2. DEFINITION
The term chronic hepatitis means active,
ongoing inflammation of the liver persisting
for more than six months that is detectable
by biochemical and histologic means.
11. Acute Hepatitis B Virus Infection with
RecoveryTypical Serologic
Course
Symptoms
HBeAg anti-HBe
Total anti-HBc
Titre
HBsAg IgM anti-HBc anti-HBs
0 4 8 12 16 20 24 28 32 36 52 100
Weeks after Exposure
12. Progression to Chronic Hepatitis B Virus
Infection Typical Serologic
Course
Acute Chronic
(6 months) (Years)
HBeAg anti-HBe
HBsAg
Total anti-HBc
Titr
e
IgM anti-HBc
0 4 8 12 16 20 24 28 32 36 52 Years
Weeks after
13. Outcome of Hepatitis B Virus Infection
100 by Age at Infection 100
80
80
Symptomatic Infection (%)
60 60
Chronic Infection
40 Chronic Infection (%) 40
) % not ce n c no h C
( i f I i r
20 20
Symptomatic Infection
0 0
Birth 1-6 months 7-12 months 1-4 years Older Children
and Adults
Age at Infection
15. Definition-HBeAg +ve
Diagnostic criteria
HBsAg + >6 months, HBeAg +ve
Serum HBV DNA >20,000 IU (1,00,000 copies)
Persistent or intermittent elevation of ALT/AST
Liver biopsy showing chronic hepatitis with
moderate or severe necro-inflammation
Lok AS, et al. Hepatology. 2007;45:507-539.
16. HBeAg-ve - Definition
Diagnostic critieria
– HBsAg+ >6 months
HBeAg-ve , anti-HBe +
Serum HBV DNA <2000 IU (10,000 copies )
Persistently normal ALT levels
Liver biopsy confirms absence of significant
hepatitis
Lok AS, et al. Hepatology. 2007;45:507-539.
17. Natural history of chronic infection
Chronic Hepatitis B
(All HBsAg +)
8-12% per yr HBeAg -
HBeAg +
Anti-HBeAg +
67-80% 10-30%
4-20%
Inactive carrier
Elevated ALT
Undetectable DNA
Detectable HBV DNA
•Lifelong follow-up of patients No inflammation
•0.5% of HBsAg carriers clear 10-20%
yearly
Reactivation
•Clearing HBeAg associated with HBeAg –
increased survival and decreased
chronic hepatitis
risk of hepatic decompensation
Lok AS, et al. Hepatology. 2007;45:507-539.
18. Impact of HBV Genotype on
Disease Progression
HBV Genotyping
Line Probe Assay
Genotype C marker line
conj. control 1
– More frequently associated with amp. control 2
3
severe liver disease and HCC than Genotype A 4
5
with genotype B Genotype B 6
7
8
Genotype B Genotype C
9
Genotype D 10
– Associated with seroconversion 11
Genotype E 12
13
from HBeAg to anti-HBe at younger Genotype F 14
15
age than with genotype C Genotype G 16
Genotypes A and B
– Higher rates of antiviral response
and HBeAg loss following peginterferon
alfa-2b than with genotypes D and C,
respectively
Slide courtesy of Clincal Care Options
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
19. Differences Between the Treatment
Algorithm and AASLD 2007 Guidelines:
HBeAg-Positive Patients
Treatment Algorithm 1 AASLD 20072
ALT <1 × ULN ALT >2 × ULN
ALT <1 × ULN HBV DNA
(HBV DNA (HBV DNA
(HBV DNA >20,000 IU/mL
20,000 IU/mL) >20,000 IU/mL)
<20,000 IU/mL)
Observe
Observe 3–6 mo
No Rx
No Rx Rx if persistent
ALT <1 × ULN ALT >1 × ULN
ALT 1–2 × ULN
Biopsy if age Rx (HBV DNA >20,000 IU/mL)
>35–40 yr;
Rx if
significant disease Observe
Biopsy if age >40 yr,
ALT persistently high, family history of HCC;
Rx if biopsy shows moderate/severe
1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936–962.
inflammation, significant fibrosis
2. Lok AS, McMahon BJ. Hepatology. 2007;45:507–539.
Courtesy of Dr. Ira Jacobson
20. Differences Between the Treatment Algorithm and
AASLD 2007 Guidelines: HBeAg-Negative Patients
Treatment Algorithm1 AASLD 20072
HBV DNA HBV DNA ALT <1 × ULN ALT ≥2 × ULN
<2,000 IU/mL >2,000 IU/mL
HBV DNA HBV DNA
No Rx <20,000 IU/mL ≥20,000 IU/mL
ALT <1 × ULN ALT >1 × ULN No Rx Rx
Consider biopsy; Rx ALT 1–2 × ULN
Rx if needed HBV DNA
2,000–20,000 IU/mL
Biopsy; Rx if needed
1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936–962.
2. Lok AS, McMahon BJ. Hepatology. 2007;45:507–539.
Courtesy of Dr. Ira Jacobson
21. Therapy for Chronic Hepatitis B: 2008
2008 and
1992 1998 2002 2005 2006
beyond…
interferon- lamivudine adefovir entecavir telbivudine Tenofovir*
alfa Clevudine**
pegylated Combination Rx
“The New Era” IFN-α
ORAL Therapy
*FDA-approved for HIV and in review by FDA for HBV indication
** in phase III trial
22. HEPATITIS D
Acute co-infection with hepatitis- D does not
increase the incidence of chronicity
Superinfection with hep-D in chronic hep-B
worsening of the liver disease occurs
24. Hepatitis C Virus Infection
Typical Serologic Course
anti-
HCV
Symptoms
Titr
e
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Mont Years
hsTime after
Exposure
25. Hepatitis C Virus Infection
Identification of Patients
Found to have elevated serum ALT during
– Routine physical examination
– Routine blood testing after starting certain medications
Test positive for anti-HCV during
– Volunteer blood donation
– Health or life insurance applications
Physician
– Inquires about previous risk behaviors
26. Hepatitis C Virus
Fate of Acute Infection
Spontaneous
resolution
15%
Chronic
85%
Alter MJ, et al. N Eng J Med. 1999;341:556-562.
35. Alcoholic Hepatitis
Can be chronic
Risk of cirrhosis variable…genetics, sex
(women more susceptible,)
Possibe nutritional factor
Presentation can range from an
asymptomatic person to a critically ill
one
36. SGOT / SGPT rarely over 400 U/L
Ratio SGOT / SGPT >2 - GGT elevated
Bilirubin level quite variable depending on
severity…can be 10 or higher
Fig20.jpg
PT/INR also may be elevated
PMN - > 5500 / Ml
Discriminant function > 32
37. Autoimmune Hepatitis
Generally affects young females
-viral,drugs,alcohol and genetical causes
excluded
Hypergammaglobulinemia
Extrahepatic manifestations are clues…
amenorrhea, thyroiditis, acne, Sjogrens, arthritis,
Coomb-positive hemolytic anemia, nephritis
38. ANA , anti-smooth muscle antibodies
(SMA),anti LKM and SLA – soluble liver
antigen are present
Old name was Lupoid Hepatitis
Liver histology-cytotoxic T cells and
plasma cells
Responds well to steroids and
immunosuppressive therapy
39. Nonalcoholic Steatohepatitis-
NASH
Asymptomatic patient with chronic mild
transaminase elevations in the absence of viral
hepatitis, drug hepatotoxicity or alcohol use.
Classically middle aged with syndrome X
Often seen with DM, obesity, high lipids
TPN, Protien malnutrition, steroids
40. NASH continued
Age > 45, ↑ BMI ,SGOT /SGPT > 1 & DM
Course usually benign, a few may 15-
30%progress to fibrosis and cirrhosis
No specific treatment exists
Focus on control of DM-insulin
sensitizers, weight loss and treatment
of lipid disorder
41. Wilson’s disease -Clinical
Presentation
Liver disease in adolescents (abnormal liver
enzymes to cirrhosis and portal HTN) Half
present this way.
Neuropsychiatric disease in young adults
(tremors, movement disorders, bulbar
dysfunction, behavior and
personalitychanges)
Kayser-Fleischer rings (pathognomonic)
Renal disorders (calculi, RTA))
42. Alpha-1 Antitrypsin
Deficiency
Patients with homozygous deficiency may
develop emphysema as adults.
About 10% of homozygous patients develop
neonatal hepatitis which can progress to
cirrhosis
In adults the most common manifestation
is asymptomatic which may progress and
develop hepatocellular carcinoma
47. Hemochromatosis
• Liver…mildly abnormal liver tests,
• eventually cirrhosis
• Skin pigmentation…slate-gray or brown
• Pancreas…glucose intolerance, diabetes
• Joints…arthralgias, especially 2nd and
3rd
• MCP joints
• Restrictive cardiomyopathy +/- CHF
• Amenorrhea, impotence
48. Primary Biliary Cirrhosis
• Liver studies reflect cholestasis
• Mostly elevated alkaline phosphatase and
cholesterol, later bilirubin
• 95% have Anti Mitichondrial Antibodies
• Elevated serum IgM levels
• Treat with ursodeoxycholic acid, possibly
MTX
• Many need liver transplantation
49. Algorithm in HIV positive
HBV DNA <2000 HBV DNA >2000
ALT Normal ALT elevated
Mild fibrosis Significant fibrosis
No Treatment Treatment
Soriano et al. AIDS 2008;21(12):1399-410
50. • Treatment should be offered in patients who meet the following criteria, regardless
of CD4 count:
– hepatitis B e antigen positive
– raised ALT (more than twice upper limit of normal)
– evidence of fibrosis on biopsy or on appropriate imaging
– hepatitis B viral load >10 000 copies/ml.
• The ART regimen should include tenofovir (TDF) and lamivudine (3TC) or
emtricitabine (FTC).
Editor's Notes
30
31
34
anti-HBe, antibody to hepatitis B e; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma. Regarding HBV genotyping, genotype C appears to be associated with a higher risk of development of cirrhosis and HCC, compared with genotype B. These are the 2 dominant genotypes in Asia. Conversely, genotype B is associated with a higher rate of seroconversion from HBeAg positivity to HBeAg negativity and is associated with greater HBV DNA suppression when treated. Genotype A and B are associated with a higher rate of response to interferon-based therapy, which is an important issue when managing adult-acquired hepatitis B.
10 10 10
How do we identify patients with hepatitis C? There are a couple of ways. First, we find patients with elevated serum liver transaminases either during routine physical examination or routine blood testing after starting certain medications. Patients may also test positive for anti-HCV during volunteer blood donations or for life or health insurance physicals. However, one of the most important ways that physicians can identify patients with hepatitis C is to inquire about previous risk behaviors and screen patients who disclose these behaviors.
As previously mentioned, the majority of individuals exposed to HCV will develop chronic infection; however, 15% of patients exposed to HCV are somehow capable of spontaneously resolving this infection. Research is currently ongoing to better understand how these people can resolve their infection, and this may shed some light on how to better treat hepatitis C in the future.
The next slide illustrates the natural history of HCV infection. As previously mentioned, a small percentage of individuals will go on to spontaneous resolution—about 15%—whereas 85% develop chronic disease. Of this 85% who develop chronic disease, about 80%, (68% of all infected individuals), will have stable chronic hepatitis without significant progression over the next 20 years. By contrast, 20% of those who develop chronic disease (17% of all infected individuals) will develop cirrhosis over the next 20-25 years. Of these cirrhotic patients, many will continue to progress slowly, and about 25% will rapidly develop hepatocellular carcinoma (HCC) or liver failure. Thus, liver cancer and liver failure occur in approximately 4% of patients who are exposed to HCV over a 20- to 25-year period.
This first slide looks at the tests that are used to identify patients with hepatitis C and assess disease severity and response to therapy. The first, aspartate aminotransferase and ALT tests, are not really liver function tests although many physicians refer to them as such. Rather, they measure liver transaminases, which are indicative of inflammation or irritation to the liver. The true tests to measure liver function include bilirubin, albumin, and prothrombin time or international normalized ratio. When the liver has dysfunction, these tests start to show abnormalities. Unfortunately, that does not occur until patients develop cirrhosis. Therefore, the majority of patients with chronic hepatitis C show normal liver function based upon these liver function tests. One of the most sensitive tests of advanced liver disease is the platelet count. A large number of studies have now demonstrated that thrombocytopenia—platelet counts below the lower limit of normal—is indicative of cirrhosis in individuals who do not have some sort of primary platelet or bone marrow disorder. Identifying thrombocytopenia is an easy way to identify patients with cirrhosis, and clearly liver histology represents the gold standard of determining the severity of disease and histologically can identify cirrhosis and the degree of scarring or fibrosis is present in the liver. One test we monitor to determine treatment response is serum ALT. If treatment is working effectively, we expect that the ALT levels will drop back down into the normal range on therapy. We also monitor the level of HCV RNA, and the goal is to have virus levels become undetectable during treatment. Hepatitis C virus genotype determines how long we need to treat patients, and liver histology can be used as a marker to show that the liver has improved after therapy.
The final way to assess liver disease severity in hepatitis C is with liver biopsy. This is the only test able to accurately assess severity of inflammation and degree of fibrosis. The baseline degree of inflammation and fibrosis are able to determine risk of cirrhosis development in the future, the need for therapy, and the need for ongoing therapy if initial treatment has failed. For example, an individual who failed interferon therapy and has mild liver disease and no apparent cirrhosis based on liver biopsy, has little urgency to undergo retreatment with new or more aggressive therapies. In contrast, an individual with more scarring and bridging fibrosis on biopsy may request such treatments. The biopsy is very useful for managing patients in these scenarios.
If you ask patients with hepatitis C how they feel, about 56% of them say they are asymptomatic, about 37% say they have symptoms, and about 7% have complications of cirrhosis. Of those who have symptoms, the most common symptom is simply fatigue—80% of symptomatic patients complain of fatigue. The symptoms can be very, very subtle indeed.
If you examine patients with cirrhosis who achieve a sustained virologic response after interferon therapy, the risk of developing liver cancer is significantly reduced. Compared with untreated controls where the risk of developing cancer was 38% over long-term follow-up, the risk was reduced to 4% in patients treated with interferon, a highly significant risk reduction.
The 2 studies shown in this slide illustrate the effectiveness of the 2 peginterferons approved for treatment of hepatitis C—peginterferon alfa-2a and peginterferon alfa-2b. Approximately 80% of individuals with genotype 2 or 3 HCV achieve a sustained virologic response with peginterferon combined with ribavirin, meaning 80% are cured of hepatitis C. Unfortunately, genotype 1 is more resistant to treatment, yet 40% to 45% of patients with genotype 1 achieve a sustained virologic response after treatment with peginterferon and ribavirin.