INTERESTING CASE PRESENTATION

DR.ILAVARASI

PROF.S.MANJUNATH UNIT

54/y male ,known chronic alcoholic and known HbsAg positive

PRESENTED WITH :

C/o gradual progressive abdominal distention

B/l pedal edema

Dry cough

Grade 2 breathlessness

CASE 1 :

PAST HISTORY………..Known case of chronic hepatitis B infection

Diagnosed to have liver cirrhosis two years back

HBsAg was positive

HBeAg was positive (ongoing viral replication,highly inf)

Treated with lamivudine

After 6 months HBeAg was negative

Anti HBe positive (decline in infection)

GENERAL EXAMINATIONConsious,oriented

Afebrile

Icteric/pallor

Congested conjunctiva

B/l pedal edema

Vitals stable

Systemic examination

CVS : S1S2 +

RS : MINIMAL CREPITATIONS +OVER RIGHT

INFRASCAPULAR REGION

PER ABDOMEN

DISTENDED

BOWEL SOUNDS +

UMBILICUS EVERTED

SHIFTING DULLNESS+

NO BRUIT

INVESTIGATIONS:CBC : NORMALRFT :NORMALLFTT.BILIRUBIN : 3.17D.BILIRUBIN : 1.61T.PROTEIN :6.1ALBUMIN :2.5GLOBULIN :3.6ALK.PHOSPHATASE:221SGOT,SGPT

CHEST X-RAY:INCREASED BRONCHOVASCULAR

MARKINGS ON LEFT LOWER ZONE

ULTRASOUND ABDOMEN

MACRONODULAR CHANGES OF THE LIVER

SPLENOMEGALY

ASCITES

PORTAL VEIN THROMBOSIS

LEFT RENAL CALCULUS

CT ABDOMENCIRRHOSIS LIVER WITH HETEROGENOUS

ENHANCEMENT IN THE ARTERIAL FACE IN THE RIGHT LOBE POSSIBLITY OF HEPATOCELLULAR CARCINOMA

SPLENOMEGALY

PORTAL VEIN THROMBOSIS

ASCITES

CT ABDOMEN PICTURES

HBeAg :NEGATIVE

HBVDNA:46,80,000

ALPHA FETO PROTEIN:1,76,990

CT THORAX

RANDOM NODULAR LESIONS B/L LUNG FIELDS SUGGESTIVE OF PULMONARY METASTASIS

CT THORAX PICTURES

MetastaticHepatocellula

rCarcinomaStage IV B

TREATMENTTREATED SYMPTOMATICALLY

COUGH SUPPRESSANTS

I.V.LASIX

ALDACTONE

LAXATIVES

MEDICAL ONCOLOGY OPINION WAS SOUGHT (ADVICED SYMPTOMATIC MANAGEMENT)

ADVICED SORAFENIB…..AND SYMPTOMATIC CARE

65 YEAR FEMALE,KNOWN CHRONIC ALCOHOLIC

>15 YEARS

Presented with abdominal pain

Abdominal distention

Mild swelling of both legs

Vomiting

CASE 2 :

On examination:ConsiousPallor+Not icteric

Per abdomen:DistentedFluid thrill +Distented veins +Speen palpable

Investigations

Hb :8.9Platelet count:90,000INR:1.50

PERIPHERAL SMEARNormocytic normochromic to macrocytic Platelets low normal

LIVER FUNCTION TESTS:

Bilirubin levels : normal

S.G.O.T : 142

S.G.P.T : 78

Alk.phosphatase: 204

HBsAg : positive

HBeAg : negative

HBV DNA : 70,900 IU/ML

USG ABDOMEN

PORTAL HYPERTENSION

ASCITIS

CIRRHOSIS

PORTAL HYPERTENSION

Alcohol related cirrhotic liver

with portal hypertension and HBsAg

positive

DISCUSSION….

HEPATITIS B…….

HEPATITIS B VIRUSWhen the hepatitis B virus infects the liver, it

replicates and produces excess surface material, some of which reaches the blood.

When there is less viral replication, the virus core is only detected in the liver but not in the blood

The marker for the surface is HBsAg (hepatitis B surface antigen) and the markers for the core are HBeAg (hepatitis B "e" antigen) and HBV-DNA.

VIRAL ANTIGENS AND AB’S PHASE OF INFECTION

HBsAG

ANTI HBs

ACUTE INFECTION

VIRUS IS CLEARED

HBeAG VIRAL REPLICATION AND INCREASED INFECTIVITY

ANTI HBe DECLINE IN INFECTIONLESS INFECTIOUS

HBV DNA ONGING LIVER DISEASEACTIVE VIRAL INFECTIONPATIENT INFECTIOUS

HBcAG NEVER DETECTABLE IN SERUM

IgM antiHBc RECENT CONTACT WITH THE VIRUS

HEPATITIS B Chronic HBV infection presents as one of three potentially successive phases: immune tolerant, immune active and low- or non-replicative.

In the immune tolerant phase, serum HBsAg and HBeAg are detectable, serum HBV DNA levels are high, serum aminotransferases are normal or minimally elevated.

In the immune active phase, serum HBV DNA levels decrease and serum aminotransferase levels increase. Flares of aminotransferases may be observed, in some patients these flares are followed by HBeAg-anti-HBe seroconversion.

In the low- or non-replicative phase the HBV replication persists but at a very low level suppressed by the host immune response. HBV DNA in serum is undetectable by conventional, non-PCR based techniques. This phase is also called the 'inactive carrier state'.

Patients with HBV-cirrhosis have a 1000 times higher risk of developing HCC compared to a HBsAg negative control group

Hepatology 1998, 27:1377-1382 Lancet 1981, 2:1129-1133.

Gut. 1985 August; 26(8): 848–860.

There is a mutant strain of HBV (pre-core mutant) in which the virus cannot manufacture HBeAg and thus the only marker for the presence of the virus core is HBV-DNA.

These patients may have antibodies to HBeAg and often have very severe liver disease

PRE CORE MUTANT :

The most common precore mutation is a guanosine (G) to adenine (A) change at nucleotide 1896 (G1896A), which leads to premature termination of the translation of the precore region at codon 28, thus preventing the production of HBeAg.

Results in severe liver disease

WILD TYPE HEPATITIS ‘B’

Significance of HBV DNA Levels in People with HBeAg Negative Chronic Hepatitis B

By Liz HighleymanOver years or decades,

chronic hepatitis B virus (HBV) infection can lead to advanced liver disease, including cirrhosis and hepatocellular carcinoma.

But much remain to be learned about the significance of HBV DNA viral load levels in patients with hepatitis B "e" antigen (HBeAg) negative chronic hepatitis B.

Journal of Clinical Microbiology, Jul 1996, 1815-1818, Vol 34, No. 7

Precore mutant of hepatitis B virus prevails in acute and chronic infections in an area in which hepatitis B is endemic

CM Chu, CT Yeh, CT Chiu, IS Sheen and YF Liaw Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung Medical College, Taipei, Taiwan.

By using an amplification-created restriction site method, the precore TAG

mutant of hepatitis B virus was detected in 6 (75%) of 8 acute fulminant

hepatitis B patients, 7 (58%) of 12 acute self-limiting hepatitis B patients, 35 (81%) of 43 hepatitis B virus surface antigen carriers with fulminant hepatitis, and 42 (70%) of 60 hepatitis B virus surface antigen carriers with chronic hepatitis. The precore TAG mutant prevails in acute and chronic hepatitis B of various severity in this area where hepatitis B is endemic.

VIRAL HEPATITIS AND HCCThe hepatitis B replication status seems to play an important role in

determining the risk of development of HCC .

A recent study found that whereas the relative risk of HCC among men with HBsAg alone was 9.6 compared to those without HBsAg, the risk increased to 60.2 when they were positive for both HBsAg and HBeAg .

Another analysis showed that the level of HBV DNA is a prognostic marker for HBV-related HCC and that HCC patients with a less favorable course appear to either clear the virus poorly or to have a greater level of virus production

Am J Gastroenterol 2002, 97:156-161 N Engl J Med 2002, 347:168-174 Cancer 2002, 94:2663-2668.

Direct carcinogenicity of HBV

A significant proportion of HBV-related HCCs arise in an otherwise normal liver, implicating that the virus can also be directly oncogenic

It has been demonstrated that HBV integrates into the DNA of the host cells. This integration may dysregulate the control mechanisms on the cell cycle by chromosomal abnormalities, production of viral proteins or alteration of human genes and proto-oncogenes

HBV integration can be present in chronically infected liver tissue without evidence of HCC . Non-neoplastic hepatocytes may have a similar pattern of rearrangement of viral sequences following integration into human DNA.

Res Virol 1998, 149:257-262. J Gen Virol 1981, 57(Pt 1):95-102

Role of alcohol consumption in HBV or HCV infection Reports suggest that HBV and ethanol act synergistically to promote HCC .

heavy drinking was reported to be a significant risk factor for HCC in patients with HCV-related liver cirrhosis by multiple logistic regression analysis .

A recent study showed synergism between alcohol drinking and HBV or HCV infection, with approximately a twofold increase in the odds ratio for each hepatitis virus infection for drinkers' > 60 g/d, with a more than additive but less than multiplicative risk .

another case-control study found a positive interaction between HBsAg positivity and

HCV RNA positivity and heavy alcohol intake in the development of HCC .

Hassan et al. showed synergistic interaction (more than additive) between heavy alcohol consumption ≥ 80 ml/d and chronic HBV or HCV infection (odds ratio 53.9) and insulin or non-insulin dependent diabetes mellitus (odds ratio 9.9).

Am J Epidemiol 2002, 155:323-331 Ann Intern Med 1992, 116:97-102. Int J Cancer 1987, 39:45-49 Hepatology 1997, 26:579-584

A YEARLY PHYSICAL ASSESSMENT:

This should include evaluation of routine liver biochemistry (AST, ALT, alkaline phosphatase) and liver function (bilirubin, albumin, prothrombin time) tests

WATCH FOR CLINICAL SIGNS OF HCC RIGHT UPPER QUADRANT ABDOMINAL PAIN INCREASE IN ABDOMINAL DISTENTION PORTAL VEIN THROMBOSIS RAISING AMINOTRANSFERASE LEVELS

ALPHA-FETOPROTEIN (AFP) every six months.

AN ULTRASOUND OF THE LIVER* every six months

HBsAg TESTING.

HBsAg should be checked every year to see if a person is still a carrier. Less than 1% of carriers clear HBsAg and develop anti-HBs each year.

Prevention of HCC….in chronic hepatitis B

HBeAg TESTING. If a person remains HBsAg positive, HBeAg should be checked

every year.

This latter test will demonstrate in most cases if the virus is actively replicating.

A person who is HBeAg positive (+) or has an AST>200 should be referred to a gastroenterologist/hepatologist for evaluation of need for liver biopsy and anti-viral treatment.

Even if HbeAg remains negative,HBVDNA should be done

Indications for referral include any of the following:

HBeAg positivity ALT >200 Deterioration in liver function Suspicion of a liver tumor

TESTING OF HOUSEHOLD MEMBERS. All members of the carrier's household and his/her sexual partners should be tested for hepatitis B. If found susceptible or if they have an indeterminate pattern (an isolated anti-HBc +) they should be vaccinated against hepatitis B, even if pregnant.

HEPATITIS B EDUCATION. Each hepatitis B carrier should receive hepatitis B education, as should his/her household members and sexual partners.

Sorafenib (Nexavar)

First oral multikinase inhibitor that targets serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation.

These kinases included RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3. Indicated for unresectable hepatocellular carcinoma

Sunitinib (Sutent)

Mulitkinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression.

Inhibits platelet-derived growth factor receptors ( PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (VEGFR1, VEGFR2, VEGFR3).

Erlotinib (Tarceva)

Pharmacologically classified as a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor.

EGFR is expressed on the cell surface of normal cells and cancer cells.

Risk of HCC is increased when both HBsAg and HBeAg are positive

Chronic HBV or HCV infection and alcohol act synergistically to promote HCC.

Precore mutant cannot manufacture HBeAg and thus the only marker for the presence of the virus core is HBV-DNA.

CONCLUSION:

THANK YOU !!!!!!!!