Answers to Multiple Choice Questions

Hepatobiliary Quiz-3 (2011)

a

Trotter JF. Hot-topic debate on hepatitis C virus: the type of immunosuppression matters. Liver Transpl 2011;17(Suppl 3): S20–3. b Watt K, Veldt B, Charlton M. A practical guide to the management of HCV infection following liver transplantation. Am J Transplant 2009;9:1707–13. c Gordon FD, Kwo P, Vargas HE. Treatment of hepatitis C in liver transplant recipients. Liver Transpl 2009;15:126–35.

2. Correct answer: 1 Weight gain occurs after liver transplantation and patients with baseline obesity have higher risk. Hyperlipidemia is common after liver transplantation. The etiology of hyperlipidemia includes the use of steroids (increase secretion of very-low-density lipoprotein [VLDL] and conversion of low-density lipoprotein [LDL]), cyclosporine (inhibits 26-hydroxylase reducing the transport of cholesterol into bile and binds to LDL receptor increasing the levels of LDL cholesterol) and sirolimus (elevates apo-CIII levels which inhibit lipoprotein lipase activity). Diabetes occurs in 30–40% of patients after transplantation. The rate of hypertension increases to 60–70%, and hyperlipidemia is seen in approximately 50–70% of patients after transplantation.a As donor liver has substantial mass of donor cells having hematopoietic and immune function themselves, it can cause graft-vs-host disease.b Hemolytic anemia may occur from ABO-incompatible blood transfusion.c a

Watt KD. Metabolic syndrome: is immunosuppression to blame? Liver Transpl 2011;17(Suppl 3):S38–42. b Knechtle SJ, Kwun J. Unique aspects of rejection and tolerance in liver transplantation. Semin Liver Dis 2009;29:91–101. c Schiff ER, Sorrell MF, Maddrey WC. Schiff’s Diseases of the Liver 10th ed. Philadelphia: Lippincott Williams & Wilkins 2007.

3. Correct answer: 4 Sustained virological response rates are near 80% for genotypes 2 or 3 HCV infection and near 50% for genotype 1; high baseline fibrosis and high ribonucleic © 2011, INASL

acid (RNA) load are the predictors of nonresponse. Pegylated interferon may induce or worsen autoimmune disorders. Interferon treatment is contraindicated in patients with solid organ transplant except in cases of fibrosing cholestatic hepatitis and in liver transplantation.a,b However, peginterferon with ribavirin has been used similarly to what is done in the nontransplant setting, and is currently the treatment of choice; sustained viral response is achieved in about 35% of cases.c a

Ghany MG, Strader DB, Thomas DL, Seeff LB. American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49:1335–74. b EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011;55:245–64. c Rubín A, Aguilera V, Berenguer M. Liver transplantation and hepatitis C. Clin Res Hepatol Gastroenterol 2011 Sep 28 [Epub ahead of print].

4. Correct answer: 2 Calcineurin inhibitors (cyclosporine and tacrolimus) inhibit normal T-cell signal transduction by binding to immunophilin (cyclophilin for cyclosporine or FK-binding protein 12 (FKBP12) for tacrolimus), resulting in subsequent interaction with calcineurin to block its phosphatase activity.a Adverse reactions to cyclosporine therapy are renal dysfunction, tremors, hirsutism, hypertension, hyperlipidemia, hyperuricemia, secondary tumors and opportunistic infections, and gum hyperplasia. Tacrolimus causes tremor, headache, motor disturbances, and seizures in addition to above mentioned side effects. The combined use of calcineurin inhibitors and glucocorticoids is particularly diabetogenic (more with tacrolimus as it has a negative effect on the pancreatic islet beta cells). Tacrolimus does not adversely affect uric acid or low-density lipoprotein (LDL) cholesterol. a

Brunton LL, Lazo JS, Parker KL. Goodman and Gilman’s The Pharmacological Basis of Therapeutics 11th ed [online].

5. Correct answer: 2 and 5 The patient has cirrhosis with decompensation and hemolysis (predominantly unconjugated hyperbilirubinemia) suggestive of Wilson’s disease.a Wilson’s disease is inherited as autosomal recessive pattern (so family screening is important), mutated gene being ATP7B on chromosome 13. ATP7B encodes a metal transporting P-type adenosine triphosphatase (ATPase), which functions in the transmembrane transport of copper within hepatocytes. Absence of its activity leads to decreased excretion of copper into bile and hepatocyte injury. Wilson’s disease may present as Coombs negative hemolytic anemia. Twenty-four hours excretion of copper of > 100 μg is seen in near 80% of patients. Liver transplantation is indicated

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Hepatobiliary Quiz

1. Correct answer: 2 Hepatitis C virus (HCV) is a major indication for liver transplantation in Western countries and virological recurrence post-transplant is universal. About one-third of HCV-infected recipients develop cirrhosis secondary to HCV recurrence by the fifth postoperative year. Strategies for minimizing severe recurrence include the avoidance of older donors, treatment of cytomegalovirus, and minimization of immunosuppression.a After transplantation, treatment may be initiated prophylactically or it may be initiated therapeutically in patients with evidence of recurrent disease. Prophylactic therapy with pegylated interferon has been associated with sustained virologic response rates lower than 20%, whereas in therapeutic intervention studies, sustained virologic response rates have ranged from 20% to 37%.b,c

Answers to Multiple Choice Questions

HEPATOBILIARY QUIZ-3 (2011) ANSWERS

for all patients with decompensated liver disease unresponsive to medical therapy. a

Roberts EA, Schilsky ML. American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47:2089–111.

6. Correct answer: 1 Serum alfa-fetoprotein levels may be raised in tyrosinemia, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, metastasis from colon, and hepatitis B flares.a–c a

Bruix J, Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–2. b Bijarnia S, Puri RD, Ruel J, Gray GF, Jenkinson L, Verma IC. Tyrosinemia type I-diagnostic issues and prenatal diagnosis. Indian J Pediatr 2006;73:163–5. c Han Y, Tang Q, Zhu W, Zhang X, You L. Clinical, biochemical, immunological and virological profiles of, and differential diagnosis between, patients with acute hepatitis B and chronic hepatitis B with acute flare. J Gastroenterol Hepatol 2008;23:1728–33.

Hepatobiliary Quiz

7. Correct answer: 1, 2, and 4 Patients with alcoholic hepatitisa have raised aspartate aminotransferase (AST) levels (more than twice, generally < 300 IU/dL) with the ratio of AST and alanine aminotransferase (ALT) > 2. Both ALT and AST require pyridoxal 5′-phosphate as a cofactor; ALT synthesis more dependent on the pyridoxal phosphate than AST. The ratio is altered in alcoholic liver disease because of the depletion of hepatic pyridoxal 5′-phosphate and increased hepatic mitochondrial AST. Alcohol causes induction of hepatic microsomal γ-glutamyltranspeptidase (GGT).b a

Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009;360:2758–69. b Schiff ER, Sorrell MF, Maddrey WC. Schiff’s Diseases of the Liver 10th ed. Philadelphia: Lippincott Williams & Wilkins 2007.

8. Correct answer: 1 and 5 Treatment modalities for alcoholic hepatitis include abstinence, nutritional support, and corticosteroids (reduced inflammation; meta-analysis showed mortality benefit in patients with Maddrey’s discriminant function of > 32 or hepatic encephalopathy),a pentoxifylline (anti-tumor necrosis factor [TNF]-α and renoprotective), infliximab, and etanercept (anti-TNF-α role, but increased risks of infection and death, hence not recommended). Other agents that were tried and have no role in treatment of alcoholic hepatitis are anti-oxidants, propylthiouracil, colchicine, silymarin, and anabolic steroids.b,c a

Mathurin P, Mendenhall CL, Carithers RL Jr, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol 2002;36:480–7.

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b

O’Shea RS, Dasarathy S, McCullough AJ. Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010;51:307–28. c Stickel F, Seitz HK. Alcoholic steatohepatitis. Best Pract Res Clin Gastroenterol 2010;24:683–93.

9. Correct answer: 2 and 4 The course of patients with chronic HBV infection can be divided into three phasesa: (1) immune-tolerant phase, (2) immune-clearance phase, and (3) residual or inactive phase. Parenteral or early childhood transmission results in immune-tolerant phase characterized by hepatitis B e antigen (HBeAg) seropositivity with high viral loads (>107–108 copies/mL), normal serum ALT, and near normal liver histology as no immunity-related injury occurs; it can last for few years to 30 years.b,c Immune-tolerant phase is absent if infection is acquired in adulthood. Immune-clearance phase is characterized by intermittent or continuing hepatitis activity or episodic acute flares, liver histology showing inflammation, and fibrosis; HBeAg may be positive or negative and HBV-DNA levels are usually > 20,000 IU/mL. In majority of patients, the immune clearance phase results in HBeAg seroconversion to antibody to hepatitis B e antigen (anti-HBe) or undetectable HBV-DNA. Seroreversion to HBeAg status occurs in nearly 20% of patients. Seroconversion occurs at the peak of clinical illness in acute hepatitis B while HBV-DNA and HBsAg are cleared by the time of recovery. a

McMahon BJ. Natural history of chronic hepatitis B – clinical implications. Medscape J Med 2008;10:91. b Lai M, Liaw YF. Chronic hepatitis B: past, present, and future. Clin Liver Dis 2010;14:531–46. c Liang TJ. Hepatitis B: the virus and disease. Hepatology 2009; 49:S13–21.

10. Correct answer: 1, 3, and 5 Malnutrition is frequently associated with chronic liver disease: the prevalence may range from 20% to 80% depending on the methods used for the nutritional assessment and the severity of liver disease.a,b The prevalence of malnutrition is related to the severity of liver impairment (20–25% in Child A–B patients but > 50% in Child C).a,b Alcohol abuse may cause malnutrition per se due to the replacement of nutrient foods with empty calories, or secondary to the conditions of maldigestion and malabsorption, induced by the reduction of the bile and pancreatic enzyme secretion, which can lead to increased nutrient losses.c Concerning the gender, a more pronounced loss of body fat has been described in woman while men more frequently experience a depletion in the lean body mass. This alteration may be present even in the early © 2011, INASL

JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY

a Merli M, Giusto M, Giannelli V, Lucidi C, Riggio O. Nutritional status and liver transplantation. J Clin Exp Hepatol 2011;1:190–8. b Italian multicentric cooperative project on nutrition in liver cirrhosis. Nutritional status in cirrhosis. J Hepatol 1994;21:317–25. c DiCecco SR, Francisco-Ziller N. Nutrition in alcoholic liver disease. Nutr Clin Pract 2006;21:245–54. d Figuerido FA, Perez De Mello R, Kondo M. Effect of liver cirrhosis on body composition: evidence of significant depletion even in mild disease. J Gastroenterl Hepatol 2005;20:209–16.

Hepatobiliary Quiz

stages of liver cirrhosis and is further accelerated in the advanced stages of the disease.d After liver transplantation in fact dietary intake rapidly normalizes and fat mass is progressively regained while the recovery of muscle mass can be slower.a In some patients, unregulated weight gain may lead to overnutrition and may favor metabolic disorders (hypertension, hyperglycemia, and hyperlipidemia).a

Journal of Clinical and Experimental Hepatology | December 2011 | Vol. 1 | No. 3 | 219–221

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