2026 Hepatology Practice Board Questions #2

This patient has acute liver failure:

1. INR ≥ 1.5
2. New hepatic encephalopathy (drowsy, asterixis)
3. No prior history of liver disease

The clinical picture strongly suggests Wilson disease (WD)–associated acute liver failure, supported by the patient’s young age, hemolytic anemia (elevated LDH and reticulocyte count, low haptoglobin), and disproportionately modest elevation of liver enzymes (ALP is classically quite low) with markedly elevated bilirubin.

The most important next step is referral for liver transplantation as WD presenting asacute liver failure is uniformly fatal without liver transplantation. Survival depends on status 1A listing.

Corticosteroids are incorrect; they have no proven benefit in WD. Chelation therapy is also incorrect, as it is effective only in chronic WD and has not been shown to improve outcomes in cases of Wilsonian crisis with acute liver failure. Liver biopsy is not necessary in acute WD and should not delay urgent transfer to an LT-capable center. In this setting, the diagnosis can be made clinically based on the information provided in the question stem. Finally, N-acetylcysteine may be initiated as supportive therapy in acute liver failure but does not alter the course of WD–associated acute liver failure.

This patient has features of hepatic artery thrombosis (HAT), which most often occurs within one week of transplant. The risk of HAT is increased with living donor liver transplant. Further features in the question stem include ischemic injury (very high AST > ALT) and rising bilirubin. ALP is also elevated as the hepatic artery supplies the biliary system with oxygen. This is a feared complication and needs to be diagnosed immediately, most often with Doppler ultrasound.

These patients require emergent re-vascularization and possibly re-transplantation. Antibiotics alone are incorrect; low-grade fevers can be associated with HAT. ERCP is incorrect because strictures typically occur later in the post-operative course; while strictures can occur as a complication of HAT, the priority should be diagnosing the condition. Corticosteroids would be used if this were a case of acute cellular rejection; liver tests tend to rise more gradually in this setting, and biopsy prior to treatment would be recommended. If doppler is negative and suspicion for HAT remains high, cross-sectional angiography should be obtained. Reassurance is not appropriate. 

The correct answer is D, “small-for-size syndrome”, which occurs when the donated graft volume is insufficient for the recipient. Specifically, small for size syndrome can occur if the graft-to-recipient weight ratio is less than 0.8%. This patient likely received a split-graft given his relatively low MELD score, as he would have been unlikely to reach the top of the transplant list; but adequate size match is essential to the success of split-graft transplantation. The significant portal inflow post-op leads to shear stress, sinusoidal injury, progressive cholestasis, and portal hypertension.

Acute cellular rejection is less likely as it typically presents with a predominantly hepatocellular liver enzyme pattern and often a bit later.  Hepatic artery thrombosis is also unlikely given patent vasculature on ultrasound. Finally, a biliary anastomotic stricture is incorrect, as there is no biliary ductal dilation on imaging, and these complications usually present weeks to months after transplant rather than in the early postoperative period.

This patient has severe liver dysfunction within 72 hours of transplantation, suggesting Primary nonfunction (PNF) The only definitive treatment is urgent re-listing for retransplantation. PNF is characterized by markedly elevated liver enzymes, profound coagulopathy and acidosis, encephalopathy, hemodynamic instability, and patent vasculature.

Acute cellular rejection is not typically associated with the coagulopathy, hemodynamic instability, or acidosis seen here. Furthermore, acute rejection is more likely to occur days to weeks following transplant rather than within the first 72 hours. MRCP is incorrect because biliary complications would not account for the marked hepatocellular injury or vasopressor requirement; imaging would delay definitive management. Hepatic artery thrombosis can cause profound graft dysfunction, imaging has already confirmed patent vasculature; returning to the operating room for hepatic artery exploration is incorrect. Lastly, PNF irreversible, and supportive care alone risks further clinical worsening. Of note, macrosteatosis of the graft is a risk factor for PNF.

This patient meets criteria for acute liver failure (no preexisting liver disease + INR > 1.5 + hepatic encephalopathy) and requires expedited transplant-center management. In ALF with suspected autoimmune hepatitis, liver biopsy can confirm AIH and identify patients who may benefit from immunosuppression, potentially sparing transplant-related morbidity; when biopsy is pursued, ACG suggests trans-jugular liver biopsy (TJLB) over other approaches. The guideline also notes observational data supporting TJLB as safe/effective in ALF despite coagulopathy.

EASL similarly emphasizes that autoantibodies can be absent or nonspecific early, and biopsy may be required to establish autoimmune etiology; if steroids are used, response should be prompt and infection risk carefully considered. 

A: Although Grade 2 HE (such as in this case) should prompt ICU level monitoring in suspected ALF, intubation is generally reserved for grade 3–4 encephalopathy/airway compromise.

B:Routine correction of coagulopathy is not recommended in ALF in the absence of active bleeding or a high-risk procedure; INR also does not reliably reflect bleeding risk, and viscoelastic testing may be more informative if available. EASL similarly discourages prophylactic coagulation factor administration because it alters INR/PT (key prognostic markers) and is rarely clinically indicated.

C: Protein restriction is not a default strategy. ALF guidance supports adequate protein (about 1.0–1.5 g/kg/day) and focuses on metabolic support. Studies have not demonstrated worsening HE with high protein diet in cirrhosis, although less data exists in HE in the setting of ALF.

E: The ACG recommends against routine prophylactic antimicrobials in ALF because they have not improved bloodstream infection rates or short-term mortality; instead, early assessment/surveillance is emphasized, with empiric therapy considered if the patient clinically deteriorates.

References

1- Shingina A, Mukhtar N, Wakim-Fleming J, et al. Acute Liver Failure Guidelines. Am J Gastroenterol. 2023;118(7):1128-1153. doi:10.14309/ajg.0000000000002340. PubMed

2- European Association for the Study of the Liver. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047-1081. doi:10.1016/j.jhep.2016.12.003. PubMed

The most common risk factors associated with post-OLT biliary complications include (1) graft related factors (DCD), older age of donor, ABO mismatch,and  prolonged cold and warm ischemia time;( 2) peri-operative factors (technical factors, T-tube placement, hepatic artery thrombosis) ;and (3) non-operative factors (CMV infection, history of PSC). 

Importantly, due to the small diameter of the donor bile duct in living donor liver transplantation, biliary strictures and anastomotic leaks are more common in living donor LT than in deceased-donor LT. In this case, the early postoperative bile leak (day 7) suggests a technical issue at the anastomotic site related to the challenging duct-to-duct anastomosis. ERCP with stent placement across the leak is the treatment of choice in anastomotic leaks.

Bile leaks should prompt investigation for hepatic artery thrombosis as the biliary tree is supplied by the hepatic artery. Bile leaks can also complicate T-tube removal, which tends to occur in the months after transplant. 

ASurgery is generally reserved for patients with peritoneal signs/sepsis risk, or when endoscopic/radiologic strategies fail. It can also be an option when ERCP is not technically feasible (e.g, Roux-en-Y patients)

B Conservative management is not appropriate in this patient with pain and fever.

D PTBD is typically used when ERCP isn’t feasible (e.g., in patients with Roux-en-Y anatomy) or after unsuccessful ERCP.

E Antibiotics may be adjunctive if infected biloma/cholangitis is suspected, but source Control and biliary decompression is the key next step.

References
1. Balderramo D, Navasa M, Cárdenas A. Current management of biliary complications after liver transplantation: Emphasis on endoscopic therapy. Gastroenterol Hepatol. 2011;34(2):107-115. S0210570510001640
2. Agostini C, et al. Complications in post-liver transplant patients. J Clin Med. 2023;12:6173. Jcm-12-06173

In an effort to combat increasing waiting list mortality due to organ shortage, extended donor criteria, such as donation after circulatory death (DCD), have been established. DCD is divided into controlled and uncontrolled. Controlled DCD donors are those awaiting cardiac arrest after withdrawal of life-sustaining treatment. Outcomes of OLT in uncontrolled DCD have generally been worse compared to average OLT outcomes. However, outcomes with controlled DCD have been promising, with comparable patient and graft survival at 1 and 3 years compared with DBD when strict donor selection criteria and NRP are applied. Additionally, primary nonfunction and hepatic artery thrombosis rates have not been shown to be significantly different between graft types in contemporary series.

Ischemic cholangiopathy (IC) is a devastating biliary complication characterized by diffuse intrahepatic strictures, bile lakes, and bile-duct casts that occurs more frequently after controlled donation after circulatory death liver transplantation compared to donation after brain death. However, the use of normothermic regional perfusion has made this complication less common, with multiple studies reporting 0% incidence of IC in NRP-treated cDCD grafts. 

Although early allograft dysfunction was initially more common in controlled DCD grafts (39.5% vs lower rates in DBD), the introduction of NRP has reduced EAD rates to 18-19%, which are comparable to or better than DBD rates of 21-32%. However, even with these advanced preservation techniques, prolonged cold ischemia time, particularly exceeding 4-6 hours, remains an independent risk factor for EAD and other post-transplant complications in controlled DCD recipients. 

References
1. Ruiz P, Valdivieso A, Palomares I, et al. Similar Results in Liver Transplantation From Controlled Donation After Circulatory Death Donors With Normothermic Regional Perfusion and Donation After Brain Death Donors: A Case-Matched Single-Center Study. Liver Transpl. 2021;27(12):1747-1757. doi:10.1002/lt.26281
2. Lucey MR, Furuya KN, Foley DP. Liver Transplantation. N Engl J Med. 2023;389(20):1888-1900. doi:10.1056/NEJMra2200923
3. Bluhme E, Gäbel M, Martinez de la Maza L, et al. Normothermic regional perfusion in controlled DCD liver procurement: Outcomes of the Swedish national implementation protocol. Liver Transpl. 2024;30(11):1132-1144. doi:10.1097/LVT.0000000000000434
4. Paterno F, Guarrera JV, Wima K, et al. Clinical Implications of Donor Warm and Cold Ischemia Time in Donor After Circulatory Death Liver Transplantation. Liver Transpl. 2019;25(9):1342-1352. doi:10.1002/lt.25453
5. Watson CJE, Hunt F, Messer S, et al. In situ normothermic perfusion of livers in controlled Circulatory death donation may prevent ischemic cholangiopathy and improve graft survival. Am J Transplant. 2019;19(6):1745-1758. doi:10.1111/ajt.15241

Prior studies have demonstrated that primary biliary cholangitis recurrence after orthotopic liver transplantation occurs in approximately 22 percent of patients at 5 years, 36 percent at 10 years, and up to 50 percent by 20 years of follow-up. To date, prophylactic ursodeoxycholic acid at a dose of 10 to 15 mg/kg/day remains the only intervention consistently shown to reduce the risk of PBC recurrence, as supported by multiple large observational studies and Meta-analyses.

Risk factors associated with PBC recurrence include younger age at the time of diagnosis, particularly under 50 years, and younger age at the time of transplantation, particularly under 60 years, as well as biochemical evidence of more severe cholestasis, including an alkaline phosphatase greater than three times the upper limit of normal or a bilirubin level greater than 5.8 mg/dL at 6 months following transplantation.

A. Switch tacrolimus to a cyclosporine-based regimen Although earlier studies suggested a possible reduction in recurrence risk with cyclosporine compared with tacrolimus, more recent data have shown either no difference or even higher recurrence rates with cyclosporine use. Overall, the available evidence is not strong enough to recommend one calcineurin inhibitor over another for the prevention of PBC recurrence.

B. Add daily low-dose prednisone Long-term low-dose corticosteroid therapy, in combination with other immunosuppressive agents, has been shown to reduce autoimmune hepatitis recurrence after liver transplantation without significantly increasing the risk of infection or osteoporosis. However, no benefit has been demonstrated for reducing PBC recurrence, and therefore, this approach is not Recommended.

C. No changes are indicated at this time Rates of PBC recurrence in the absence of ursodeoxycholic acid are substantial, particularly in patients with risk factors such as younger age at transplantation. As a result, deferring therapy at this stage would not be appropriate.

D. Discontinue mycophenolate mofetil The addition of mycophenolate mofetil to tacrolimus has been shown to reduce acute rejection rates compared with tacrolimus monotherapy. Discontinuing mycophenolate, particularly this early after transplantation, would increase the patient’s risk of acute rejection and is therefore not advised.

References

1- Montano-Loza AJ, Hansen BE, Corpechot C, et al. Factors Associated With Recurrence of Primary Biliary Cholangitis After Liver Transplantation and Effects on Graft and Patient Survival. Gastroenterology. 2019;156(1):96-107.e1. doi:10.1053/j.gastro.2018.10.001

2- Corpechot C, Chazouillères O, Belnou P, et al. Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis. J Hepatol. 2020;73(3):559-565. doi:10.1016/j.jhep.2020.03.043

3- European Association for the Study of the Liver. EASL Clinical Practice Guidelines on liver transplantation. J Hepatol. 2024;81(6):1040-1086.

Acute T cell-mediated rejection best explains this case: switching from tacrolimus to cyclosporine (which carries higher acute rejection risk), missed cyclosporine doses with a subtherapeutic trough, new LFT elevation, and a biopsy showing portal vein endothelialitis, lymphocytic cholangitis, and a mixed lymphocytic-eosinophilic portal infiltrate in more than half of portal tracts are classic features of acute cellular rejection. This pattern fits early post-liver transplant rejection in the first few months, where inadequate T cell immunosuppression is the dominant driver.

In this case, the direct pathway of allorecognition is the key mechanism to emphasize. Donor-derived antigen-presenting cells within the liver graft present donor antigens on donor MHC to recipient CD4 and CD8 T cells, which recognize the intact allogeneic MHC-antigen complexes as foreign and become activated. This direct recognition is thought to be particularly important early after transplantation, when donor APCs are still abundant in the graft, and it drives the portal-based inflammation, bile duct injury (lymphocytic cholangitis), and venular/portal vein endothelialitis seen on biopsy. In contrast, indirect allorecognition, in which recipient APCs process donor antigens and presents them on self (recipient) MHC, plays a larger and more established role in chronic/ductopenic rejection and alloantibody generation; while it can contribute to acute rejection, it is less central early in the post-transplant course.

The other rejection modes are less consistent with the findings. Acute antibody-mediated rejection (aAMR) typically requires compatible histology (microvascular injury with endothelial swelling, sinusoidal/inlet venule dilation), evidence of complement activation (C4d deposition in appropriate vascular beds), and circulating donor-specific antibodies; in this case, C4d staining is negative and the described injury pattern is classic for T cell–mediated rejection rather than AMR. Plasma cell hepatitis (de novo AIH-like rejection) is also unlikely; it is characterized by plasma cell-rich portal and/or perivenular infiltrates with interface and perivenular necroinflammatory activity. 

This patient has post-transplant cholangitis with imaging showing intrahepatic biliary dilation and ERCP demonstrating multifocal intrahepatic strictures without an anastomotic lesion, on a background of slowly rising alkaline phosphatase, cholestatic biopsy without ductopenia, and adequate immunosuppression, which are features most consistent with ischemic cholangiopathy after DCD liver transplantation. DCD grafts are particularly susceptible to ischemia-reperfusion injury, which increases the risk of primary non-function, hepatic artery thrombosis, and non-anastomotic (ischemic) cholangiopathy. Donor and procurement related factors that heighten this risk include older donor age (especially >40–50 years), higher BMI (>30), significant macrosteatosis (generally > 30%), prolonged cold ischemia (> 8 hours), and prolonged donor warm ischemia, particularly when functional donor warm ischemia time exceeds about 30 minutes.

Donor warm ischemia time is typically defined as the interval from withdrawal of life support to initiation of cross-clamping and cold perfusion and can be divided into an agonal phase (withdrawal to circulatory arrest) and an asystolic phase (circulatory arrest to cold perfusion). Functional donor warm ischemia time (fDWIT) refines this to the time from physiological deterioration (e.g., systolic blood pressure or oxygen saturation falling below prespecified thresholds) to cold perfusion and is widely used to better capture the period of clinically relevant ischemia; many U.S. and European protocols use SpO2 <70–80% and/or systolic blood pressure <50–80 mmHg as the onset of fDWIT, and a 30-minute cutoff is commonly cited as the upper acceptable limit. In this case, the fDWIT is 35 minutes, exceeding this threshold and representing the most important contributor to his ischemic cholangiopathy. The donor’s young age (35 years) and only mild macrosteatosis (25%) fall below the more clearly defined high-risk ranges seen in observational studies, making them less likely to be the primary drivers of this complication, and the absence of ductopenic changes on biopsy plus adequate immunosuppression argues against chronic rejection as the main etiology.

All liver transplant candidates require cardiopulmonary risk stratification, and those with abnormalities on initial workup or with clinical risk factors should undergo advanced evaluation.

While initial studies may vary by center, all candidates should undergo an electrocardiogram and transthoracic echocardiography. Commonly used risk factors that prompt advanced coronary evaluation include older age, MASLD, diabetes, chronic kidney disease, left ventricular hypertrophy, family history of premature coronary artery disease, active or past tobacco use, or a coronary calcium score > 0. Advanced cardiac evaluation may include stress echocardiography, cardiac CT angiography, or nuclear/PET imaging, typically decided in multidisciplinary discussion with cardiologists experienced in transplant evaluation.

Evaluation should also identify complications such as hepatopulmonary syndrome and portopulmonary hypertension. The lack of visualization of bubbles in the left heart on agitated-saline echocardiography makes hepatopulmonary syndrome less likely. In contrast, if the RVSP is in the range of ≥40–50 mm Hg, or there is evidence of right-sided dysfunction or structural abnormalities, right heart catheterization should be performed to evaluate for portopulmonary hypertension (Choice C), as uncontrolled pulmonary hypertension is a contraindication to transplantation. Given her otherwise unremarkable workup (normal ECG, no additional CAD risk factors), CCTA and stress echocardiography (Choices A and B) are not the next best step, because clarification of possible portopulmonary hypertension with right heart catheterization is more urgent. She is <45 years old and does not have a high-risk family history, so screening colonoscopy (Choice D) is not yet indicated, although she should be up to date on cervical cancer screening per standard preventive guidelines.

Liver Donor Liver Transplant (LDLT) has allowed expansion of the donor pool but it presents additional challenges to the transplant evaluation. Given that a donor hepatectomy provides significant risk without any medical benefit, significant caution needs to be exercised to prevent catastrophic outcomes to the donor. 

The recipient needs to receive an adequate amount of graft tissue for proper functioning and prevent complications such as small for size syndrome. The amount of graft needed can be calculated by the Graft-to-Recipient Weight Ratio (GRWR) by taking the graft weight and dividing it by the recipient weight, then multiplying it by 100. Generally, a value ≥0.8% is considered adequate, but there have been reports of successful outcomes in select patients down to 0.6%.

In adult living donor transplants, usually a right hepatectomy is performed to provide adequate liver tissue for the recipient. However, the remnant liver tissue volume must be adequate to prevent post-hepatectomy liver failure in the donor. Remnant liver volume can be calculated by subtracting the planned graft volume (800 mL) from the total liver volume (1,000 mL, which is on the small side), then dividing by the total liver volume and multiplied by 100 to express the fraction of the original liver volume remaining (20% in this calculation). Minimum remnant liver volume to prevent liver failure is considered 30-35%. Thus, in this scenario, the donor sister would be left with inadequate liver volume after a hepatectomy even with a minimum calculated GRWR for her brother and is not a suitable donor (Choice C).

Her blood type of O- makes her a universal donor; she is ABO compatible with her brother (Choice A).

This patient has developed acute liver failure. The likely cause is acetaminophen toxicity. This can occur at apparently therapeutic dosing levels in patients who have additional risk factors which deplete glutathione, such as fasting, chronic medications (e.g. phenytoin), and alcohol consumption. Serum paracetamol levels may not be elevated. The Rumack-Matthew nomogram should not be used, as it is intended for single ingestions, rather than multiple ingestions.
Patients with low body weight should be considered for paracetamol dose reduction as they can develop toxicity (including ALF) at apparently therapeutic doses. The British National Formulary recommends a maximum dose of 60mg/kg/day (which is exceeded by the standard dose of 1g four times daily in adults >50kg). Similar recommendations are made in the Australia and New Zealand guidelines on paracetamol poisoning.

Lactulose and rifaximin can be used to treat hepatic encephalopathy in the context of cirrhosis.
However, evidence of benefit is limited in ALF.

Hydrocortisone can be used to treat vasopressor resistant shock in ALF, however this patient is normotensive.

References:
Chiew AL, Reith D, Pomerleau A, et al. Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand. Med J Aust. 2020;212(4):175-183. doi:10.5694/mja2.50428
Freo U, Ruocco C, Valerio A, Scagnol I, Nisoli E. Paracetamol: A Review of Guideline Recommendations. J Clin Med. 2021;10(15):3420. Published 2021 Jul 31. doi:10.3390/jcm10153420
What dose of paracetamol for older people?Drug and Therapeutics Bulletin 2018;56:69-72.
 

The risk of donor derived HCV infection is 100% when a graft from a HCV-viremic donor is transplanted into a HCV-naive recipient. All patients in such a scenario will require treatment with a pangenotypic direct-acting anti-viral (DAA) once stabilised post transplant. Timing and details of antiviral therapy must be considered thoughtfully as there are drug interactions between DAAs and commonly used immunosuppressants. Utilisation of HCV viremic donors increases the available donor organ pool and hence is expected to decrease waitlist mortality. With highly effective DAAs, outcomes would be expected to be comparable to receipt of non HCV-viremic grafts. 

References

https://www.hcvguidelines.org/guidance/treatment-of-hcv-uninfected-transplant-recipients-receiving-organs-from-hcv-viremic-donors/

Selzner N, Berenguer M. (2018) Should organs from hepatitis C‐positive donors be used in hepatitis C‐negative recipients for liver transplantation?. Liver Transplantation 24(6):p 831-840

The patient has developed a postoperative biliary leak. The main predisposing factor is ischemia at the anastomosis, which can be caused by surgical technical factors (excessive dissection, tension, or electrocautery for hemostasis), increased ischemia in the graft (e.g. prolonged warm/cold ischemia time, living donor liver transplantation) and hepatic artery thrombosis. Duct-to-duct biliary reconstruction is not an established risk factor for post-operative biliary leak.

Fasullo M et al. (2022). Post-transplant biliary complications: advances in pathophysiology, diagnosis, and treatment. BMJ Open Gastroenterology. 2022;9:e000778.

This patient has small for size syndrome, a form of early allograft dysfunction where the graft is ‘small’ relative to the recipient’s metabolic needs or portal inflow. It is diagnosed after other forms of early allograft dysfunction (e.g. primary nonfunction, hepatic artery thrombosis, portal venous thrombosis) are excluded. Patients present with worsening bilirubin and INR towards the end of the first postoperative week, and may have uncorrectable coagulopathy, large volume ascites, and hepatic encephalopathy. Risk factors relate to the recipient (high BMI, high MELD, multi organ dysfunction), graft sizing (graft-to-recipient weight ratio <0.8, left lobe transplant), poor graft quality (older donor, steatotic and fibrotic grafts) and high portal inflow (high portal pressures >15mHg, recipient splenomegaly). Hence, key strategies to reduce the risk of small for size syndrome include selection of larger and/or better quality grafts (option E), and portal inflow modulation (options A,B,C). Option D is incorrect, as maintaining a high central venous pressure impedes portal outflow, and causes higher postoperative portal venous pressures (which are a risk factor for small for size syndrome).

References:
Lauterio A et al (2024). Small for size syndrome in adult-to-adult living donor liver transplantation: a review of the latest literature. European Journal of Transplantation 2 (Special Issue)
Ikegami T et al (2026). Essential Updates 2024/2025: History, Pathogenesis, Definition, Prevention, and Management of Small-for-Size Syndrome in Living-Donor Liver Transplantation. Annals of Gastroenterological Surgery 2026 10(1) 35-41
Reddy MS, Gopal PV (2025). Small for Size Syndrome in Living Donor Liver Transplantation-
Prevention and Management. Journal of Clinical and Experimental Hepatology 2025 15(2) 102458

Based on the presentation, there is concern for acute liver failure, likely due to acetaminophen overuse. Acute liver failure is an indication for liver transplantation. In this case, AIDS is an absolute contraindication to liver transplantation. Smoking, alcohol and lack of social support can be barriers to liver transplantation but are assessed on a case-by-case basis Infections of the liver (eg. Hepatic abscess, ascending cholangitis) are not a contraindication to liver transplantation. Importantly, well controlled HIV (undetectable VL, CD4 count >100  is not a contraindication to liver transplant. 

REFERENCE
Lucey MR, Furuya KN, Foley DP. Liver Transplantation. N Engl J Med. 2023;389(20):1888-
1900. doi:10.1056/NEJMra2200923

GRWR : graft-to-recGRWR : graft-to-recipient weight ratio
Donor RLV : donor remnant liver volume
Answer A. GRWR 0.83%, Donor RLV 40%

EXPLANATION
Two important considerations in evaluating a potential candidate with regards to liver volume are:
- the volume (weight) of the graft and its correlation to the recipient’s need and size
- the volume of the remnant liver

In adult recipients, a well-accepted goal is a graft-to-recipient weight ratio of 0.8% or
greater. GRWR should not exceed 5%, since it may lead to difficulty with abdominal wound closure. The remnant liver volume reflects the percentage of liver remaining following donation. This should be ≥ 30% to ensure donor recovery.

REFERENCES
1. Lucey MR, Furuya KN, Foley DP. Liver Transplantation. N Engl J Med.
2023;389(20):1888-1900. doi:10.1056/NEJMra2200923
2. Powers, C., Gunabushanam, V., Centonze, L. et al. Current perspectives on living donor selection in liver transplantation. Updates Surg 77, 1745–1753 (2025).
https://doi.org/10.1007/s13304-025-02131-2

Steatosis assessment is an important component of donor selection. Every percentage increase in fat in the donor graft decreases the functional mass of the liver by 1% and disrupts microcirculation.

The normal liver has a higher attenuation than the spleen on an unenhanced CT scan. Liver Attenuation index (LAI) is used for hepatic steatosis assessment. LAI is calculated by placing a circular region of interest of at least 1 cm 2  at multiple places on the liver and the spleen and calculating the difference between the mean hepatic attenuation and the mean splenic attenuation. The attenuation value of a normal liver is approximately 50–57 Hounsfield Units (HU), which is around 10 HU more than that of the spleen.

LAI >5 : absence of significant macrovascular steatosis;
LAI values of - 10 to 5 HU : mild to moderate steatosis (6–30%);
LAI values of less than - 10 HU : moderate to severe hepatic steatosis (i.e.,≥30% fat).
LAI values of 5–15 are acceptable, but LAI values of less than −10 are not acceptable for liver
donation. Donors with LAI values of −10 to 5 need further evaluation by liver biopsy. Potential living donors with ≥30% macrosteatosis may be at higher risk.

REFERENCE
Puri P, Kumar A, Qaleem M. Donor Evaluation Protocol for Live and Deceased Donors. J Clin
Exp Hepatol. 2024;14(1):101217. doi:10.1016/j.jceh.2023.07.004

The clinical picture is concerning for late T-cell mediated rejection(TCMR). Liver biopsy shows fewer lymphocytes, greater interface and perivenular necroinflammation, less venous endotheliitis and slightly more lobular activity compared to early TCMR, which typically occurs before the 3rd month. 

The Banff rejection activity index (RAI) is a quantitative method of assessing allograft rejection wherein each of the triad of histologic findings for acute cellular rejection (portal inflammation, bile duct inflammation, and venous endothelial inflammation) are each graded on a 3-point scale, resulting in a scoring scheme ranging up to 9, with 9 being most severe. An RAI score of 5-6 falls in the moderate range. 

Initial treatment of mild TCMR includes augmentation of existing immunosuppression. Patients on cyclosporine should be switched to TAC if there are no contraindications. In patients with moderate or severe TCMR, intravenous pulse steroid therapy is required, with exact regimens varying across transplant centers. In patients with severe/resistant TCMR showing significant graft injury and cholestasis, lymphodepleting antibody therapy (most often antithymocyte globulin) may be required. 

REFERENCES
1. Te, Helen S.1; Agopian, Vatche G.2; Demetris, Anthony J.3; Kwo, Paul Y.4; McGuire, Brendan M.5; Russo, Mark W.6; Selzner, Nazia7; Washburn, W. Kenneth8; Winder, Gerald Scott9; Schiano, Thomas D.10. AASLD AST Practice Guideline on adult liver transplantation: Diagnosis and management of graft-related complications. Liver Transplantation(): 10.1097/LVT.0000000000000715, August 22, 2025. | DOI:10.1097/LVT.0000000000000715
2. Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation. Montano-Loza,

Answer: D. HIV infection is not a contraindication to liver transplant as long as patients are treated and ideally managed by an ID professional and have suppressed viral loads and adequate CD4 counts (>100). Patients with HIV-HCV coinfections have worse outcomes, but patients with HIV alone have similar outcomes to the general population. 

References:
Martin P, DiMartini A, Feng S, Brown R, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014;59(3):1144-1165. doi: 10.1002/hep.26972

The rate of acute cholangitis after Roux-En-Y hepaticojejunostomy is higher than with duct-duct anastomosis, potentially due the lack of Sphincter of Oddi, which typically prevents reflux of luminal contents into the biliary tree. While Roux-en-Y has historically been the operative approach for patients with PSC due to early data indicating a lower rate of cholangiocarcinoma, in general the rates of anastomotic strictures (A) and bile leak (C) are not different between the two techniques. However, hepaticojejunostomy requires longer operative and ischemia times (D) and makes endoscopic evaluation of post-operative biliary complications more challenging anatomically (E). For patients with PSC, AASLD does not comment on a preference for either biliary reconstruction technique, while ESOT recommends that the choice be left to operator discretions, with duct-to-duct reconstruction recommended when technically feasible.

References:
Prieto M, Valdivieso A, Gastaca M, et al. Hepaticojejunostomy in Orthotopic Liver Transplant: A Retrospective Case Control Study. Transplantation Proceedings. 2019;51(1):58-61. doi:10.1016/j.transproceed.2018.03.135
Kaldas FM, Korayem IM, Russell TA, et al. Assessment of Anastomotic Biliary Complications in Adult Patients Undergoing High-Acuity Liver Transplant. JAMA Surg. 2019;154(5):431. doi:10.1001/jamasurg.2018.5527
Bowlus CL, Arrivé L, Bergquist A, et al. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology. 2022;77(2):659-702. doi: 10.1002/hep.32771
Carbone M, Della Penna A, Mazzarelli C, et al. Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)—A European Society of Organ Transplantation (ESOT) Consensus Statement. Transpl Int. 2023;36. doi:10.3389/ti.2023.11729

Joint AASLD-IDSA guidelines support the use of HCV-viremic donor grafts in HCV- seronegative recipients given that recipients undergo informed consent for accepting such grafts. Accepting such grafts reduces wait time (A). In general, DAA treatment should be started as soon as possible after transplant (B), given the risks of non-hepatic HCV complications, including a documented case of HCV-related membranous nephropathy resulting in ESRD. DAA regimens should be for 12 weeks (C), drug-drug interactions should be taken into account (D), and in general graft survival rates may in fact be superior in HCV-viremic grafts (E), potentially due to these donors being younger on average.

References:
Debika Bhattacharya, Andrew Aronsohn, Jennifer Price, Vincent Lo Re, the American Association for the Study of Liver Diseases–Infectious Diseases Society of America HCV Guidance Panel , Hepatitis C Guidance 2023 Update: American Association for the Study of Liver Diseases– Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection, Clinical Infectious Diseases, 2023;, ciad319, https://doi.org/10.1093/cid/ciad319
Aqel, Bashar, et al.;Outcomes following liver transplantation from HCV-seropositive donors to HCV-seronegative recipients; Journal of hepatology 74.4 (2021): 873-880. Bekki, Yuki, et al.;Varying utilization rates but superior outcomes in liver transplantation from hepatitis C− positive donors in the United States: An analysis of the OPTN/UNOS database; Transplantation 106.9 (2022): 1787-1798.
Levitsky, J., et al.;The American Society of Transplantation Consensus Conference on the use of hepatitis C viremic donors in solid organ transplantation; American Journal of Transplantation 17.11 (2017): 2790-2802.

Liver transplant recipients should discuss vaccination with their transplant providers in addition to consulted CDC recommendations. Regarding the herpes zoster vaccine, transplant recipients should receive the recombinant zoster vaccine (Shingrix) and in general not receive live vaccines, including the live attenuated vaccine (Zostavax) (B). Close family contacts should not receive live vaccines when a recombinant or inactivated alternative is available (E). Patients who complete zoster vaccination prior to transplant do not require further doses after transplant (D, correct answer). If patients were not vaccinated prior
to transplant, CDC recommends that all liver transplant recipients age 19 and older be vaccinated. Localized non-severe dermatomal zoster infections can be treated with oral acyclovir or alternative oral regimens for at least 7 days or until lesions crust over, whichever is longer (A). Patients may require IV acyclovir or ocular or aural involvement or with severe or disseminated infections.

References:
Sharma, Pratima; Izzy, Manhal2; Ghabril, Marwan S.; Serper, Marina; Clark, Virginia C.; Ison, Michael G.; Hameed, Bilal; Volk, Michael; Brown, Robert S. Jr; Humar, Abhinav; Martin, Paul. AASLD AST Practice Guideline on adult liver transplantation: Diagnosis and post-transplant management of non-graft-related complications. Liver Transplantation():10.1097/LVT.0000000000000785, December 17, 2025. | DOI: 10.1097/LVT.0000000000000785
Pergam SA, Limaye AP; AST Infectious Diseases Community of Practice. Varicella zoster virus in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13622. doi:10.1111/ctr.13622. Epub 2019 Jul 22. PMID: 31162727.

One of the mainstay pillars of management in patients with cirrhosis is HCC surveillance every 6 months with ultrasound and AFP (Option D). In the past, all patients with cirrhosis were recommended to undergo endoscopic screening for varices (Option A). The 2024 AASLD Practice Guidance on portal hypertension and the Baveno VII consensus now allow safe deferral of EGD when the risk of clinically significant portal hypertension (CSPH) is low (See Figure below)

Figure 1 from 2025 AASLD Practice Guideline on noninvasive liver disease assessment of portal hypertension

Specifically, CSPH can be ruled out if LSM is less than 15 kPa and platelets ≥150,000/µL. This patient has an LSM of 14.1 kPa and platelets of 166k, which fits squarely within the “rule-out” criteria, and her recent CT abdomen pelvis does not show any evidence of portosystemic collaterals (which could be used as a surrogate to “rule-in” CSPH). Thus, her likelihood of having varices that require treatment is negligible, and an EGD is unnecessary.

Since this patient does not need an EGD and has compensated disease without decompensation, the best next step is to continue HCC surveillance. For this patient, whose underlying etiology is being addressed, it is still recommended to screen periodically for CSPH with VCTE and platelet levels measurement.

B. Refer for liver transplant evaluation
Referral for transplant (answer choice B) is generally warranted with a MELD score ≥15 or after the first decompensating event (ascites, variceal hemorrhage, hepatic encephalopathy, jaundice, or HCC). With a MELD 3.0 score of 13 and compensated status, this patient does not yet meet referral criteria.
C. Start carvedilol 3.125 mg twice daily Nonselective beta blockers (NSBBs) are recommended for patients with medium/large varices
or documented CSPH. The PREDESCI trial (2019) showed that NSBBs reduce the risk of decompensation and death in patients with compensated cirrhosis and CSPH (HVPG ≥10 mmHg). However, in this case, noninvasive criteria indicate that CSPH is absent  so NSBB therapy is not appropriate at this time (answer C is incorrect). The target dose for carvedilol is 12.5mg of carvedilol daily or in two divided doses. 
E. Start resmetirom
Resmetirom is approved for non-cirrhotic NASH with F2–F3 fibrosis. It is contraindicated in cirrhosis (F4), making it inappropriate in this setting (answer E is not correct).

Reference List
1. Kaplan DE, Ripoll C, Thiele M, Fortune BE, Simonetto DA, Garcia-Tsao G, Bosch J. AASLD Practice Guidance on Risk Stratification and Management of Portal
Hypertension and Varices in Cirrhosis. Hepatology. 2024;79(5):1180-1211. doi:10.1097/HEP.0000000000000647.
2. Villanueva C, Albillos A, Genescà J, Garcia-Pagan JC, Calleja JL, Aracil C, et al. β-blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomized, double-blind, placebo-controlled, multicenter trial. Lancet. 2019;393(10181):1597-1608.
3. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C, Baveno VII Faculty. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959-974.
4. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;68(2):723-750.
5. Harrison SA, Bashir MR, Guy CD, et al. Resmetirom (MGL-3196) for nonalcoholic steatohepatitis: the MAESTRO-NASH trial. N Engl J Med. 2023;389(13):1231-1242.