Hepatobiliary Quiz (Answers)—16 (2015)

• 1.Correct Answers: B, C, D and E

  Liver transplant recipients are twice as prone to develop malignancies as compared to the general population.^{1, 2, 3, 4} The risk is most in patients transplanted for alcohol-related liver disease or primary sclerosing cholangitis (PSC).^{3, 4, 5} The most common malignancies in this population include dermatological cancers, post-transplantation lymphoproliferative disease and gastrointestinal, lung, oropharyngeal and gynecological solid tumors.

  Screening strategies recommended for early detection are mostly similar to that in general population. Exceptions include an annual dermatological screening, as the risk of skin cancers up to 20-fold higher than general population,⁵ and annual colonoscopies in patients with PSC and inflammatory bowel disease, as they may have a 10 times higher risk compared to other liver transplant patients.⁶ In some patients with post-transplantation lymphoproliferative disease, reduction of immunosuppression alone might lead to regression of malignancy.⁷

• 2.Correct Answers: A, B, and E

  Vascular invasion is an important feature of advanced hepatocellular carcinoma (HCC). Microvascular invasion cannot be visualized on imaging. However, macrovascular invasion is often seen as a malignant thrombus, and precludes transplantation as well as locoregional therapies.^{8, 9, 10} Portal vein invasion is more common, though hepatic veins may also be involved.

  Due to the coagulation abnormalities and slow flow in the portal circulation in patients with cirrhosis, bland thrombi are also common. They may even arise superimposed on malignant thrombus, complicating the imaging picture.¹¹

  Tumor thrombus may expand the vein, and are likely to be contiguous with the source HCC. There is streak-like enhancement within the thrombus in the arterial-phase owing to arterial neovascularity. Enhancement of tumor thrombus often follows enhancement of the source HCC.¹¹

• 3.Correct Answers: B and C

  In transplant recipient patients, any pregnancy is deemed as high-risk pregnancy. They are more prone to develop pre-eclampsia and hypertension, and are more likely to deliver pre-term.¹²

  Conception should be delayed till after the first year of transplant so that the patient is on the lowest dose of immunosuppression with stable allograft function. Steroid doses >20 mg/day of prednisolone have been associated with higher incidence of cleft palate.¹³ However, the overall risk of structural malformations in liver transplant recipients remains similar to the general population.^{12, 14}

  Calcineurin inhibitors are considered to be low risk when used at the lowest possible dose.¹⁵ While they may be associated with low birth weight and renal impairment in the baby, no structural abnormalities in the fetus have been documented. They are also acceptable during breastfeeding.^{16, 17, 18} Mycophenolate mofetil is contraindicated during pregnancy and must be discontinued before conception.¹⁸ Oral contraceptives may be safely used in liver transplant recipients with good allograft function.^{14, 19}

• 4.Correct Answers: B, C and E

  Hepatitis C virus core-antigen (HCV-Ag) may be an alternative for diagnosis of hepatitis C, and monitoring of therapy.²⁰ HCV-Ag protein has a highly conserved sequence, which can be detected using enzyme-immunoassays.²¹ The assay is cheap, simple, and does not require skilled manpower, thereby enabling small laboratories where HCV RNA testing may not be feasible, to detect active HCV infection. Commercial automated platforms like Abbott Architect^® are available which can perform both anti-HCV and HCV-Ag together.^{20, 21, 22}

  HCV-Ag is valuable in detection of HCV infection in seronegative hemodialysis patients, early treatment monitoring and as a cost-effective alternative to nucleic acid technology for the identification of blood donors in the pre-seroconversion window.^{22, 23, 24, 25, 26, 27} However, the test needs further evaluation before it can replace the need for HCV RNA testing.^{28, 29}

• 5.Correct Answers: A, C and E

  Bilirubin encephalopathy, also known as kernicterus, is a syndrome of jaundice and encephalopathy in infants. It involves the deposition of unconjugated bilirubin into the cortical gray matter, predominantly the basal ganglia.^{30, 31} Most common cause is a hemolytic anemia, usually due to Rh or ABO incompatibility. The risk of developing bilirubin encephalopathy is higher in neonates with low birth weight, hypothermia, anoxia, acidosis, sepsis, hypoalbuminemia, and meningitis.³²

  The infants initially present with somnolence and hypotonia. Over several days, they develop the irreversible stage characterized by spasticity. Patients who survive the neonatal period may also develop choreoathetosis, sensorineural hearing loss, dental dysplasia, gaze abnormalities (particularly vertical gaze palsy) and mild mental retardation.³³

• 6.Correct Answers: A, B, C and E

  Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever, splenomegaly, cytopenias, jaundice, and hemophagocytosis in bone marrow, lymph nodes, liver and other tissues.^{30, 34} It may be primary (genetic), or secondary (acquired) to viral infections, autoimmune diseases or malignancies. It occurs secondary to excessive inflammation by a lack of normal downregulation of activated macrophages and lymphocytes.³⁵ Excessive cytokine production is a primary mediator of tissue damage and leads to multiorgan dysfunction. Immune activation is commonly initiated by an infection both in primary and secondary cases. The most common infectious trigger is viral infection, especially Epstein–Barr virus.³⁰

  Clinically, the patients present with fever, hepatosplenomegaly, lymphadenopathy, jaundice (in more than 2/3 cases), and maculopapular rash. Neurological manifestations are seen in nearly half of the cases: encephalopathy, meningismus, and seizures are the most common.^{36, 37} Laboratory abnormalities include cytopenias, hyperbilirubinemia, hypertriglyceridemia and hyperferritinemia. Serum fibrinogen levels are typically low. Histological evidence of hemophagocytosis is typically seen in bone marrow, spleen, and lymph nodes and even in the liver. Lymphocytic portal tract infiltration is also commonly seen.³⁸

• 7.Correct Answers: A, B, C and E

  Cardiovascular manifestations of cirrhosis stem from involvement of both the heart as well as the vascular system. Cirrhosis leads to peripheral vasodilatation and hyperdynamic circulation. In response, the renin-angiotensin system is activated, leading to Na⁺ retention and volume overload. In order to maintain blood pressure, the cardiac output also rises.

  Almost half of the patients with cirrhosis develop at least mild diastolic dysfunction. Though the mechanisms of myocardial stiffness and remodeling are unclear, it occurs more commonly in patients who have more advanced liver disease with higher MELD and Child-Pugh scores.^{39, 40, 41}

  Patients with cirrhosis are also more likely to have a prolonged QT interval, independent of other known risk factors for this condition.^{39, 42, 43}

  Hereditary hemochromatosis often involves the heart, and can lead to congestive heart failure, conduction abnormalities, and, rarely, a restrictive cardiomyopathy. In patients who develop heart failure, cardiac function improves with therapeutic phlebotomies.⁴⁴

  Non-alcoholic fatty liver disease (NAFLD) may be considered a hepatic manifestation of the metabolic syndrome, and a risk factor for coronary artery disease. Institution of statin therapy in patients with abnormal liver enzyme levels attributable to NAFLD may reduce cardiovascular morbidity.^{45, 46}

• 8.Correct Answers: B, C, D and E

  Hepatopulmonary syndrome (HPS) is characterized by right-to-left shunting of blood within the pulmonary vasculature via intrapulmonary vascular dilatations (IPVDs) leading to ventilation perfusion mismatch. Shunting occurs due to precapillary and postcapillary dilatation of the pulmonary microvasculature, as well as by the formation of new blood vessels.^{39, 47, 48}

  HPS may occur in at least 10% of all patients with cirrhosis and portal hypertension, and in one third of patients evaluated for liver transplantation.^{47, 48, 49}

  HPS is a diagnosis of exclusion, and none of the teats are specific for its diagnosis. Presence of IPVDs may be seen in up to 60% of patients with cirrhosis, and their presence without hypoxemia is not associated with adverse events.^{48, 49, 50, 51}

  Spider angiomas are more common in patients with HPS.³⁹

• 9.Correct Answers: A, D and E

  Antimicrobials are the commonest cause of idiosyncratic drug induced liver injury (DILI) worldwide. In Europe and USA, amoxicillin-clavulanate is the most common, in contrast to antituberculosis drugs in India.^{52, 53, 54, 55, 56, 57} Idiosyncratic DILI is not dose dependent per se, however, most cases occur at a dose of more than 50 mg DILIs. Drugs that undergo over 50% hepatic metabolism are also more likely to lead to hepatotoxicity.⁵⁸

  Age is a risk factor for specific drugs.⁵⁹ Children generally have a lower risk for DILI except from aspirin used during viral illnesses and valproate.^{60, 61, 62} Women do not seem to be at an increased overall risk for DILI, however, they are more likely to progress to acute liver failure.^{59, 63, 55}

• 10.Correct Answers: B and E

  Amoxicillin-clavulanate is the most frequent cause of idiosyncratic DILI in several European and American series.^{64, 65, 66, 67} The incidence of DILI is much higher with the amoxicillin-clavulanic acid combination than with amoxicillin alone.^{68, 69} The risk increases with age, and males are at a slightly greater risk. Presence of HLA DRB1*15 and DQB1*06 and double-null heterozygosity for glutathione S-transferase (GSTT1/GSTM1) is also associated with a higher risk.^{70, 71} Young patients are more likely to have a hepatocellular pattern of DILI, while older patients are more likely to have a cholestatic or mixed pattern. Most patients recover within 4–6 months following DILI.^{65, 71, 72}