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

2. No conflicts of interest No financial disclosures

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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
HCV IgG negative

10. 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

11. 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

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

13. Management?

14. 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

15. 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?

16. 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 May 22;58(3):1-27.

17. 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 May 22;58(3):1-27.

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

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

20. 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 May 22;58(3):1-27.

21. Management of severe acute HBV

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

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

24. 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
Tillman HL et al. J Viral Hepat 2006; 13:

25. 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:

26. 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.

27. 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

28. References
Daniels D, Grtydal S, Wasley A; Centers for Disease Control and Prevention. Surveillance for acute viral hepatitis – United States, MMWR Surveill Summ May 22;58(3):1-27.
De Socio GV et al. Severe acute hepatitis B treated with entecavir. Mediterr J hematol Infect Dis ;3(1):
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:
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 Jan; 45(1):

29. 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 Apr;32(4):
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:
Yu JW et al. The study of efficacy of lamivudine in patients with severe acute hepatitis B. Dig Dis Sci Mar; 55(3):
Yu JW et al. Lamivudine treatment is associated with improved survival in fulminant hepatitis B. Liver Int 2011; 31:

30. Questions?