Id clinical case conference 14 april 2003
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ID Clinical Case Conference 14 April, 2003. Munshi Moyenuddin, M.D. Ph.D. Fellow, Infectious Diseases WFU Baptist Medical Center. A 46 y/o white male with abdominal pain, nausea, vomiting. HIV diagnosed in 1991. No complications/ no medical care for 5-yrs.

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Id clinical case conference 14 april 2003

ID Clinical Case Conference14 April, 2003

Munshi Moyenuddin, M.D. Ph.D.

Fellow, Infectious Diseases

WFU Baptist Medical Center


A 46 y o white male with abdominal pain nausea vomiting
A 46 y/o white male with abdominal pain, nausea, vomiting

  • HIV diagnosed in 1991. No complications/ no medical care for 5-yrs.

  • Presented on 2/28/96 with oral/esophageal candidiasis.

  • CD4-10, VL-49,939

  • Wbc-2.1, ANC-1400, Hg-11.2, plt-30, Cr-0.6, TB-0.9, AP-159, AST-62, Alb-3.7, ALT-21


H p contd
H & P (contd)

  • PMH: Hospitalization- none, STD- none, Bronchopneumonia in 1995- treated with doxycycline, no h/o liver disease or jaundice

  • Medications- none

  • Allergies- none

  • SHx- gay male, NC native, restaurant manager, smoker-1ppd, denied ETOH, no pets.


Physical exam
Physical Exam

  • Ht- 5’8’’, wt-112.5 lb, T-98, P-78, BP-114/74

  • Gen- thin white male, no distress

  • Skin- facial seborrhea

  • HEENT- moderate oropharyngeal candidiasis

  • Chest- scattered rhonchi, L-nipple ring

  • Abd- unremarkable, no organomegaly

  • Anorectum- external hemorrhoid

  • Ext- no edema


Labs treatment
Labs & treatment

  • CMV IgG +, Toxo IgG -, RPR –

  • Anti-HCV -, Anti-HBc +,

  • Anti-HBs -, HBsAg +

  • Treatment started with AZT+ ddI, also, fluconazole and TMP/SMX.

  • VL- 5030 in 6-months

  • AZT was changed to d4T, continue ddI

  • VL- 2487, crixivan was added.

  • 2-years on treatment: VL-100,785; CD4-90


Treatment course
Treatment course

  • Episode of fever with RUQ pain with gas.

  • CT abdomen & pelvis- no mass or stone; low-density lesions in kidneys, likely cysts; no liver lesion, enlargement of the portal vein with associated collaterals; the spleen was mildly enlarged; large hiatal hernia.

  • Abd pain was resolved with antacid.

  • Subsequently, no GI complaints.


Labs and course of treatment
Labs and course of treatment

  • Genotype- RT mutations 215, 41; PI mutations 36, 71, 77

  • Crixivan was stopped,EFV and HU were added to d4T and ddI (3/99)

  • VL <50, CD4-250 (8/99)

  • VL remained <50, developed peripheral neuropathy, ddI dose was decreased

  • On 9/01 – ddI & HU were d/cd and 3TC was added to d4T and EFV

  • VL remained <50, CD4-260


Labs treatment course
Labs & treatment course

  • HBV DNA= 4.37 pg/ml (1 pg= 150,000 copies)

  • TB- 0.7, AP- 159, AST- 43, ALT 24

  • VL remained <50 and CD4 >250

  • Viread was added to 3TC, d4T, EFV (on 6/02)

  • After 6-months, pt developed abd pain, nausea, wt loss of 9-lbs in 3-months.

  • Alb- 4.2, TB- 0.8, AP- 238, AST- 61, ALT-39, Hg- 14.1, plt- 186


Labs contd
Labs (contd)

  • Amylase- 103, lipase- 22, lactate- 1.3

  • CD4- 220, VL- <50

  • Pt continued to work, was tolerating food, gained back 3-lb wt, abd pain continued

  • Good compliance with meds

  • Rept HBV DNA (12/02)- <0.01 pg/ml.


Labs contd1
Labs (contd)

  • CT abd & pelvis (on 2/03)- multifocal enhancing masses within the R & L hepatic lobes with tumor thrombus in the portal vein. The largest lesion measured about 8x8.6 cm.

  • Liver bx (2/03)- hepatocellular carcinoma.


Topics of discussion
Topics of Discussion

  • Natural Course of Chr HBV infection.

  • Prognosis of Chr HBV infection

  • HBV Carrier State and HCC

  • Aims of Treatment of Chr HBV

  • Molecular Mechanisms of HBV-associated Liver Cancer

  • Screening for HCC

  • Prevention of HCC Associated with Chr Hepatitis


Natural course of chr hbv inf
Natural Course of chr. HBV inf

  • Determined by the interplay between virus replication and the host immune response.

  • Outcome depends upon the severity of liver disease at the time HBV replication is arrested.

  • Two phases: 1) Early replicative phase with active liver disease.

  • 2) Late or nonreplicative phase with remission of disease.

  • In perinatally acquired inf, there is an additional immune tolerance phase.


Natural course of chr hbv inf1
Natural course of chr HBV inf

  • Replicative phase: Immune tolerance: In the initial phase of perinatally acquired inf, high level of HBV replication without active liver disease (Hepatology 1992; 15: 770).

  • This phase lasts 10 to 30 yrs with very low rate of HBeAg clearnce (Gastroenterology 1987; 92: 1839).

  • Studies found HBeAg in 90% of children <5-yrs of age and in 80% of <20 yrs of age with chr HBV.


Natural course of chr hbv inf2
Natural Course of chr HBV inf

  • Replicative phase: Immune clearance: Occurs during 2nd and 3rd decade of life.

  • HBeAg clearance increases 10 to 20% annually.

  • HBeAg seroconversion is frequently accompanied by increased ALT due to immune mediated lysis of hepatocytes (Gastroenterology 1993; 105: 1141).

  • Exacerbation may be associated with IgM anti-HBc and increase in AFP.


Natural course of chr hbv inf3
Natural Course of chr HBV inf

  • Late or nonreplicative phase: Pts are usually HBeAg negative and anti-HBe positive.

  • May remain HBsAg positive with undetectable HBV DNA.

  • Some pts become HBsAg negative. Annual rate of HBsAg clearance is 0.5 to 2% in western pts and 0.1 to 0.8% in asian pts.

  • A study of 218 pts over 62 months showed, of 189 pts who were not cirrhotic at the time of HBsAg clearance, 3 developed cirrhosis and 3 developed hepatocellular carcinoma (2 had concurrent HCV or HDV) (Gastroenterology 2002;123:1084).


Natural course of chr hbv inf4
Natural Course of chr HBV inf

  • Clearance of HBsAg does not preclude development of cirrhosis or HCC.

  • In a series of 55 pts who cleared HBsAg, complications developed in 33% (11 HCC, 6 cirrhosis, 1 fulminant liver failure) during a follow-up of 23 months (Hepatology 1998;28:231).

  • Pts may be infected with a mixture of wild-type virus and HBV variants with deletion in pre-S1 region, associated with reduction in HBsAg synthesis (Hepatology 2000; 32: 116).


Prognosis of chr hbv infection
Prognosis of chr HBV infection

  • The estimated 5-year rates of progression in endemic areas are:

    • Chronic hepatitis to cirrhosis- 12 to 20%

    • Compensated cirrhosis to hepatic decompensation- 20 to 23%

    • Compensated cirrhosis to hepatocellular carcinoma- 6 to 15%

      (J Hepatol 1994; 21: 656; Hepatology 1995; 21: 77).

      A study in chinese pts, the life-time risk of a liver-related death has been estimated at 40 to 50% in men and 15% in women (Hepatology 1982; 2: 215).


Prognosis of chr hbv infection1
Prognosis of chr HBV infection

  • Pts with a prolonged replicative phase have a worse prognosis mostly due to cirrhosis and HCC.

  • This was illustrated in a study of 98 pts with positive HBsAg + cirrhosis (Gastroenterology 1992;103: 1630).

  • The 5-yr survival rate was significantly lower in pts with +HBeAg.

  • Clearance of HBeAg was associated with a 2.2-fold decrease in death rate.


Hbv carrier state and hcc
HBV carrier state and HCC

  • A study of HBV carriers (HBsAg +) in Taiwan over 4-yrs showed the relative risk of HCC was 223 times that of noncarriers (Lancet 1981; 2: 1129).

  • A prospective study of HBV carriers in North America showed, the incidence of new cases of HCC was 0.47% per year (Hepatology 1995; 22: 432).

  • In a series of 317 HBV carrier in Canada, 16-yrs follow-up revealed no cases of HCC (Gastroenterol 1994;106 : 1000)


Hbv carrier state and hcc1
HBV Carrier state and HCC

  • The risk of HCC is much higher in pts who are HBeAg + compared to those who are HBsAg + but HBeAg – (Anticancer Res 1991; 11: 2063; Br J Cancer 1996; 73:1498; NEJM 2002;347:168).

  • One of the largest study included 11,893 Taiwanese men and were followed for 10-yrs, HCC was significantly higher in those who were both HBsAg + & HBeAg +


Hbv carrier state and hcc2
HBV Carrier state and HCC

  • The risk of developing HCC is substantially greater in HBV pts who have cirrhosis.

  • In one series, HCC occurred in 9% of such pts within a 6-yr period (Hepatology 1995; 21:77)

  • Other hepatotrophic stimuli, such as environmental toxins, are likely to act synergistically in the multistep pathogenesis of HCC.


Aims of treatment of chr hbv
Aims of treatment of chr HBV

  • Sustained suppression of HBV replication.

  • Remission of liver disease.

  • The end-points to assess treatment response include-

    • Normalization of ALT level

    • Undetectable HBV DNA

    • Loss of HBeAg

    • Improvement of liver histology.


Molecular mechanisms of hbv associated liver cancer
Molecular Mechanisms of HBV-associated Liver Cancer

  • In cases of human HCC, integrated HBV DNA sequences can be found and viral proteins are expressed from the integrations.

  • An altered expression of oncogenes and tumor suppressor genes is found in the HBV-infected liver (Oncogene 2001;20:3674).

  • Hepatitis B x (HBx) protein, encoded by many integrated sequences, has transactivating function (J Virol 1987;61:3448).


Molecular mechanisms of hbv associated liver cancer1
Molecular Mechanisms of HBV-associated Liver Cancer

  • Integration of HBV sequences often leads to carboxy-terminal truncation of the middle hepatitis B surface protein (HBs).

  • This truncation yields a protein (MHBs’) that can transactivate the transcription of a variety of genes (Proc Natl Acad Sci USA 1990;87:2970).

  • Overexpression of the large HBs protein can cause liver cancer in transgenic mice (Cell 1989;59:1145).


Molecular mechanisms of hbv associated liver cancer2
Molecular Mechanisms of HBV-associated Liver Cancer

  • One of the transactivator sequences (HBx or MHBs’) could be found in 81% of HBV-related HCC (Oncogene 1994;9:3335).

  • HBx can transactivate a variety of targets including cellular genes and viral regulatory elements.

  • HBx either complex with or alter the DNA binding of transcription factors.


Molecular mechanism of hbv associated liver cancer
Molecular mechanism of HBV-associated liver cancer

  • Mice expressing the HBx protein under authentic promoter control exhibited HCC development (J Hepatology 1999;31:123).

  • A study of immunepathogenesis of HCC demonstrated that continuous induction of HBV-specific T-cells and their migration into the liver fuels a chr inflammatory process which may cause hepatocarcinogenesis (J Exp Med 1998;188:341).


Screening for hcc
Screening for HCC

  • HCC may have a long asymptomatic stage lasting 2-yrs or longer in Alaskan Eskimos (Lancet 1982;2:889).

  • In the majority of pts, the cancer begins as a single tumor that is often encapsulated.

  • The doubling time of HCC has been estimated to range from 2 to 12 months with a median of 4-months (Gastroenterol 1985;89:259).


Screening for hcc1
Screening for HCC

  • Using alpha-fetoprotein (AFP) as a screening method, small HCC (tumors with a diameter of <5 cm) were found in 37 to 59% of pts with HCC (Hepatology 2000;32:842; J Gastroenterol Hepatol 1994;9:361).

  • Periodic screening utilizing both AFP and ultrasound, small tumors were detected in 57 and 83% respectively with HCC (Hepatology 1995;22:432; Cancer 1985;56:660).


Screening for hcc2
Screening for HCC

  • Asymptomatic chr HBV Carrier with normal ALT and minimal or absent liver disease can develop HCC.

  • The optimal age to initiate periodic screening is not known.

  • The sensitivity of AFP test depends on the cutoff level. If a level of 20 ng/ml is used (normal level 8-12 ng), the sensitivity for small HCC ranges from 50 to 75% (Hepatology 2000; 32: 842).


Screening for hcc3
Screening for HCC

  • AFP levels that rise in a step-like manner strongly suggest the presence of HCC.

  • Persons with persistent mild elevation of AFP (<200 ng/ml) are at higher risk of HCC than those with a single increased value (Hepatology 2000;32:842)

  • Other markers that have been shown to be elevated in small HCC include des-gamma carboxy prothrombin (DCP), serum-gamma glutamyl transferase isoenzyme II, and alpha-L-fucosidase (Dig Dis Sci 1991;36: 1787; Am J Gastroenterol 1992;87:991).


Screening for hcc4
Screening for HCC

  • Studies suggested that DCP and AFP are complimentary and result in a higher sensitivity than either test alone (Cancer 1998;82:1643; Am J Gastroenterology 1999;94:650)

  • Ultrasound (US) is more sensitive than AFP for small HCC.

  • The combination of US and AFP appears to be superior to either alone (Hepatology 1995:22:432).


Screening for hcc5
Screening for HCC

  • Studies utilizing US and AFP, involving pts with cirrhosis due to HBV or HCV, screening every 6-months appeared superior to yearly screening in the detection of small HCC.

  • No difference between screening every 3 or 6-months (Hepatology 1995;22:432; Cancer 1996;78:977)

  • Periodic testing can detect HCC at a resectable stage in >50% of the instances.


Screening for hcc6
Screening for HCC

  • Evidence suggests that carriers with low risk of HCC could be screened with AFP, and those at high risk (men >45 yrs, cirrhosis, FHx of HCC) with AFP and US.

  • Carriers can experience long-term survival after resection of small HCC.

  • Screening with AFP alone has been shown to detect HCC early in some carriers from endemic areas.


Prevention of hcc associated with chr hepatitis
Prevention of HCC Associated with Chr Hepatitis

  • A persistent immune responses against HBsAg are involved in the development of chr hepatitis leading to HCC.

  • Studies demonstrated that Fas ligand (FasL), one of the major cytocidal molecules produced by CTLs plays an important role in the pathogenesis of HCC (J Immunol 1995; 154: 3806)

  • Administration of soluble Fas that neutralizes FasL rescues mice from the fatal disease (J Immunol 1997;158:5692).


Prevention of hcc associated with chr hepatitis1
Prevention of HCC associated with Chr. Hepatitis

  • Using an animal model of chr hepatitis that induces HCC, a recent study demonstrated that neutralization of the activity of Fas-ligand prevented hepatocyte apoptosis, proliferation, liver inflammation, and the development of HCC (J Exp Med 2002; 196:1105).


Prevention of hcc associated with chr hepatitis2
Prevention of HCC associated with Chr Hepatitis

  • The results provide a rationale for developing a therapy for hepatitis using anti-FasL antibody or inhibitors for the Fas signal transduction pathway.

  • This is the first demonstration that amelioration of chr inflammation by treatment caused reduction of cancer development.


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