GI Grand Rounds Johanna Chan Gastroenterology Fellow Baylor College of Medicine 6/27/13

No conflicts of interest No financial disclosures

HPI RFC: abnormal liver function tests 39yo transvestite man with DM1, frequent hospitalizations for DKA Admitted to hospital 4/4/13 with DKA ALT 765, AST 629, total bilirubin 0.5, alk phos 229, albumin 3.4 No documented hypotension, no available INR, no other specific GI symptoms Referred to GI clinic for follow up of LFTs

Past Medical History DM1, diagnosed in his 20s HTN HLD Hypothyroid poorly controlled (Hgb A1c 13.7%) frequent hospitalizations for DKA complicated by peripheral neuropathy chronic early satiety and nausea (?gastroparesis) HTN HLD Hypothyroid

Medications Insulin Gabapentin Enalapril Esomeprazole 20 mg PO daily Simvastatin 40 mg PO QHS (stopped after 4/2013) Levothyroxine 100 mcg PO daily Tylenol 500 mg PO BID (stopped after 4/2013) No herbs or supplements

HPI continued Presents to GI clinic approximately 6 weeks post-hospitalization Malaise, poor appetite, nausea, vomiting of clear yellow emesis, early satiety Clearly now markedly jaundiced, scleral icterus No abdominal pain, change in stools 60 lb unintentional weight loss over the past 10 years

Other history Family history Social history Mother DM2 Brother DM1, HTN, HLD No rheumatologic or other autoimmune disease No family history of liver disease Social history Complete EtOH abstinence No history of IVDA or tobacco No blood transfusions or tattoos Unprotected sex (MSM) “Black market” hormone injections, Mexico, 1990s

Exam T 98.2, BP 113/72, HR 85, RR 12, O2 sat 99% RA 5’8”, 189 lbs Gen: markedly jaundiced, AAOx4, NAD, groomed casually in women’s clothing HEENT: marked scleral icterus Neck: supple, no LAD CV: RRR no m/r/g Chest: no spider angiomata, no gynecomastia Lungs: CTAB no wheezes/rales/rhonchi Abd: S/NT/ND, NABS, no fluid wave Ext: no edema

Available labs HIV negative HAV IgM negative HBsAg positive (negative in 2008) HBcAb IgM positive (negative in 2008) HBV DNA PCR 108,000,000 HBV DNA log 10 8.04 HCV IgG negative

Labs in clinic 137 100 15 13 144 200 4.8 4.1 27 0.9 38.2 68% PMNs MCV 89 Total protein 7.1 Albumin 3.3 Total bili 8.8 ALT 2143 AST 1302 Alk phos 193 INR 1.1 PTT 39.9 TSH 3.02 HCV DNA PCR negative HDV Ab negative

LFT trend 4/5 4/22 5/14 T prot 5.6 6.9 7.1 Albumin 2.7 3.4 3.3 ALT 765 947 2143 AST 629 727 1302 Alk phos 229 317 193 T bili 0.5 1.4 8.8 D bili 0.3 1 6.6 INR -- 1.1

Imaging RUQ U/S: mild hepatomegaly (17cm at right mid-clavicular line) with normal echogenicity, smooth contour; small sludge, CBD 0.3cm

Management?

LFT trend 4/5 4/22 5/14 5/20 5/28 T prot 5.6 6.9 7.1 7.4 Albumin 2.7 3.4 3.3 3.6 ALT 765 947 2143 1083 334 AST 629 727 1302 493 30 Alk phos 229 317 193 199 137 T bili 0.5 1.4 8.8 3.9 0.2 D bili 0.3 1 6.6 3 -- INR 1.1 1.0 HBV DNA 108 million 95,500 8190 HBV DNA log 10 8.04 4.98 3.91

Clinical questions Who is getting acute HBV in the U.S.? What is severe acute HBV? How and when should we treat severe acute HBV?

Acute HBV demographics Acute HBV incidence has declined 82% since 1990 8.5 cases per 100,000 in 1990 1.5 cases per 100,000 in 2007 (the lowest rate ever recorded) Declines in all age groups, but especially in children <15 yrs, attributable to vaccination (national vaccination strategy implemented in 1991) 1991 vaccination strategy: Vaccination of all infants at birth Routine screening of all pregnant women, immunoprophylaxis to infants of infected mothers Routine vaccination of children/adolescents Vaccination of adults at risk (healthcare workers, dialysis patients, household contacts of chronic HBV pts, IVDA, MSM Daniels et al. MMWR Surveill Summ. 2009 May 22;58(3):1-27.

Acute HBV demographics In 2007, 4,519 acute symptomatic cases reported (43,000 additional new infections, asymptomatic) Risk factors for infection: 38% multiple sex partners, 11% MSM, 6% sexual contact with a person known to have hepatitis B. IVDU reported for 15% of persons. 2007 reports: 76% had jaundice, 40% were hospitalized, and 2% died. Daniels et al. MMWR Surveill Summ. 2009 May 22;58(3):1-27.

Acute HBV incidence Daniels et al. MMWR Surveill Summ. 2009 May 22;58(3):1-27.

Acute HBV incidence HBV rates begin to plauteau in 2006 for all age groups Highest rate in 2007 among the 25-44 group, lowest in <15yo Daniels et al. MMWR Surveill Summ. 2009 May 22;58(3):1-27.

Acute HBV incidence Since 2004, rates plateau in all ethnic groups 2007: highest rates of HBV highest for nonHispanic blacks (2.3 cases per 100,000 population) Daniels et al. MMWR Surveill Summ. 2009 May 22;58(3):1-27.

Management of severe acute HBV

Typical acute HBV clearance Frequently cited 90-97% spontaneous HBV clearance in adults Tillman et al. Liver Int. 2012 Apr;32(4):544-53.

Acute hepatitis B In approximately 1% of cases, acute HBV progresses to liver failure with need for transplantation

Treatment with lamivudine for severe acute HBV Large series of 37 patients (multicenter) Definition of severe acute hepatitis: Bilirubin >=10 mg/dl INR > 1.6 Presence of hepatic encephalopathy Transplant-free survival with lamivudine for severe/acute to fulminant hepatitis B was 78.3% (29 of 37 patients) compared with 21.6% of historic controls (p < 0.001). Multiple other studies (approx 20 others in the literature) showing mean survival rate around 80% with lamivudine Randomized controlled trial from India (71 pts) no statistical benefit with lamivudine 100mg PO daily x 3 months, trend towards improvement RCT from China (80 pts) lamivudine improved mortality - 2010 Tillman HL et al. J Viral Hepat 2006; 13:256-63.

Treatment with newer antivirals for acute HBV Prospective study, 6 patients in Germany with HBV-related acute liver failure Entecavir 1 mg/day within 1-18 days of admission, continued for at least 3 months Normalization of INR, ALT, and bilirubin within 3 months 1 patient went on to develop chronic hepatitis B Case reports from italy and Germany Overall not enough data: some data extrapolated from studies in acute reactivation of chronic HBV show ?drug induced liver injury or lactic acidosis Lamivudine is logical because the antiviral treatment is potentially self-lmited Ideally an RCT (multicenter double blind) to compare entecavir and lamivudine, but small numbers of pts Jochum C et al. Digestion 2009; 80:235-40.

Risk of increasing chronicity with treating acute HBV 57 patients hospitalized with acute HBV acquired in adulthood in Japan 7 of 57 patients developed persistence (HBsAg positive 6 months after index hospitalization) 6 of the 7 received prednisolone or glycyrrhizin during acute illness, 1 did not Infection persisted in 86% of patients who received treatment vs. 2% of patients who did not (p = 0.01) Kobayashi M et al. J Med Virol 2002; 68:522-8.

Take home points Fortunately, frequency of severe acute to fulminant liver failure in acute HBV is low For acute severe to fulminant HBV-related liver failure, lamivudine has shown benefits in transplant-free survival Small case series promising for entecavir in the setting of acute severe to fulminant HBV-related liver failure

References Daniels D, Grtydal S, Wasley A; Centers for Disease Control and Prevention. Surveillance for acute viral hepatitis – United States, 2007. MMWR Surveill Summ. 2009 May 22;58(3):1-27. De Socio GV et al. Severe acute hepatitis B treated with entecavir. Mediterr J hematol Infect Dis. 2011;3(1):32011010. Jochum C et al. Hepatitis B-associated acute liver failure: immediate treatment with entecavir inhibits hepatitis B virus replication and potentially its sequelae. Digestion 2009; 80:235-40. Kobayashi M et al. Viral genotypes and resonse to interferon in patients with acute prolonged hepatitis B virus infection of adulthood in Japan. J Med Virol 2002; 68:522-8. Kumar M et al. A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology. 2007 Jan; 45(1):97-101.

References continued Tillman HL, Zachou K, Dalekos GN. Management of severe acute to fulminant hepatitis B: to treat or not to treat or when to treat? Liver Int. 2012 Apr;32(4):544-53. Tillman HL et al. Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat 2006; 13:256-63. Yu JW et al. The study of efficacy of lamivudine in patients with severe acute hepatitis B. Dig Dis Sci. 2010 Mar; 55(3):775-83. Yu JW et al. Lamivudine treatment is associated with improved survival in fulminant hepatitis B. Liver Int 2011; 31:499-506.

Questions?