Hepatology Practice Questions, Edition 2

This patient’s presentation is concerning for post-transplant lymphoproliferative disorder (PTLD). PTLD can present any time after transplant but the incidence follows a bimodal distribution with most cases occurring either within the first year or more than 5 years post-transplant. Her risk factors for developing PTLD include donor/recipient EBV mismatch and high doses of immunosuppression given her proximity to transplant. Given the high index of suspicion, the next step is securing a diagnosis. While physical exam, CBC with differential and a positive EBV viral load all support PTLD, a definitive diagnosis is made with histology (Answer choice B). A PET scan (Answer choice C) will also be necessary for staging but is not the next step. Treatment for PTLD involves reduction of immunosuppression, surgical resection or radiation if applicable, and systemic chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, and prednisone). There is no effective antiviral for the treatment of EBV (Answer choice A) and no evidence that EBV eradication is effective for treating PTLD.   While it is important to consider enteric infections in the differential for her presentation, obtaining cultures and treating the patient with antibiotics (Answer choice D) without endoscopic evaluation would be inappropriate.

KEY POINT:PTLD can present at any time after transplant and requires a high index of suspicion to diagnose. While clinical history, labs and imaging can suggest a diagnosis of PTLD, a definitive diagnosis requires tissue.

AUTHOR, TOPIC: Nisha Howarth, Post-LT Malignancy

Outcomes of liver transplantation for patients with HCC who meet Milan criteria (one tumor <5 cm or 2-3 tumors <3 cm) are excellent and similar to outcomes for patients transplanted for non-malignant indications. Despite meeting Milan criteria, most HCC recurrence occurs within the first two years post-transplant, and it is imperative to screen patients appropriately for early detection. Use of risk calculators can help determine the time and duration of post-transplant HCC surveillance. The RETREAT score is a well-validated tool that estimates the risk of HCC recurrence based on the size of the largest tumor, the number of viable tumors, microvascular invasion, and serum AFP at the time of transplant. RETREAT scores range from 0 (low risk) to ≥ 5 (high risk, nearly 80% 5-year recurrence) with our patient falling in the low-intermediate risk range. While surveillance strategies may vary slightly by center, AFP plus cross-sectional imaging with CT or MRI every 6 months (Answer choice D) for two years and annually thereafter is appropriate for a RETREAT score of 2. An ultrasound (Answer choice B) is inappropriate for post-transplant HCC surveillance. Although atezolizumab plus bevacizumab (Answer choice C) is now first-line combination systemic therapy for patients with advanced HCC, adjuvant systemic therapy is not recommended for any patient undergoing liver transplant for HCC.

While institutional immunosuppression protocols vary, calcineurin inhibitors have been associated with increased HCC recurrence. mTOR inhibitors, such as sirolimus, have antineoplastic properties and a phase III randomized control trial (SiLVER) demonstrated improved recurrence-free survival between 3- and 5-years post-transplant with mTOR inhibitor-based immunosuppression, and the benefits were most notable in patients who were within Milan criteria, like our patient. Unfortunately, these results were not sustained after 5 years.

KEY POINT: Most post-transplant HCC recurrence occurs within the first two years of transplant. Risk scores, such as the RETREAT score, can risk-stratify patients for HCC recurrence based on tumor characteristics at the time of transplant. Frequent surveillance with tumor markers and cross-sectional imaging is recommended.

AUTHOR, TOPIC: Nisha Howarth, Post-LT Malignancy

Based on the patient’s imaging findings of ascites, she has clinically significant portal hypertension (CSPH). The 2023 AASLD guidelines for Risk Stratification and Management of Portal Hypertension and Varices in Cirrhosis recommend considering treating patients with compensated cirrhosis with CSPH with a non-selective beta-blocker (NSBB, preferably carvedilol) to prevent decompensation. Guidance also recommends that if NSBB is started, EGD to screen for varices can be avoided (Answer choice B). While a diagnostic paracentesis (Answer choice C) may be appropriate and follow-up (Answer choice A) is needed, these interventions will not reduce rates of future decompensation.

KEY POINT:Non-selective beta-blockers are now recommended to prevent hepatic decompensation, including ascites and variceal hemorrhage in patients with clinically significant portal hypertension. Carvedilol is the preferred non-selective beta-blocker, and a 2023 guidance statement from the AASLD recommends starting with low dose (carvedilol 3.215mg daily) and up-titrating as able. While individual practices may vary, this guidance statement concludes that variceal screening can be avoided in patients taking non-selective beta-blockaders.

AUTHOR, TOPIC: Nisha Howarth, Portal Hypertension

This patient with refractory ascites is on near-maximal doses of diuretics and requires weekly paracenteses. It is reasonable to seek a more definitive management for his refractory ascites (Answer A not appropriate). His recent history of overt hepatic encephalopathy despite medical therapy is a relative contraindication for TIPS insertion (Answer choice D). The safety and efficacy of indwelling peritoneal catheters (IPCs) remain to be established in this population. Although existing data is low quality, there is a noteworthy risk of average bacterial infection rate in patients with IPCs, thus this strategy is typically withheld until the patient is seeking treatment with palliative intent (Answer choice B).

KEY POINT: A patient with decompensated cirrhosis with diuretic-refractory ascites should be evaluated for transplant and considered for TIPS placement. Depending on the clinical scenario, potential contraindications to a TIPS include heart failure, difficult to control hepatic encephalopathy, hepatocellular carcinoma, and elevated MELD score, among others.

AUTHOR, TOPIC: Nisha Howarth, Portal HTN

This patient has a FIB-4 score of 3.1, indicating a high likelihood of advanced fibrosis. This patient should be referred for specialized care under a gastroenterologist or hepatologist and not referred back to her primary care physician (Answer choice A). The patient has an elevated BMI and several risk factors for developing steatotic liver disease. She should be encouraged to exercise 5 times a week (a total of 150 minutes), adopt a diet which is low in saturated fats and carbohydrates (such as the Mediterranean diet), and attempt to lose weight. Given that she has a diagnosis of diabetes, glucagon-like peptide receptor agonists (GLP-1 RA) should be considered as they have been demonstrated to improve liver steatosis and NASH resolution in addition to weight loss and improved insulin sensitivity. However, this patient has a history of idiopathic pancreatitis, therefore she should not receive a GLP-1 RA (Answer choice C). Furthermore, the first step would still be to risk stratify and perform fibrosis assessment. Bariatric surgery should be considered in patients who meet criteria for weight loss surgery, however, while the patient’s BMI does reach the criteria of ≥ 35 kg/m² with metabolic comorbidities (Answer choice D), this would not be the immediate next step. The next step in management for this patient should be additional risk stratification with MRE +/- liver biopsy and cirrhosis-based management if applicable.

KEY POINT: The FIB-4 score is a non-invasive test to risk-stratify patients for the presence of fibrosis, and recent guidance from the AASLD recommends that patients with metabolic dysfunction-associated steatotic liver disease and FIB-4 ≥ 1.3 should undergo a secondary risk assessment for fibrosis (e.g. elastography).

AUTHOR, TOPIC: Nisha Howarth, MASLD

Biliary atresia is a progressive, fibro-obliterative disease of the biliary tree that presents with biliary obstruction in the neonatal period. Diagnosis is usually made with imaging during work up for new onset jaundice, acholic stools and elevated bilirubin. Infants with suspected biliary atresia should undergo rapid surgical intervention with hepatoportoenterostomy (HPE), known as the Kasai procedure, to improve cholestasis. With a successful HPE, bilirubin should reduce significantly (and normalize) post-operatively. Earlier surgical intervention (Answer choice E) has been shown to improve overall long-term outcomes. Despite initially successful HPE, many patients will still have progressive liver disease. Redo Kasai procedures (Answer choice A) historically have poor outcomes, and are typically avoided. Patients with progressive biliary excretion failure ultimately require liver transplantation. Liver transplant for biliary atresia has excellent outcomes (Answer choice C).

KEY POINT: Early surgical intervention with a Kasai procedure can improve outcomes in Biliary Atresia. However, patients who have progressive liver dysfunction despite a Kasai procedure should be evaluated for liver transplant as redo Kasai procedures typically have poor outcomes.

AUTHOR, TOPIC: Mary Khiew, Biliary Atresia

Post transplant lymphoproliferative disorders (PTLD) are lymphoid/and or plasmocytic proliferations that occur in solid organ transplant patients who receive chronic immunosuppression. Risk factors for PTLD include level of immunosuppression (which causes uncontrolled expansion of B cells) and EBV status. Diagnosis requires a high degree of clinical suspicion (as some patients may exhibit B symptoms), radiological evaluation, measurement of EBV viral load, and tissue biopsy of lymphoid tissue. While there is initial concern for sepsis, infectious evaluation has been unrevealing and antibiotics should be discontinued unless suspicion for infection remains (Answer choice A). This patient does not have signs of graft dysfunction (Answer choice D), and a new malignancy would be a contraindication to re-transplant, so this needs to be evaluated first (Answer choice B). The cornerstone of PTLD treatment is minimizing immunosuppression, and while steroids (Answer choice E) are often part of treatment for PTLD, a diagnosis needs to be made first.

KEY POINT: PTLD can occur at any time post-transplant. Diagnosis requires a tissue biopsy, and treatment includes minimizing immunosuppression, oncology consultation for consideration of chemotherapy, and occasionally surgical resection or radiation therapy for patients with localized disease.

AUTHOR, TOPIC: Mary Khiew, Post-Transplant Complications

Alcohol-related hepatitis is used to describe an acute onset of acute hepatitis in the setting of heavy alcohol use. It can present in patients with or without chronic alcohol related liver disease. Patients often have palpable, tender hepatomegaly in the setting of acute inflammation of the liver, jaundice, with elevated bilirubin and mild elevation in AST and ALT (usually in a ~2:1 ratio). Clinically, they may also have characteristics of clinically significant portal hypertension with abdominal distension due to ascites, which can predispose to acute kidney injury. With patients with new onset ascites, it is important to evaluate for infection with a diagnostic paracentesis as well as obtain imaging to ensure hepatic vasculature patency. This patient also has tense ascites, which could be contributing to her renal dysfunction and should have a large volume paracentesis (LVP) with albumin replacement. Diuretics alone are unlikely to be an effective treatment for her volume overload and may exacerbate her acute kidney injury. Steroids for treatment of alcohol-related hepatitis are controversial but can be considered in select patients. If steroids are considered, it is typically in patients with high MDF (>32) or MELD >20 without evidence of infection. Response to treatment should be reassessed with a Lille score at either 4 or 7 days to determine likelihood of benefit from continuing steroids. If benefit is unlikely, steroids should be stopped to minimize unnecessary risk of prolonged steroid use.  Alcohol use disorder assessment and treatment is also paramount in long term management of alcohol related liver disease.

KEY POINT: Alcohol-related hepatitis (AH) presents with sudden onset hepatitis, and even though it can occur without cirrhosis, patients with AH often have features of portal hypertension. Treatment for AH involves evaluating for infection, considering steroids with the assistance of risk scores (Maddrey and Lille), alcohol cessation, and nutritional support.

AUTHOR, TOPIC: Mary Khiew, Alcohol-Related Liver Disease

Recurrence of the primary liver disease is an important consideration after transplant and can have potentially detrimental effects on graft survival and mortality. The natural history of recurrent PSC is variable, with severe cases requiring re-transplantation. Risk factors for recurrence are not well understood, and currently, influence of immunosuppression regimen has not been shown to increase rate of recurrence.

KEY POINT: PSC recurrence post-transplant is variable. Like PSC prior to transplant, recurrent PSC is a poorly understood entity with limited treatment options that can require re-transplantation.

AUTHOR, TOPIC: Mary Khiew, Recurrence of Liver Disease Post-Transplant

Vascular complications after liver transplant significantly increase risk for graft loss and mortality.  Prolonged arterial interruption from hepatic artery stenosis can lead to graft ischemia that can result in graft loss, and even after revascularization, can increase risk of ischemic cholangiopathy. Hepatic artery pseudoaneurysms can cause sudden death from spontaneous rupture and require timely intervention.  As with this patient, they may present with an initial “sentinel bleed” with intra-abdominal bleeding; if not addressed and aneurysm rupture occurs, mortality approaches 100%.  Any concern for hepatic artery vascular compromise – including thrombosis, stenosis, rupture, or pseudoaneurysm – warrants urgent intervention. In this case, it is reasonable to assess for IR intervention prior to proceeding to surgical exploration.

KEY POINT: Hepatic artery compromise requires urgent intervention and a multidisciplinary discussion between transplant surgery and interventional radiology to determine the best approach.

AUTHOR, TOPIC: Mary Khiew, Non-Immune Complications Post-Transplant

This patient presents with an acute liver failure (ALF), defined by acute liver injury, synthetic dysfunction (elevated INR), and hepatic encephalopathy. His presentation of ALF is most likely due to an acetaminophen overdose. N-acetylcysteine (Answer choice A) is currently the only treatment available, as well as intensive care unit support. While not universally used, many centers do perform plasmapheresis or other techniques (such as albumin dialysis) in this clinical setting (Answer choice B). The patient meets the Kings College transplant criteria for acetaminophen overdose that include: Arterial pH < 7.3, INR > 6.5 (PT > 100), creatinine > 3.4 (300), and HE (grade III or IV). Among patients who are treated with NAC, approximately half still die without emergency liver transplant, and thus early referral to a transplant center for evaluation (Answer choice C) is imperative. Intraoperative and post-operative treatments are challenging, and survival rates are consistently lower than those associated with elective liver transplant. Despite severe coagulopathy (INR 6.8), coagulopathy correction with plasma and platelets (Answer choice D) is recommended only if there is an active bleeding or prior to an invasive procedure.

KEY POINT: N-acetylcysteine (NAC) is a mainstay for treatment of ALF from acetaminophen overdose and is becoming accepted for treatment of non-acetaminophen-related ALF. Even with NAC treatment, ALF carries a high risk of death, so prompt referral to a transplant center is indicated.

AUTHOR, TOPIC: Laia Aceituno, Acute Liver Failure

Acute liver failure (ALF) is characterized by acute liver injury (< 26 weeks), coagulopathy (INR > 1.5), and altered mental status. The liver is a central site of ammonia metabolism, and during acute liver failure, there is significant hepatocyte dysfunction with impaired ammonia metabolism. This results in acute ammonia elevations, which can lead to cerebral edema, intracranial hypertension, and ultimately, cerebral herniation and death. Therefore, worsening altered mental status needs prompt attention. Management of worsening mental status in patients with ALF involves ensuring adequate airway protection (similar to non-ALF patients) but also prompt CT imaging and maneuvers to relieve ICH, including elevating the head of bed, hyperventilating, and using hypertonic solutions (such as mannitol). While hemodialysis (Answer choice C) can clear ammonia, the use of hemodialysis (and albumin dialysis or Molecular Absorbent Recirculating System) for ALF remains controversial. Additionally, this patient’s airway needs prompt attention, and dialysis, if used, does not replace other methods for reducing ICH. While this patient needs airway protection, the ICH needs prompt attention, which is not addressed by albumin boluses (Answer choice D). Infection (Answer choice B) should be high on the differential diagnosis with worsening mental status in ALF; however, ICH is the highest concern in this case.

KEY POINT: Defective hepatic ammonia metabolism in acute liver failure can lead to intracranial hypertension, which can be deadly if not promptly diagnosed and managed. ICH should be high on the differential diagnosis for an ALF patient with declining mental status. Management should be done in conjunction with a neurology (or neurology ICU) team and may involve maneuvers to reduce ICH.

AUTHOR, TOPIC: Laia Aceituno, Acute Liver Failure

This patient is presenting with acute liver failure, which is defined by an acute liver injury (< 26 weeks), coagulopathy (INR > 1.5), and altered mental status. While ALF requires the absence of pre-existing liver disease, one exception to this rule is Wilson disease, which should be suspected in this young patient presenting with ALF. Wilson disease is a genetic disorder of copper excretion (due to mutations in the ATP7B transporter), which results in elevations in free copper, which is toxic to cells, and low levels of ceruloplasmin. Diagnosis of Wilson is made by serum ceruloplasmin (low), 24-hour urine copper (elevated), presence of KF rings by slit lamp exam, and liver biopsy with weighted copper. While many viruses (Answer choice B) can cause a similar presentation and should be tested for, Wilson Disease is more likely. An echocardiogram (Answer choice C) and hepatic imaging (Answer choice D) are both necessary for her transplant evaluation, but they are unlikely to yield a diagnosis.

KEY POINT: Wilson’s disease can present as an ALF and should be excluded in young patients with ALF. Diagnosis is made by measurement of serum ceruloplasmin (low) and 24-hour urine copper (elevated), the presence of KF rings by slit lamp exam, and liver biopsy with weighted copper.

AUTHOR, TOPIC: Laia Aceituno, Acute Liver Failure

Solid organ transplant recipients are at an increased risk of de novo cancer compared to the general population, and this is at least in part due to chronic immunosuppression. While the risk of other malignancies is controversial, transplant recipients are particularly prone to non-melanoma skin cancer due to both reduced immune surveillance of tumor antigens and increased risk of UV-mediated DNA damage. In addition to standard sun precautions (e.g. UV-protective clothing), minimizing immunosuppression is an important part of preventing skin cancer. Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus, have anti-proliferative effects that result in improved cancer risk profiles but are not routinely used for immunosuppression protocols. However, in the event of de novo malignancy, mTOR inhibitors are important to consider (Answer choice A). There is no indication to increase immunosuppression (Answer choice B) as there is no sign of rejection. While it is generally recommended to minimize tacrolimus dosing to the minimum necessary, her level of 3-5ng/mL is a reasonable dose (D is incorrect). Anti-metabolites (e.g. MMF and azathioprine) are generally insufficient for monotherapy (Answer choice C).

KEY POINT: Chronic immunosuppression increases the risk of malignancy, particularly non-melanomatous skin cancer, in transplant recipients. Immunosuppression should be adjusted to the minimal amount necessary to prevent graft rejection, and special consideration should be given to mTOR inhibitors (e.g. sirolimus and everolimus), which have antiproliferative effects.

AUTHOR, TOPIC: Laia Aceituno, Mechanism of Action and Pharmacokinetics (PK) of Immunosuppressive Medications

This patient’s presentation is concerning for posterior reversible encephalopathy syndrome (PRES), which is a neurologic condition that presents with a range of symptoms from headaches, altered mental status, and seizures. Diagnosis is usually made with brain imaging demonstrating classic features (white matter edema in the posterior hemispheres) in the proper clinical setting. While symptoms are not specific, additional causes for altered mental status, including infection (Answer choice D) and structural brain issues (Answer choice E) should be ruled out. However, this case is so concerning for PRES that management should begin prior to performing these additional diagnostics. Immunosuppression with a calcineurin inhibitor is a major risk factor for developing PRES, and it often presents within days to weeks of starting CNI. Management involves reducing or discontinuing offending immunosuppression. MMF can cause myelosuppression and gastrointestinal symptoms (nausea, vomiting, diarrhea) but does not cause neurotoxicity (Answer choice A). Corticosteroids can cause neuropsychiatric symptoms such as anxiety, insomnia, and even psychosis, but they do not cause seizures (Answer choice B).

KEY POINT: Calcineurin inhibitors (cyclosporine and tacrolimus) are well-known causes of neurotoxicity, it is important to balance the need of discontinuation if severe adverse effects.

AUTHOR, TOPIC: Laia Aceituno, Short-Term Immune and Nonimmune Toxicity of Immunosuppressive Medications

This patient with chronic inactive hepatitis B is about to undergo therapy with the anti-CD20 agent rituximab. While patients who have seroconverted (i.e. HBsAg negative) are at lower risk of reactivation that those who have not, AASLD guidelines recommend antiviral prophylaxis for HBsAg(-)/HBcAb(+) patients undergoing stem cell transplantation or anti-CD20 antibody therapy.

Tenofovir disoproxil fumarate (TDF) should be avoided or dose reduced given renal dysfunction (option D). Close monitoring for “on-demand” therapy (option A) may be appropriate for patients undergoing other non-anti-CD20 immunosuppressive therapies. There is no indication for HCV prophylaxis in this patient who has cleared HCV infection (option B).

KEY POINT: Patients with chronic hepatitis B are at risk of reactivation when undergoing immunosuppressive therapy. Anti-CD 20 therapy (i.e. rituximab) poses special risk of reactivation, and AASLD recommends antiviral prophylaxis for these patents.

AUTHOR, TOPIC: Christopher Coe, Viral Hepatitis

Both the American College of Obstetricians and Gynecologists and the AASLD recommend antiviral therapy for pregnant women at the beginning of the third trimester if the HBV DNA is greater than 200,000 IU/mL (B is correct). Both organizations also recommend that HBIG and the HBV vaccine be given to neonates born to all HBsAg positive mothers. Neither organization recommends C-section for the sole purpose of reducing vertical transmission of hepatitis B. Both HBIG and the hepatitis B vaccine should be offered to the neonate to reduce vertical transmission. Breastfeeding is not contraindicated, although low levels of antiviral may be present in breastmilk.

KEY POINT: Pregnant patients with active hepatitis B and an HBV viral load > 200,000 IU/mL should be offered antiviral therapy in the third trimester. HBIG and the HBV vaccine should be given to the neonate. Breastfeeding and vaginal delivery are not contraindicated in the setting of active HBV.

AUTHOR, TOPIC: Christopher Coe, Viral Hepatitis

Receipt of HCV positive solid organs should be discussed with potential organ recipients as this increases their potential donor pool. Patients who receive HCV positive solid organ transplants should be treated with DAA therapy, and not simply observed (option a) According to joint AASLD-IDSA guidance, this should be started as soon as possible (ideally within 1 week) after transplantation. There is not yet sufficient data to support abbreviated courses of DAA therapy in this setting, and standard-duration therapy is advised (option c). F1 fibrosis should not be a contraindication to heart transplantation or HCV antiviral therapy (option d). Outcomes have not been shown to be worse in those who receive HCV+ solid organs (option e).

KEY POINT: Recipients of HCV positive solid organs should be offered DAA as soon as feasible after transplantation.

AUTHOR, TOPIC: Christopher Coe, Viral Hepatitis

This patient with pruritus, fatigue, and ALP-predominant liver test elevations has a presentation concerning for PBC. 95% of patients with PBC will have positive AMA. PBC can be diagnosed if 2 of the 3 following criteria are met: 1) chronically elevated ALP, 2) AMA-associated autoantibodies (usually, AMA, but as we see here not always), and 3) histology showing typical bile duct inflammation. AMA-negative PBC can be diagnosed without a biopsy if other PBC specific autoantibodies (namely anti-sp100 and anti-gp210) are present.

While AIH can overlap with PBC, AIH is less likely in this case given the normal AST and ALT. Prednisone (option C) is not a treatment for PBC without AIH overlap, and there is no obvious role for ERCP (option A) in this case in the setting of a normal MRCP. Serum bile acid levels (option D) do not play an important role in the diagnosis of PBC.

KEY POINT: Anti-sp100 and anti-gp210 antibodies are PBC specific autoantibodies that may be positive in AMA-negative PBC.

AUTHOR, TOPIC: Christopher Coe, Autoimmune Disorders

Nitrofurantoin, along with anti-TNF inhibitors and minocycline, are classically associated with autoimmune-hepatitis like drug-induced liver injury. Features of hypersensitivity (peripheral eosinophilia, low grade fever) and elevated autoantibody titers further support this diagnosis. The liver biopsy shows interface hepatitis and periportal inflammation which is classic in AIH and AIH-like DILI.  Drug withdrawal is the next step (option c).

Steroids (option a) should be considered if the liver injury is severe (AST and ALT > 3x ULN, bilirubin > 2x ULN) or if liver tests fail to improve with withdrawal of the offending agent. Nitrofurantoin is more likely to cause an AIH like DILI than mesalamine (option e). Relapse after drug withdrawal is rare in AIH-like DILI. If this does occur, a diagnosis of AIH should be considered. Azathioprine (option b) is often started a few weeks after steroid initiation and is used to maintain remission in patients with AIH. Weight loss of 10% total body weight is recommended in people with MASH (option d).

KEY POINT: Nitrofurantoin can cause an AIH-like DILI. Drug withdrawal is the next best step. Adalimumab, infliximab, and minocycline are among the other drugs associated with AIH-like DILI.

AUTHOR, TOPIC: Christopher Coe, Autoimmune Disorders

Frailty, sarcopenia, and malnutrition pre-transplant are associated with poorer outcomes post-transplant. In fact, BMI <18.5 is identified as a key predictor. These parameters have been associated with infectious complications, increased length of ICU and hospital stay, post-transplant survival, as well as hemorrhagic complications and strokes. Interventions such as enteral feeding and physical therapy are associated with improvement in sarcopenia and frailty, but studies demonstrating benefit post-transplant are lacking. Nevertheless, these supportive measures are recommended for all transplant candidates. There is no age cut-off for liver transplant; physiological age with an assessment of comorbidities determines appropriateness of transplant (Answer choice B). This patient’s HCC tumor falls within Milan criteria and has favorable transplant outcomes (Answer choice C). Treatment of Hepatitis B with antivirals pre-transplant and prophylaxis with HBV immune globulin (HBIG) post-transplant leads to excellent post-transplant survival rates (Answer choice D).

KEY POINT: Malnutrition with a BMI <18.5 is associated with poor outcomes post-transplant. All patients should undergo a nutritional assessment as part of a transplant evaluation, and individualized pre-habilitation efforts with both physical therapy and nutrition should be considered.

AUTHOR, TOPIC: Sarah Park, Selection and Evaluation for Liver Transplant

This patient is presenting in acute liver failure from Wilson’s disease. Like other causes of acute liver failure, Wilson’s Disease has a high mortality rate without liver transplant. It is imperative to initiate an expedited evaluation for an urgent UNOS Status 1a liver transplant. D-penicillamine (Answer choice A) is a chelating agent that is a first line therapy for Wilson disease, and zinc (Answer choice B) decreases intestinal absorption of copper. While these can be used for chronic treatment of Wilson’s disease, they are not likely to provide benefit in acute liver failure. Ursodeoxycholic acid (Answer choice C) is not an appropriate therapy for Wilson’s Disease. It is used for primary biliary cirrhosis (PBC).

KEY POINT: Urgent liver transplant is indicated for acute liver failure of any cause. Wilson’s Disease is unique in that it is a chronic liver disease that can present with ALF. Chelation agents are of limited use when Wilson’s Disease presents with ALF, and similar to other cause of ALF, urgent transplant evaluation is indicated for ALF from Wilson’s Disease.

AUTHOR, TOPIC: Sarah Park, Selection and Evaluation for Liver Transplant

Hepatopulmonary syndrome (HPS) is a complication of cirrhosis that causes dyspnea due to intrapulmonary shunting leading to inadequate oxygenation. Liver transplantation leads to near-total resolution of HPS. Since some patients with HPS have mild liver disease and the MELD score does not capture their overall clinical severity, UNOS assigns standard MELD exception points if specific criteria are met. All of the following criteria must be met:

1. Ascites, varices, splenomegaly, or thrombocytopenia.
2. A shunt, shown by either contrast echocardiogram or lung scan.
3. PaO2 less than 60 mmHg on room air within 30 days prior to submission of the initial exception request.
4. No clinically significant underlying primary pulmonary disease.

If these criteria are met, a score of the median MELD at transplant (MMaT) for the region is given. Our patient has clinical evidence of HPS with progressive dyspnea and orthodeoxia in the setting of cirrhosis with portal hypertension. She has no known underlying lung disease and normal pulmonary testing. Therefore, if she has a PaO2 of < 60mmHg on room air, she would qualify for MELD exception points for HPS. Age and presence of portal hypertension (Answer choices A and D) do not increase prioritization on the waitlist, and MELD score (Answer choice B) is the standard method for prioritizing patients on the waitlist.

KEY POINT: Patients with severe HPS who meet defined criteria can receive a MELD exception score that is the median MELD at transplant (MMaT) for the region. 

AUTHOR, TOPIC: Sarah Park, Selection and Evaluation for Liver Transplant

Although most transplant centers have historically mandated a 6-month period of sobriety from alcohol prior to transplant, the 6-month mortality rate associated with severe acute AH is exceedingly high. Studies have demonstrated that highly selected patients with severe AH have improved survival with early transplant.  Important considerations to address in the multidisciplinary meeting are social support, no prior episodes of alcohol hepatitis, and a commitment to future abstinence (regardless of the amount of time that they had been abstinent prior to the acute presentation).

KEY POINT: Patients with severe AH should be referred to a transplant center where they can be evaluated by a multidisciplinary committee for an early liver transplant if they meet favorable inclusion criteria.

AUTHOR: TOPIC: Sarah Park, Selection and Evaluation for Liver Transplant

This patient has newly diagnosed HCC that falls within Milan criteria (one lesion <5 cm or 2-3 lesions <3 cm) that have been established to guide selection of optimal candidates with HCC for liver transplant. Transplant is both curative for the cancer and the underlying cirrhosis (Answer choice A), and she should be evaluated for transplant. Depending on anatomical considerations, surgical resection (Answer choice B) would be the treatment of choice if the patient did not have cirrhosis with clinically significant portal hypertension (splenomegaly, varices, Plt <100, hepatic venous pressure gradient >10 mm Hg). Patients with HCC but without cirrhosis have better postoperative outcomes and lower risk of HCC recurrence compared to those with cirrhosis. Since the patient can undergo curative therapy with transplant, she does not need to undergo downstaging to meet Milan criteria (Answer choice C) and should not have a purely palliative approach to her care (Answer choice D).

KEY POINT: In HCC, if a single tumor lesion is <5 cm or there are 2-3 lesions that are <3 cm, this fulfills the Milan criteria for curative therapy with a liver transplant.

AUTHOR, TOPIC: Sarah Park, Selection and Evaluation for Liver Transplant

Amiodarone hepatotoxicity follows two distinct patterns, one associated with chronic use of amiodarone and an acute injury associated with use of IV amiodarone, usually in elderly patients.

Between 15 and50% of patients on long term oral amiodarone may have elevated serum enzyme elevations, which can resolve spontaneously despite continuation of the drug. Clinically significant hepatotoxicity occurs only in 1% of patients and resembles alcohol-related liver disease both histologically and clinically, though the AST/ALT are usually elevated to a similar degree (as opposed to AST > ALT with alcohol-related liver disease).

Intravenous formulations of amiodarone contain a vehicle (polysorbate 80) that can cause a distinct form of liver injury, particularly when given to elderly or frail patients. This injury is characterized by rapid and marked elevations in AST/ALT, relatively preserved ALP, and often elevated total bilirubin with jaundice. Rarely, this can lead to acute liver failure. This injury usually improves rapidly with cessation of Amiodarone and AST/ALT may normalize in days (Answer choice A). The mechanism of injury is different than that for patients chronically on amiodarone and so while re-exposure to IV amiodarone is high risk for recurrent injury (Answer choice C), these patients usually tolerate oral amiodarone without issue (Answer choice D). There are no targeted therapies for amiodarone related hepatotoxicity (Answer choice B).

KEY POINT: Amiodarone causes two distinct forms of liver injury; chronic usage of oral amiodarone can lead to elevated liver enzymes that are rarely clinically significant and can resolve spontaneously despite continuous usage. However, IV amiodarone usage particularly in elderly patients can lead to severely elevated LFTs and acute liver failure, this usually rapidly resolves with withdrawal of the medication.

AUTHOR, TOPIC: Hannah Roth, DILI

This patient has a hepatic hemangioma, which is the most common benign liver tumor and are often incidentally diagnosed on imaging done for other indications. Hemangiomas are hepatic vascular malformations, and liver imaging with contrast characteristically shows nodular peripheral enhancement on arterial phases with progressive central filling on later phases. These are entirely benign but do carry a risk of rupture with large (>5cm) or quickly growing (>2cm / year) tumors, and treatment is indicated in these cases or if there are symptoms associated with the lesion. Guidelines currently state that for classically appearing hemangiomas <5cm without symptoms, no further imaging is required (A is correct, B is incorrect, surveillance imaging is not necessary). Surveillance imaging is recommended for lesions 5-10cm. Referral to surgery is reserved for lesions >10cm and those causing significant symptoms (Answer choice C). Biopsies are avoided due to the vascular nature of the tumor and bleeding risk associated with biopsy (Answer choice D).

KEY POINT: Classically appearing, asymptomatic small hemangiomas do not require follow up imaging. If symptomatic or >10cm, consider surgery or interventional radiology referral. Biopsy should be avoided due to bleeding risk. 

AUTHOR, TOPIC: Hannah Roth, Benign Liver Tumor

All pregnant women should be screened for hepatitis B given the risk of maternal to fetal transmission. If screening serologies are positive, viral load should be checked during the second trimester and if above 200,000 copies/ml, prophylactic antiviral therapy, usually with tenofovir, should be initiated at 28 weeks gestation to reduce the risk of transmission. Risk of transmission is also reduced by early vaccination and HBIG treatment. Cessation of antivirals can safely occur at delivery or up to 3 months postpartum (C, D). While pregnant women are at an increased risk of ALT flares during pregnancy and postpartum, these are usually mild and self-limited in duration, and continuation of prophylactic postpartum antivirals has not been shown to be protective. Antiviral therapy would not be otherwise indicated in this patient, as in a non-pregnant adult less than 30 years of age with a normal ALT treatment would not be indicated. Cesarean section has not been shown to reduce risk of maternal to fetal transmission and should be used for obstetric indications only (Answer choice A). Breastfeeding is not contraindicated, even in women who continue on antiviral therapy (Answer choice B).

KEY POINT: All pregnant women should be screened for HBV. Those who are HBsAg positive should have viral load checked in the second trimester and if >200,000 treatment with Tenofovir should be initiated at 28 weeks to decrease maternal to fetal transmission. While there is an increased risk of ALT flare in the postpartum period, continued antiviral prophylaxis has not been shown to be protective and prophylactic antivirals can be discontinued postpartum.

AUTHOR, TOPIC: Hannah Roth, Liver disease in pregnancy

Primary Budd-Chiari Syndrome is a rare and potentially fatal disease characterized by obstruction of the hepatic venous outflow tract due to thrombosis or disease of the venous wall. This is in contrast to secondary Budd-Chiari Syndrome in which obstruction is due to external compression on the vein from tumor or other abnormality. Etiologies of Primary Budd-Chiari syndrome are diverse and include disorders that lead to hypercoagulable state. Myeloproliferative disorders (with JAK2 mutations) are the most common etiology, and are present in 40-50% of cases (Answer choice C).  Splenomegaly from portal hypertension may mask thrombocytosis so it is important to have a high index of suspicion.  APLS is present in up to 10-12% of cases (Answer choice B). Paroxysmal nocturnal hemoglobinuria is present in 7-12% of cases. FVL is present in 8% cases (Answer choice D), Protein C and S deficiency present in 4-5% each. Hormonal factors are important to consider as well, OCP use is present in 22% of cases (Answer choice A).

 KEY POINT: Primary BCS is a rare but potentially life-threatening condition caused by obstruction of hepatic venous outflow tract most often due to thrombus. Every patient diagnosed with primary BCS should undergo hypercoagulable workup to evaluate for underlying treatable causes. Myeloproliferative disorders are the most common of these etiologies and so patients should be tested for JAK2 mutations in addition to more standard hypercoagulable workup.

 AUTHOR, TOPIC: Hannah Roth; Budd Chiari, Veno-occlusive disease, congestive hepatopathy

The incidence of TB among transplant patients is significantly higher than the general public (20-74 times higher), with a mortality rate of up to 30% (Answer choice C). Risk factors for development of symptomatic TB after liver transplant include a prior infection with TB (most infections post-transplant represent reactivation of latent TB as opposed to new infections) (Answer choice B), intensified immunosuppression, diabetes and co-infection with CMV, PJP or nocardia. Donor derived TB is rare. Transplant candidates are screened prior to transplant but both tuberculin skin test and IGRA are suboptimal screening tests in cirrhotic patients due to alterations in the immune system and may not catch latent disease (Answer choice A). Presentations of active disease are more varied in transplant patients and can include extra-pulmonary disease only or even be isolated to fever of unknown origin. Treatment of TB in transplant patients is complicated by both hepatotoxicity as well as drug-drug interactions, specifically rifampin, which interferes with the metabolism of CNI and mTOR inhibitors leading to decreased levels (Answer choice D), making maintaining immunosuppression difficult while treating TB, and increasing the risk of subsequent rejection. For these reasons, it is preferred to treat TB prior to transplant if able.

 KEY POINT: There is a higher incidence of TB in post-transplant patients with increased mortality. Screening prior to transplant is imperfect so the possibility of reactivated TB post-transplant should remain on the differential. Treatment is complicated by interactions with immunosuppressive agents, so close monitoring of drug levels and for allograft rejection is needed during therapy.

AUTHOR, TOPIC: Hannah Roth, Infectious complications post liver transplant

Both calcineurin inhibitors (tacrolimus and cyclosporine) and mTOR inhibitors (sirolimus and everolimus) are metabolized through the CYP3A4 enzymatic pathway.  Grapefruit juice is a known inhibitor of CYP3A4, which will result in increased levels of these medications. Patients should be counseled to avoid medications or supplements that either inhibit or stimulate this pathway to prevent unpredictable fluctuations. B) is incorrect because amoxicillin does not affect the enzymatic pathway, however certain antibiotics like macrolides can result in increased levels of tacrolimus. C) is incorrect because St. John’s wort will decrease rather than increase levels as it is an inducer of this enzymatic pathway. D) is incorrect. Amlodipine does not affect the enzymatic pathway and is a good choice for managing the hypertension that commonly occurs with tacrolimus.  However, both diltiazem and verapamil can increase the concentrations by inhibiting CYP3A4

KEY POINT: Calcineurin inhibitors and mTOR inhibitors are metabolized through the CYP3A4 pathway. Close drug and allograft monitoring are necessary when patients receive other medications, foods, or supplements that can inhibitor or induce this pathway.

AUTHOR, TOPIC: Parth Thaker, Drug hepatotoxicity post-LT

This is likely small-for-size syndrome, which is a clinical syndrome seen in living donor recipients characterized by large volume ascites (>1L/day), persistent encephalopathy, cholestasis and hyperbilirubinemia, and coagulopathy. It is thought that portal hyper perfusion leading to portal hypertension is the main factor in its development. Treatment is typically supportive care while the partial liver regenerates.

A) is incorrect. Bile leaks are a common complication in LDLT compared to DDLT due to bile leaking from the cut edge of the partial liver graft. It may present with worsening cholestatic markers, but does not cause high volume ascites, coagulopathy or encephalopathy. C) is incorrect because HAT typically presents with significant elevations of aminotransferases rather than bilirubin and typically does not present with large volume ascites. D) is incorrect. Splenic artery steal syndrome is a rare complication of liver transplant that presents with elevated aminotransferases. Hypoperfusion of the hepatic artery is sometimes seen on doppler studies. Large volume ascites and encephalopathy is not typical.

KEY POINT: Small-for-size syndrome is a clinical syndrome most commonly seen in living donor liver transplant recipients in which portal hyper perfusion leads to signs and symptoms of portal hypertension (including ascites and encephalopathy), coagulopathy and hyperbilirubinemia.

AUTHOR, TOPIC: Parth Thaker, Living Donor and Surgical Complications

This patient has primary non-function (PNF), which is a characterized by severe decline in allograft function that typically occurs within the first week of transplant, that requires transplantation. There are several risk factors for PNF including a prolonged warm (>60 min) and cold ischemia time (> 10 hours), older donor, and >30% steatosis in allograft. The presentation is similar to acute liver failure, with hemodynamic instability, coagulopathy, encephalopathy, and hypoglycemia.

UNOS criteria to list Status 1A for re-transplant for PNF include the following within 7 days of transplant: AST ≥ 3,000 AND at least one of the following: INR > 2.5, pH < 7.3 (arterial, 7.25 venous), or lactate > 4mmol/L. This patient meets all of these criteria and has a clinical picture consistent with PNF. She should be re-listed for LT.

B) is incorrect. An ERCP can be used to diagnose or treat a bile leak or stricture, which would present as jaundice or cholestatic liver injury, rather than liver failure. C) is incorrect. Acute cellular rejection rarely presents within days of a liver transplant and would not lead to such profound multi-organ failure.  D) is incorrect. While septic shock can occur in transplant patients as a result of intra-operative complications and immunosuppression, such a significant liver injury would not be typical.

KEY POINT: Primary non-function (PNF) is characterized by severe allograft dysfunction within the first week of transplant. Considering re-transplant is important, and patients meeting criteria of AST ≥ 3,000 AND at least one of the following: INR > 2.5, pH < 7.3 (arterial, 7.25 venous), or lactate > 4mmol/L within 7 days of transplant can be listed as Status 1A.

AUTHOR, TOPIC: Parth Thaker, Surgical Complications

Basiliximab is a monoclonal antibody against IL-2, which prevents downstream proliferation of T-cells. While institutional protocols vary, it is commonly used in the induction phase of immunosuppression after liver transplant.

Answer B) describes the mechanism of both mTOR inhibitors (sirolimus or everolimus) and tacrolimus. Tacrolimus interacts with FKBP-12 to inhibit calcineurin which blocks nuclear factor of activated T-cells (NFAT) from translocating into the nucleus and stimulating the production of IL-2, which will result in decreased activation of T-cells. mTOR inhibitors work similarly to block the activation of mammalian target of rapamycin (mTOR) which also stimulates production of T-cells. Answer C) describes the mechanism of anti-proliferative agents like mycophenolate or azathioprine, which both inhibit the purine synthesis needed for lymphocyte proliferation by inhibiting IMPDH. Answer D) describes the mechanism of steroids. Steroids will also suppress the migration of leukocytes and suppress antibody and complement binding.

KEY POINT: Basiliximab is a monoclonal antibody against IL-2, which prevents downstream proliferation of T-cells. While institutional protocols vary, it is commonly used in the induction phase of immunosuppression after liver transplant.

AUTHOR, TOPIC: Parth Thaker, Basic Immunology

Hepatic artery thrombosis (HAT) is a feared surgical complication that can result in graft failure requiring re-transplantation or mortality. Hepatic artery reconstruction is consistently associated with an increased risk of HAT. Many centers routinely place patients who have undergone HA reconstruction on anti-platelet or anticoagulation to prevent HAT. Multiple retrospective studies have been done to determine other risk factors for HAT, and while not conclusive, other risk factors for HAT that have been suggested include: CMV mismatch (particularly CMV– recipient, CMV+ donor), ACR within 1 week of transplant, female donors and male recipients, small donor weight, chronic HCV in recipients.

KEY POINT: Hepatic artery thrombosis (HAT) is a feared surgical complication that can result in graft failure requiring re-transplantation or mortality. Hepatic artery reconstruction is a risk for HAT, and many centers routinely place patients who have undergone HA reconstruction on anti-platelet or anticoagulation to prevent HAT.

AUTHOR, TOPIC: Parth Thaker, Surgical Complications

BRIC is a rare disorder characterized by recurrent, self-limited episodes of clinically apparent cholestasis (often with pruritus, jaundice, anorexia and fatigue). Episodes of cholestasis are classically precipitated by stress, such as a viral illness or pregnancy (classically in the 1st and 2nd trimesters). While self-limited, these episodes can last for months. Diagnosis includes a classic presentation with at least one other episode of cholestasis and excluding other causes of cholestasis. Elevated bile acids and conjugated hyperbilirubinemia with abnormally low or normal GGT is a hallmark of BRIC. Diagnosis is confirmed with genetic testing for mutations in ATP8B1 or ABCB11 genes, which are both involved in bile salt export from hepatocytes.

While gallstone disease (Answer choice A) can cause cholestasis, her ultrasound is not consistent with gallstone disease, and it generally would not have stereotyped presentations after infections. Recurrent hepatitis A (Answer choice B) is not generally associated with pruritus, and viral serologies would be expected to be positive. In contrast to BRIC, ICP (Answer choice C) classically presents in the 3^rd trimester and is less commonly associated with jaundice, fatigue, and nausea. Additionally, ICP occurs only during pregnancy by definition. 

KEY POINT: Benign recurrent intrahepatic cholestasis (BRIC) is characterized by recurrent, self-limited episodes of jaundice and pruritis that are classically precipitated by stress. Diagnosis can be confirmed with genetic testing for ATP8B1 or ABCB11 bile salt transport genes. No treatment is necessary as these episodes are self-limited.

AUTHOR, TOPIC: Paige McLean Diaz, Genetic Liver Disease

This patient has hereditary hemochromatosis (HH), which is most commonly caused by mutations in the HFE gene. The HFE gene product positively regulates hepcidin, which inhibits intestinal iron absorption (more detail below). More than 80% of patients with hemochromatosis have the C282Y mutation in the HFE gene on chromosome 6 that leads to C282Y in the gene product. Hereditary hemochromatosis secondary to C282Y mutations are autosomal recessive disorders (up to 1 in 250 Northern Europeans are carriers) with incomplete penetrance. Males are more likely to have symptomatic disease and present earlier than females. Variants of HFE-mediated mutations with H63D can also be seen in patients who are compound heterozygotes, particularly for about 10% of patients who have symptomatic HH without homozygosity. Non-HFE mutations are seen in 20% of cases, and they can be related to any of the remaining 8 genes responsible for regulating the biology of hepcidin, including hemojuvelin (HJV), transferrin receptor 2 (TFR2), and hepcidin (HAMP). Iron homeostasis requires hepcidin, which binds to ferroportin, a transmembrane protein responsible for iron exportation found on duodenal enterocytes, splenic macrophages, and hepatocytes. When this binding occurs ferroportin can be internalized and degraded, and further iron absorption is inhibited. When hepcidin is not available, the increased availability of ferroportin leads to increased iron export and systemic iron overload.

KEY POINT: Hereditary hemochromatosis is most commonly caused by mutations in the HFE gene (either C282Y or H63D compound heterozygosity). This leads to reduced hepcidin levels and subsequent increased iron absorption.

AUTHOR, TOPIC: Paige McLean Diaz, Genetic Liver Disease

There is no regulatory mechanism for the body to excrete iron in the event of iron overload. Phlebotomy is a mainstay of HH treatment as it removes iron in red blood cells, and over time, phlebotomy can reduce iron stores to normal levels. This can improve many symptoms of HH, including prevention of cirrhosis and HCC, most joint symptoms, and can even improve HH-associated heart disease. Hypogonadism secondary to testicular atrophy and arthropathy secondary to chondrocalcinosis are unlikely to improve after phlebotomy.

KEY POINT: Phlebotomy removes iron from the body in the form of red blood cells and is the mainstay of HH treatment as it can restore body iron stores to normal levels over time. While some symptoms of HH can improve with phlebotomy, others (like hypogonadism) are not expected to improve.

AUTHOR, TOPIC: Paige McLean Diaz, Genetic Liver Disease

This patient most likely has Wilson’s Disease, a disorder of copper metabolism caused by a mutation in the ATP7B gene. ATP7B gene encodes for ATP7B, an ATPase copper transporting protein, which facilitates the binding of copper to ceruloplasmin and is necessary for copper export into bile canaliculi. Most patients who present with acute Wilsonian crisis are at least compound heterozygotes for one of more than 500 disease-associated alleles affecting ATP7B on chromosome 13. WD has a wide spectrum of clinical manifestations, that include asymptomatic liver enzyme elevations, neuropsychiatric disease, cirrhosis, and acute liver failure. HFE gene mutations (Answer choice A) are associated with hereditary hemochromatosis, which typically presents much later in life (especially in females) with asymptomatic liver chemistry elevations. SPINK1 mutations (Answer choice C) are associated with chronic pancreatitis. APC mutations (Answer choice D) are associated with familial adenomatous polyposis syndrome, which is characterized by a significantly increased risk of colorectal cancer.

KEY POINT: Wilson’s Disease is a disorder of copper excretion caused by mutations in the ATP7B gene.

AUTHOR, TOPIC: Paige McLean Diaz, Genetic Liver Disease

This presentation is highly concerning for an early hepatic artery thrombosis (eHAT). This patient had several risk factors for consideration of eHAT, including a donor with variant anatomy and need for a vascular reconstruction. In addition, his interval ultrasound showed abnormalities in the hepatic artery, which are a sensitive, non-specific marker of possible artery dysfunction. Diagnosis of HAT can be confirmed with a CT angiogram, and treatment can include thrombectomy (either by interventional radiology or surgery) or re-transplantation. Endoscopic retrograde cholangiopancreatography (ERCP) is an important tool for managing biliary complications after liver transplant, but it is not an appropriate next diagnostic or therapeutic step in a patient with suspected hepatic artery thrombosis.

KEY POINT: Hepatic artery thrombosis (HAT) is a feared surgical complication that can result in graft failure requiring re-transplantation or mortality. Prompt diagnosis with cross-sectional imaging (typically a CT angiogram) and treatment with either a thrombectomy (surgical or with catheter-based approaches) or re-transplantation significantly improve prognosis.

 AUTHOR, TOPIC: Paige McLean Diaz, Genetic Liver Disease