonly seen among DDLT recipients, which is also thought to be related to more cold ischemia time. Biliary complications (including leaks and late anastomotic strictures, answer choice B) have been shown time and again to be more common among LDLT recipients, even when centers have significant LDLT experience. Reasons for this include: need for reconstruction of multiple bile ducts prior to anastomosis, size mismatches between donor and recipient, and variable biliary anatomy, among others.

KEY POINT: As a whole, when living donor liver transplants areperformedat a center with sufficient experience with the technique, overall outcomes are comparable to those of deceased donor liver transplants; however, biliary complications are observed more frequently among living donor liver transplant recipients.

AUTHOR, TOPIC: LC, living donor

REFERENCES:

1.         Barbetta A, Aljehani M, Kim M, et al. Meta-analysis and meta-regression of outcomes for adult living donor liver transplantation versus deceased donor liver transplantation. Am J Transpl. 2021;21(7):2399-2412. doi:10.1111/ajt.16440.

2.         Lee-Riddle GS, Samstein B. CAQ Corner: Evaluation and management of the living donor recipient. Liver Transplantation. 2023;29(4):449-455. doi:10.1097/LVT.0000000000000096

3.         Miller CM, Quintini C, Dhawan A, et al. The International Liver Transplantation Society Living Donor Liver Transplant Recipient Guideline. Transplantation. 2017;101(5):938-944. doi:10.1097/TP.0000000000001571

She is child C and BCLC stage D (terminal), therefore she does not qualify for any locoregional or systemic therapies. Answer A, B, and C are incorrect as she cannot tolerate locoregional therapy due to decompensation and poor synthetic function. Answer D is also incorrect, as for systemic therapy, patients need to have preserved liver function.

KEY POINT: Patients with decompensated child C cirrhosis, do not benefit from locoregional or systemic therapy for HCC. Therefore it is recommended to proceed with palliative care and symptomatic management.

AUTHOR, TOPIC: AR, liver tumors

REFERENCE: Journal of Hepatology 2022 76681-693DOI: (10.1016/j.jhep.2021.11.018)

Her lesions are LIRADS 5 and consistent with hepatocellular carcinoma.  Answer A) is incorrect as while she does not have portal hypertension, she has multifocal disease that is not amenable to resection due to bilobar tumor location.  Answer C) is incorrect as while AFP >1,000 does prevent standardized assignment of MELD exception points, AFP may be lowered with downstaging by locoregional therapy and transplant may become an option for this patient.  Option D)  is incorrect as survival outcomes are better after transplant than after systemic chemotherapy.

KEY POINT: Patients with HCC and disease that is beyond Milan criteria (3 lesions <3 cm or single lesion <5 cm) or high AFP (>1,000) may be eligible for transplant and exception point if their disease is downstaged via locoregional therapy.

AUTHOR, TOPIC: JPED, liver tumors