Patologia sistematica V Gastroenterologia Prof. Stefano Fiorucci. Acute viral hepatitis Chronic hepatitis

Transcription

1 Patologia sistematica V Gastroenterologia Prof. Stefano Fiorucci Acute viral hepatitis Chronic hepatitis Harrison s Principles of Internal Medicine 18 Ed. 2012

2 Acute hepatitis Acute viral hepatitis is a systemic infection affecting the liver predominantly. Almost all cases of acute viral hepatitis are caused by one of five viral agents: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), HBV-associated delta agent or hepatitis D virus (HDV), hepatitis E virus (HEV). Other transfusion-transmitted agents, e.g., "hepatitis G" virus and "TT" virus, have been identified but do not cause hepatitis. All these human hepatitis viruses are RNA viruses, except for hepatitis B, which is a DNA virus. Clinical manifestations range from asymptomatic and inapparent to fulminant and fatal acute infections Progression to subclinical persistent infections and progressive chronic liver disease with cirrhosis and even hepatocellular carcinoma, occurs in bloodborne types (HBV, HCV, and HDV).

3 Hepatitis Type HAV HBV HCV HDV Virus nm Genome Type Antigens Antibodies Remarks kb RNA, linear, ss, kb DNA, circular, ss/ds Hepatovirus HAV Anti-HAV Early fecal shedding Hepadnavirus HBsAg HBcAg HBeAg 27 HBcAg HBeAg Anti-HBs Anti-HBc Anti-HBe Anti-HBc Anti-HBe Diagnosis: IgM anti-hav Previous infection: IgG anti-hav Bloodborne virus; carrier state Acute diagnosis: HBsAg, IgM anti-hbc Chronic diagnosis: IgG anti-hbc, HBsAg Markers of replication: HBeAg, HBV DNA Liver, lymphocytes, other organs Nucleocapsid contains DNA and DNA polymerase; present in hepatocyte nucleus; HBcAg does not circulate; HBeAg (soluble, nonparticulate) and HBV DNA circulate correlate with infectivity and complete virions 22 HBsAg Anti-HBs HBsAg detectable in >95% of patients with acute hepatitis B; kb RNA, linear, ss, + Hepacivirus kb RNA, viroids and circular, ss, plant satellite viruses HCV C100-3 C33c C22-3 NS5 HBsAg HDV antigen Anti-HCV Anti-HBs Anti-HDV Bloodborne agent. Acute diagnosis: anti-hcv (C33c, C22-3, NS5), HCV RNA Chronic diagnosis: anti-hcv (C100-3, C33c, C22-3, NS5) and HCV RNA; cytoplasmic location in hepatocytes Defective RNA virus, requires helper function of HBV (hepadnaviruses); Diagnosis: anti-hdv, HDV RNA; HBV/HDV HEV kb RNA, linear, ss, + Hepevirus HEV antigen Anti-HEV Agent of enterically transmitted hepatitis; rare in USA; occurs in Asia, Mediterranean countries, Central America hepatocyte cytoplasm

4 Hepatitis A Hepatitis A virus is a nonenveloped 27-nm, heat-, acid-, and ether-resistant RNA virus in the hepatovirus genus of the picornavirus family Its virion contains four capsid polypeptides, designated VP1 to VP4, which are cleaved posttranslationally from the polyprotein product of a 7500-nucleotide genome. Inactivation of viral activity can be achieved by boiling for 1 min, by contact with formaldehyde and chlorine, or by ultraviolet irradiation. Despite nucleotide sequence variation of up to 20% among isolates of HAV, all strains of this virus are immunologically indistinguishable and belong to one serotype.

5 Hepatitis A Hepatitis A has an incubation period of ~4 weeks. Its replication is limited to the liver, but the virus is present in the liver, bile, stools, and blood during the late incubation period and acute pre-icteric phase of illness. Despite persistence of virus in the liver, viral shedding in feces, viremia, and infectivity diminish rapidly once jaundice becomes apparent. HAV can be cultivated reproducibly in vitro.

6 Hepatitis B HBV is recognized as one of a family of animal viruses, hepadnaviruses (hepatotropic DNA viruses), and is classified as hepadnavirus type 1. Hepatitis B virus is a DNA virus with a small, circular, 3200-bp size, HBV DNA that codes for four sets of viral products with a complex, multiparticle structure. Viral Proteins and Particles Of the three particulate forms of HBV the most numerous are the 22-nm particles, which appear as spherical or long filamentous forms; these are antigenically indistinguishable from the outer surface or envelope protein of HBV and represent excess viral envelope protein. 42-nm, double-shelled spherical particles, which represent the intact hepatitis B virion The envelope protein expressed on the outer surface of the virion and on the smaller spherical and tubular structures is referred to as hepatitis B surface antigen (HBsAg). The concentration of HBsAg and virus particles in the blood may reach 500 g/ml and 10 trillion particles per milliliter, respectively. The envelope protein, HBsAg, is the product of the S gene of HBV.

7 Hepatitis B Genomic structure of HBV. 1. The S gene codes for the "major" envelope protein, HBsAg. Pre-S1 and pre-s2, upstream of S, combine with S to code for two larger proteins, "middle" protein, the product of pre-s2 + S, and "large" protein, the product of pre-s1 + pre-s2 + S. 2. The largest gene P codes for DNA polymerase. 3. The C gene codes for two nucleocapsid proteins, HBeAg, a soluble, secreted protein (initiation from the pre- C region of the gene) and HBcAg, the intracellular core protein (initiation after pre-c). 4. The X gene codes for HBxAg, which can contribute to carcinogenesis by binding to p53

8 Hepatitis B HBV, replicative strategy is unique among DNA viruses but typical of retroviruses. Instead of DNA replication directly from a DNA template, hepadnaviruses rely on reverse transcription (by the DNA polymerase) of minus-strand DNA from a "pregenomic" RNA intermediate.

9 Hepatitis B Initially, HBV particles are taken up by hepatocytes through mechanisms that involve NTCP (sodium/bile acid cotransporter, also known as SLC10A1). After internalization, viral capsids are released and subsequently directed to the nucleus where the HBV genomes are liberated. In the nucleus, relaxed circular DNA (rcdna) genomes are converted into cccdna that can persist in the nucleus of infected cells as a minichromosome and which serves as template for viral RNA transcription.

10 Hepatitis B Double-stranded linear DNA (dsldna) is also produced that can be integrated into the cellular genome or also converted into cccdna. Viral mrnas are transported to the cytoplasm where they are translated into viral proteins and together with the viral polymerase, the pregenomic RNA (pgrna) is encapsidated and reverse transcribed within the nucleocapsid into progeny rcdna.

11 Hepatitis B Mature nucleocapsids are then either directed to the multivesicular body (MVB) pathway for envelopment with HBV envelope proteins or re-directed to the nucleus to establish a cccdna pool. HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBx, hepatitis B x protein; MVB, multivesicular body.

12 Serological biomarker Hepatitis B surface antigen (HBsAg) Antibodies to HBsAg (anti-hbs) Property of the biomarker Surface protein contained within the lipoprotein coat. Indicates acute hepatitis, chronic hepatitis or carrier state. Antibody to HBsAg, indicator of recovery/immunity to HBV infection Hepatitis B e antigen (HBeAg) Viral product secreted in blood, marker of infectivity, active replication (though absent in precore mutants) Antibodies to HBeAg (Anti-HBe) Hepatitis B core antigen (HBcAg) Anti-HBc immunoglobulin M (Anti- HBcIgM) Anti-HBc immunoglobulin G(Anti- HBcIgG) Hepatitis B virus DNA (HBV DNA) Antibody to HBeAg, denoting decreased infectivity Core antigen (viral capsid), intracellular and not detected in serum Antibody denoting recent HBV infection or exacerbation Contamination marker, positive after HBV contact Quantitative indicator of virus in blood

13 Acute vs delayed seroconversion A replicative stage of HBV infection is the time of maximal infectivity and liver injury; HBeAg is a qualitative marker and HBV DNA a quantitative marker of this replicative phase, during which all three forms of HBV circulate, including intact virions. Over time, the replicative phase of chronic HBV infection gives way to a relatively nonreplicative phase. This occurs at a rate of ~10% per year and is accompanied by seroconversion from HBeAg-positive to anti-hbe-positive. In most cases, this seroconversion coincides with a transient, acute hepatitis-like elevation in aminotransferase activity. In the nonreplicative phase of chronic infection, when HBV DNA is demonstrable in hepatocyte nuclei, it tends to be integrated into the host genome. Acute Hepatitis B Seroconversion

14 HBV molecular variants : mutation in the precore region leading to HBeAg- HBeAb+ HBV-DNA+ Two major categories of naturally occurring HBV variants One of these was identified initially in Mediterranean countries among patients with an unusual serologic-clinical profile. They have severe chronic HBV infection and detectable HBV DNA but with anti-hbe instead of HBeAg. These patients were found to be infected with an HBV mutant that contained an alteration in the precore region rendering the virus incapable of encoding HBeAg. The pre-c region, is the region of the C gene necessary for the expression of HBeAg. The most commonly encountered in such patients is a single base substitution, from G to A, which occurs in the second to last codon of the pre-c gene at nucleotide This substitution results in the replacement of the TGG tryptophan codon by a stop codon (TAG), which prevents the translation of HBeAg.

15 HBV molecular variants : mutation in the precore region leading to HBeAg- HBeAb+ HBV-DNA+ Characteristic of such HBeAg-negative chronic hepatitis B are lower levels of HBV DNA (usually 10 5 copies/ml) and one of several patterns of aminotransferase activity persistent elevations, periodic fluctuations above the normal range, and periodic fluctuations between the normal and elevated range.

16 HBV mutations in the precore region escape mutations HBsAg mutations that fails to evoke protective HBsAb The second important category of HBV mutants consists of escape mutants, in which a single amino acid substitution, from glycine to arginine, occurs at position 145 of the immunodominant a determinant common to all subtypes of HBsAg. This change in HBsAg leads to a critical conformational change that results in a loss of neutralizing activity by anti-hbs. Is been observed in two situations,: 1) active and passive immunization, in which humoral immunologic pressure may favor evolutionary change ("escape") in the virus in a small number of hepatitis B vaccine recipients who acquired HBV infection despite the prior appearance of neutralizing anti-hbs : 2) liver transplant recipients who underwent the procedure for hepatitis B and who were treated with a high-potency human monoclonal anti-hbs preparation.

17 Immune-tolerant phase: Characterized by high levels of serum HBV DNA, HB e Ag +, normal ALT levels, and absent liver necroinflammation. Disease progression is minimal in patients who remain in this phase Patients are highly contagious in this phase. Immune-reactive phase (HB e Ag-positive CHB): Patients enter this phase after a variable time, linked to the age when HBV infection occurred. The immune system becomes more active and the infected hepatocytes are attacked. Characterized by highly fluctuating, but progressively decreasing, HBV-DNA levels, elevated ALT, and hepatic necroinflammation (HB e Ag-positive CHB). A prolonged immune-active phase with multiple ALT flares may result in progressive liver fibrosis, leading to cirrhosis. Immune-control phase (and inactive carrier state): Transition into this phase as an outcome of the immune-active phase is marked by seroconversion from HB e Ag to anti-hbe positivity. Characterized by low (< 2000 IU/mL) or undetectable serum HBV DNA, normal ALT levels, and disappearance of liver

18 Reactivation phase (HB e Ag-negative CHB): Despite HBe seroconversion, reactivation of HBV replication may occur due to the selection of HB e Ag-defective HBV mutants. Characterized by positive anti-hbe antibody levels, fluctuating HBV DNA and ALT levels, and a high risk of progression to severe hepatic fibrosis (HB e Ag-negative CHB). Periodic ALT flares with intervening normalization may make it difficult to distinguish between HB e Ag-negative CHB and inactive disease, and thus continued follow-up is required before patients with normal ALT and low HBV DNA levels are designated as inactive carriers. Emerging evidence suggests that a low HBV DNA titer (< 2000 IU/mL) combined with a low hepatitis B surface antigen (HB s Ag) titer (< 1000 IU/mL) may help identify inactive carriers, particularly those with genotype D infection HB s Ag-negative phase: After HB s Ag loss, low-level HBV replication may persist, with detectable HBV DNA in the liver and rarely in the serum In patients with occult HBV infection, persistence of effective HBV immunological control has been demonstrated Significant immunosuppression may lead to HBV reactivation, with reappearance of HB s Ag, known as reverse seroconversion.

19 HBV mutations in the the reverse transcription polymerase are of relevance in the therapeutic strategy HBV variants Level of susceptibility Lamivudine Telbivudine Entecavir Adefovir Tenofovir Wild-tipe S S S S S M204V R S I I S M204I R R I I S L180M + M204V R R I I S A181A/T I S S R S N236T S S S R I L180M + M204V/I ± I196T ± V173L ± M250V L180M + M204V/I ± T184G ± S202I/G R R R S S R R R S S

20 HVD Hepatitis delta virus (HDV) was first discovered in 1977 by Mario Rizzetto in Turin, Italy Hepatitis D virus (Delta agent) is a defective (36 nm-43 nm) enveloped RNA virus, which requires co-infection with Hepatitis B virus (HBV) for its replication. Transmitted sexually or percutaneously through contact with infected blood or blood products, HDV is associated with the most severe forms of chronic and acute hepatitis in many Hepatitis B -HBsAg positive patients. Since the infection with HDV requires infection with HBV, the development of the disease depends on whether the two viruses infect simultaneously (coinfection) or whether the newly infected HDV patient is also a chronic HBV carrier (superinfection).

21 HDV The genome is a small, 1700-nucleotide, circular, single-strand RNA (minus strand) that is non-homologous with HBV DNA. Its nucleocapsid expresses delta antigen, which bears no antigenic homology with any of the HBV antigens, and contains the virus genome. The delta core is "encapsidated" by an outer envelope of HBsAg, indistinguishable from that of HBV except in its relative compositions of major, middle, and large HBsAg component proteins. HDV RNA requires host RNA polymerase II for its replication via RNA-directed RNA synthesis by transcription of genomic RNA to a complementary antigenomic (plus strand) RNA; the antigenomic RNA, in turn, serves as a template for subsequent genomic RNA

22 HVD HDV can be transmitted only in the existence of concomitant HBV infection as one of two patterns, simultaneous HBV/HDV infection (coinfection) or HDV infection of an individual already chronically infected with HBV (superinfection). The coinfection pattern ranges from mild to severe or fulminant hepatitis. Coinfection is usually self-limited, with 20 % of cases progressing to cirrhosis. However, coinfection can lead to more severe fulminant hepatitis compared to superinfection. Superinfection may present as exacerbation of disease in previously asymptomatic CHB patients, worsening of disease in CHB patients, or as acute hepatitis.

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25 Hepatitis C Hepatitis C virus, was labeled "non-a, non-b hepatitis," Is a linear, single-strand, positive-sense, 9600-nucleotide RNA virus, the genome of which is similar in organization to that of flaviviruses and pestiviruses; HCV is the only member of the genus Hepacivirus in the family Flaviviridae. The HCV genome contains a single large open reading frame (gene) that codes for a virus polyprotein of ~3000 amino acids, which is cleaved after translation to yield 10 viral proteins.

26 HCV: hepatocytes entry

27 Hepatitis C The 5' end of the genome consists of an untranslated region (containing an internal ribosomal entry site) adjacent to the genes for four structural proteins, the nucleocapsid core protein, C; two envelope glycoproteins, E1 and E2; and a membrane protein p7. The 3' end of the genome also includes an untranslated region and contains the genes for six nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B. The NS2 cysteine protease cleaves NS3 from NS2, and the NS3-4A serine protease cleaves all the downstream proteins from the polyprotein. Important NS proteins involved in virus replication include the NS3 helicase, NS3-NS4A serine protease, and the NS5B RNA-dependent RNA polymerase. Because HCV does not replicate via a DNA intermediate, it does not integrate into the host genome. Because HCV tends to circulate in relatively low titer, virions/ml, visualization of virus particles, estimated to be nm in diameter, remains difficult. Still, the replication rate of HCV is very high, virions per day; its half-life is 2.7 h.

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29 HCV protein and pharmacological targets

30 Hepatitis C: six genotypes At least six distinct genotypes, as well as >50 subtypes within genotypes, of HCV have been identified by nucleotide sequencing. Genotypes differ one from another in sequence homology by 30%. Because divergence of HCV isolates within a genotype or subtype, and within the same host, may vary insufficiently to define a distinct genotype, these intragenotypic differences are referred to as quasispecies and differ in sequence homology by only a few percent. The genotypic and quasispecies diversity of HCV, resulting from its high mutation rate, interferes with effective humoral immunity. Thus, neither heterologous nor homologous immunity appears to develop commonly after acute HCV infection.

31 HCV infection: genotypes Principal genotypes in Europe

32 Hepatitis C genotypes Genotypes 1 (a,b) and 4 are less responsive to IFN-based treatments Viral load al baseline genotypes are the best predictors for sustained response to IFN-based therapies Patients factors, such as IL-28 polymporphism help also to predict response to INF-based regimens

33 Acute Hepatitis C clinical course The most sensitive indicator of HCV infection is the presence of HCV RNA, which requires molecular amplification by PCR or transcription-mediated amplification (TMA).

34 Hepatitis C vs B: natural history

35 Hepatitis E Previously labeled epidemic or enterically transmitted non-a, non-b hepatitis, HEV is an enterically transmitted virus that occurs primarily in India, Asia, Africa, and Central America; in those geographic areas, HEV is the most common cause of acute hepatitis. This agent, with epidemiologic features resembling those of hepatitis A, is a 32- to 34-nm, nonenveloped, HAV-like virus with a nucleotide, single-strand, positive-sense RNA genome.

36 Hepatitis E HEV has three open reading frames (ORF) (genes), the largest of which, ORF1, encodes nonstructural proteins involved in virus replication. All HEV isolates appear to belong to a single serotype, despite genomic heterogeneity of up to 25% and the existence of five genotypes, only four of which have been detected in humans; genotypes 1 and 2 appear to be more virulent, while genotypes 3 and 4 are more attenuated and account for subclinical infections. Contributing to the perpetuation of this virus are animal reservoirs, most notably in swine. The virus has been detected in stool, bile, and liver and is excreted in the stool during the late incubation period; immune responses to viral antigens occur very early during the course of acute infection. Both IgM anti-hev and IgG anti-hev can be detected, but both fall rapidly after acute infection, reaching low levels within 9 12 months. Currently, serologic testing for HEV infection is not available routinely.

37 Hepatitis B and C: Pathogenesis Under ordinary circumstances, none of the hepatitis viruses is known to be directly cytopathic to hepatocytes. Evidence suggests that the clinical manifestations and outcomes after acute liver injury associated with viral hepatitis are determined by the immunologic responses of the host.

38 Mechanisms of liver damage Hep B

39 Clinical and Laboratory Features Acute hepatitis Symptoms Acute viral hepatitis occurs after an incubation period that varies according to the responsible agent. Generally, incubation periods for hepatitis A range from days (mean, 4 weeks), for hepatitis B and D from days (mean, 8 12 weeks), for hepatitis C from days (mean, 7 weeks), and for hepatitis E from days (mean, 5 6 weeks). The prodromal symptoms of acute viral hepatitis are systemic and quite variable. Constitutional symptoms of anorexia, nausea and vomiting, fatigue, malaise, arthralgias, myalgias, headache, photophobia, pharyngitis, cough, and coryza may precede the onset of jaundice by 1 2 weeks. The nausea, vomiting, and anorexia are frequently associated with alterations in olfaction and taste.

40 Clinical and Laboratory Features Acute hepatitis Symptoms A low-grade fever between 38 and 39 C ( F) is more often present in hepatitis A and E than in hepatitis B or C, except when hepatitis B is heralded by a serum sickness like syndrome; rarely, a fever of C may accompany the constitutional symptoms. Dark urine and clay-colored stools may be noticed by the patient from 1 5 days before the onset of clinical jaundice. With the onset of clinical jaundice, the constitutional prodromal symptoms usually diminish, but in some patients mild weight loss (2.5 5 kg) is common and may continue during the entire icteric phase. A substantial proportion of patients with viral hepatitis never become icteric.

41 Clinical and Laboratory Features Hepatomegaly and right upper quadrant pain and discomfort are present in 80-90% of patients. Splenomegaly and cervical adenopathy are present in 10 20% of patients with acute hepatitis Infrequently, patients present with a cholestatic picture, suggesting extrahepatic biliary obstruction. Sonography shows enlargement of liver and spleen and adenopathy. No further investigations are needed.

42 Hepatitis C extrahepatic manifestations

43 Clinical and Laboratory Features During the recovery phase, constitutional symptoms disappear, but usually some liver enlargement and abnormalities in liver biochemical tests are still evident. The duration of the posticteric phase is variable, ranging 2 12 weeks, and is usually more prolonged in acute hepatitis B and C. Complete clinical and biochemical recovery is to be expected 1 2 months after all cases of hepatitis A and E and 3 4 months after the onset of jaundice in threequarters of uncomplicated, self-limited cases of hepatitis B and C (among healthy adults, acute hepatitis B is self-limited in 95 99% while hepatitis C is self-limited in only ~15%).

44 Clinical and Laboratory Features Hepatitis B and D Infection with HDV can occur in the presence of acute or chronic HBV infection; the duration of HBV infection determines the duration of HDV infection. When acute HDV and HBV infection occur simultaneously, clinical and biochemical features may be indistinguishable from those of HBV infection alone, although occasionally they are more severe. As opposed to patients with acute HBV infection, patients with chronic HBV infection can support HDV replication indefinitely. This can happen when acute HDV infection occurs in the presence of a non resolving acute HBV infection. More commonly, acute HDV infection becomes chronic when it is superimposed on an underlying chronic HBV infection. In such cases, the HDV superinfection appears as a clinical exacerbation or an episode resembling acute viral hepatitis in someone already chronically infected with HBV. Superinfection with HDV in a patient with chronic hepatitis B often leads to clinical deterioration (see below).

45 Complication hepatitis B/D The most feared complication of viral hepatitis is fulminant hepatitis (massive hepatic necrosis); fortunately, this is a rare event. Fulminant hepatitis is primarily seen in hepatitis B and D, as well as hepatitis E, but rare fulminant cases of hepatitis A occur primarily in older adults and in persons with underlying chronic liver disease, including, according to some reports, chronic hepatitis B and C. Hepatitis B accounts for >50% of fulminant cases of viral hepatitis, a sizable proportion of which are associated with HDV infection and another proportion with underlying chronic hepatitis C.

46 Prognosis hepatitis A, B and D Virtually all previously healthy patients with hepatitis A recover completely from their illness with no clinical sequelae. Similarly, in acute hepatitis B, 95 99% of previously healthy adults have a favorable course and recover completely. Certain clinical and laboratory features, however, suggest a more complicated and protracted course. Patients of advanced age and with serious underlying medical disorders may have a prolonged course and are more likely to experience severe hepatitis. Initial presenting features such as ascites, peripheral edema, and symptoms of hepatic encephalopathy suggest a poorer prognosis. In addition, a prolonged PT, low serum albumin level, hypoglycemia, and very high serum bilirubin values suggest severe hepatocellular disease. Patients with these clinical and laboratory features deserve prompt hospital admission. The case-fatality rate in hepatitis A and B is very low (~0.1%) but is increased by advanced age and underlying debilitating disorders. Among patients ill enough to be hospitalized for acute hepatitis B, the fatality rate is 1%.

47 Prognosis hepatitis C and E Hepatitis C is less severe during the acute phase than hepatitis B and is more likely to be anicteric; fatalities are rare, but the precise case-fatality rate is not known. In outbreaks of waterborne hepatitis E in India and Asia, the case-fatality rate is 1 2% and up to 10 20% in pregnant women.

48 Treatment acute hepatitis: general (1) In cases of typical acute viral hepatitis, specific treatment generally is not necessary. Although hospitalization may be required for clinically severe illness, most patients do not require hospital care. Forced and prolonged bed rest is not essential for full recovery, but many patients will feel better with restricted physical activity. A high-calorie diet is desirable. Intravenous feeding is necessary in the acute stage if the patient has persistent vomiting and cannot maintain oral intake. Drugs capable of producing adverse reactions such as cholestasis and drugs metabolized by the liver should be avoided.

49 Treatment acute hepatitis: general (2) If severe pruritus is present, the use of the bile salt sequestering resin cholestyramine is helpful. Glucocorticoid therapy has no value in acute viral hepatitis and may be deleterious, even increasing the risk of chronicity (e.g., of acute hepatitis B). Physical isolation of patients with hepatitis to a single room and bathroom is rarely necessary except in the case of fecal incontinence for hepatitis A and Because most patients hospitalized with hepatitis A excrete little if any HAV, the likelihood of HAV transmission from these patients during their hospitalization is low. Therefore, burdensome enteric precautions are no longer recommended.

50 Treatment acute hepatitis B In hepatitis B, among previously healthy adults who present with clinically apparent acute hepatitis, recovery occurs in ~99%; therefore, antiviral therapy is not likely to improve the rate of recovery and is not required. In rare instances of severe acute hepatitis B, treatment with a nucleoside analogue, such as lamivudine, at the 100-mg/d oral dose used to treat chronic hepatitis B, has been attempted successfully.

51 Treatment acute hepatitis C In typical cases of acute hepatitis C, recovery is rare, progression to chronic hepatitis is the rule, and metaanalyses of small clinical trials suggest that antiviral therapy i.e. 24-week course (beginning within 2 3 months after onset) of the best regimen identified for the treatment of chronic hepatitis C, long-acting pegylated interferon plus the nucleoside analogue ribavirin or sofosbuvir.

52 Hepatitis A and B Profilaxis Currently, for hepatitis A and B, active immunization with vaccines is the preferable approach to prevention

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54 Chronic hepatitis Chronic hepatitis represents a series of liver disorders of varying causes and severity in which hepatic inflammation and necrosis continue for at least 6 months and characterized by increased levels of AST/ALT Milder forms are nonprogressive or only slowly progressive, while more severe forms may be associated with scarring and architectural reorganization, which, when advanced, lead ultimately to cirrhosis.

55 Chronic hepatitis Type of hepatitis Diagnostic test(s) Autoantibodies Therapy Chronic hepatitis B HBsAg, IgG anti-hbc, HBeAg, HBV DNA classification by cause Uncommon IFN-, PEG IFN-, lamivudine, adefovir, entecavir,tenofovir, telbivudine Chronic hepatitis C Anti-HCV, HCV RNA Anti-LKM1 a PEG IFN- plus ribavirin, telaprevir boceprevir Chronic hepatitis D Anti-HDV, HDV RNA, HBsAg, Anti-LKM3 IFN-, PEG IFN- b IgG anti-hbc Autoimmune hepatitis ANA c (homogeneous), anti- LKM1(±), Hyperglobulinemia ANA, anti-lkm1, anti-sla d Prednisone, azathioprine Drug-associated Uncommon Withdraw drug Cryptogenic All negative None Prednisone (?), azathioprine (?)

56 Chronic hepatitis Classification by Grade of inflammation Grade, a histologic assessment of necroinflammatory activity, is based on examination of the liver biopsy. Classification by Stage of fibrosis The stage of chronic hepatitis, which reflects the level of progression of the disease, is based on the degree of hepatic fibrosis. When fibrosis is so extensive that fibrous septa surround parenchymal nodules and alter the normal architecture of the liver lobule, the histologic lesion is defined as cirrhosis. Staging is based on the degree of fibrosis as categorized on a numerical scale from 0 6 (HAI) or 0 4 (METAVIR)

57 METAVIR staging Grade: degree of inflammation, piecemeal or bridging necrosis Grade 0: no / minimal inflammation Grade 1: portal inflammation or lobular inflammation without necrosis Grade 2: mild periportal inflammation and piecemeal necrosis or focal hepatocellular necrosis Grade 3: moderate periportal inflammation and piecemeal necrosis or severe focal cell damage Grade 4: severe periportal inflammation and piecemeal necrosis or bridging necrosis Stage: degree of fibrosis Stage 0: no fibrosis Stage 1: enlarged fibrotic portal tracts Stage 2: periportal fibrosis or portal to portal septa, without architectural distortion Stage 3: bridging fibrosis with architectural distortion, no obvious cirrhosis Stage 4: cirrhosis (probable or definite)

58 Fibrosis: staging by metavir score Progression of fibrosis from periportal fibrosis to cirrhosis according to the Metavir scoring system shown through photomicrographs (original magnification, 10; Hematoxylin and Eosin stains) of histologic sections from liver biopsy specimens. (a) No fibrosis (stage F0). (b) Portal and periportal fibrosis only (stage F1). (c) Periportal fibrosis with few septa (stage F2). (d) Septal fibrosis and bridging without cirrhosis (stage F3). (e) Cirrhosis (stage F4) which appears as nodules of liver parenchyma separated by thick fibrous bands.

59 Fibrosis staging by transiet elastography Biopsy Recomended in HBV DNA+ HBeAg- HBeAb+

60 Chronic Viral Hepatitis The entire clinicopathologic spectrum of chronic hepatitis occurs in patients with chronic viral hepatitis B and C as well as in patients with chronic hepatitis D superimposed on chronic hepatitis B.

61 Hepatitis C vs B: natural history

62 Chronic Viral Hepatitis Clinical findings The spectrum of clinical features of chronic hepatitis B is broad, ranging from asymptomatic infection to debilitating disease or even end-stage, fatal hepatic failure Fatigue is a common symptom, and persistent or intermittent jaundice is a common feature in severe or advanced cases. Intermittent deepening of jaundice and recurrence of malaise and anorexia, as well as worsening fatigue, are reminiscent of acute hepatitis; such exacerbations may occur spontaneously, often coinciding with evidence of virologic reactivation; may lead to progressive liver injury; and, when superimposed on well-established cirrhosis, may cause hepatic decompensation. Complications of cirrhosis occur in end-stage chronic hepatitis

63 Chronic Viral Hepatitis Laboratory features of chronic hepatitis do not distinguish adequately between histologically mild and severe hepatitis. AST/ALT tend to be modest for chronic hepatitis B (<2) but may fluctuate in the range of units for hepatitis C (<4) (flare might have value up 1000). ALT tends to be more elevated than AST Levels of alkaline phosphatase activity tend to be normal or only marginally elevated. In severe cases, moderate elevations in serum bilirubin (3 10 mg/dl)] occur. Hypoalbuminemia and prolongation of the prothrombin time occur in severe or end-stage cases. Hyperglobulinemia and detectable circulating autoantibodies are distinctly absent in chronic hepatitis B and C (in contrast to autoimmune hepatitis). Viral markers of chronic HBV infection and C.

64 Chronic Viral Hepatitis B Age of infection The likelihood of chronicity after acute hepatitis B varies as a function of age. Infection at birth is associated with clinically silent acute infection but a 90% chance of chronic infection, while infection in young adulthood in immunocompetent persons is typically associated with clinically apparent acute hepatitis but a risk of chronicity of only approximately 1%. The 5-year survival rate is: - 97% occurs for patients with mild chronic hepatitis, - 86% for patients with moderate to severe chronic hepatitis, - 55% for patients with chronic hepatitis and postnecrotic cirrhosis.

65 Chronic Viral Hepatitis B HBeAg+/- HBeAb+ HBV DNA+ Chronic HBV infection can occur in the presence or absence of serum HBeAg and generally for both HBeAg-reactive and HBeAg-negative chronic hepatitis B the level of HBV DNA correlates with the level of liver injury and risk of progression.

66 Chronic HBV infection Inactive carrier state

67 The natural history of chronic HBV infection Vassilopoulos, D. & Calabrese L. H. (2012) Management of rheumatic disease with comorbid HBV or HCV infection Nat. Rev. Rheumatol. doi: /nrrheum

68 HBV infection: HBsAg+ vs HBsAg- Who should be treated

69 Chronic Viral Hepatitis B HBeAg+/- HBeAb+ HBV DNA+ HBe-negative chronic hepatitis B, i.e., chronic HBV infection with active virus replication, readily detectable HBV DNA but without HBeAg (anti-hbe-reactive), is more common than HBeAg-reactive chronic hepatitis B in Mediterranean and European countries and in Asia (and, correspondingly, in HBV genotypes other than A). Compared to patients with HBeAg-reactive chronic hepatitis B, patients with HBeAg-negative chronic hepatitis B have levels of HBV DNA that are several orders of magnitude lower (no more than virions/ml) than those observed in the HBeAg-reactive subset. Most such cases represent precore or core-promoter mutations acquired late in the natural history of the disease (mostly early-life onset; age range years, older than that for HBeAg-reactive chronic hepatitis B);

70 Chronic Viral Hepatitis B (3) Important points: the level of HBV replication is the most important risk factor for the ultimate development of cirrhosis and HCC in both HBeAg-reactive and HBeAg-negative patients. Although levels of HBV DNA are lower and more readily suppressed to undetectable levels in HBeAgnegative (compared to HBeAg-reactive) chronic hepatitis B, achieving sustained responses that permit discontinuation of antiviral therapy is less likely in HBeAg-negative patients.

71 Hepatitis B treatment: polymerase inhibitors nucleoside and nucleotide analogues

72 Hepatitis B Therapy

73 HBV Antiviral drug-resistance Antiviral drug-resistance is defined as the reduced susceptibility of a virus to the inhibitory effect of a drug due to adaptive mutations selected under the selective pressure of antiviral therapy. In CHB patients treated with NAs, antiviral drug-resistance is due to mutations within the Polymerase gene of HBV, thus resulting in amino acid substitutions within the polymerase/reverse transcriptase, target of all NAs. These amino acid changes reduce the affinity of the enzyme for the antiviral drug, in favor of natural substrates. Resistance-associated mutations selected by a particular NA confer at least some degree of cross-resistance to other members of its structural group but may also diminish the sensitivity to NAs from a different chemical group, thus limiting future treatment options

74 Genotypic resistance to approved HBV polymerase nucleos(t)ide analogues Kwon, H. & Lok, A. S. (2011) Hepatitis B therapy Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro

75 Response rates (%) to approved therapies for HBeAgpositive and HBeAg-negative chronic hepatitis B Kwon, H. & Lok, A. S. (2011) Hepatitis B therapy Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro

76 Salvage therapies for antiviral drug-resistant HBV Kwon, H. & Lok, A. S. (2011) Hepatitis B therapy Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro

77 Chronic Hepatitis C Regardless of the epidemiologic mode of acquisition of hepatitis C virus (HCV) infection, chronic hepatitis follows acute hepatitis C in 50 70% of cases; Furthermore, in patients with chronic transfusion-associated hepatitis followed for years, progression to cirrhosis occurs in about 20%. Most cases of hepatitis C are identified initially in asymptomatic patients who have no history of acute hepatitis C, e.g., those discovered while attempting to donate blood, while undergoing lab testing as part of an application for life insurance, or as a result of routine laboratory tests. The source of HCV infection in many of these cases is not defined, although a long-forgotten percutaneous exposure in the remote past can be elicited in a substantial proportion and probably accounts for most infections; most of these infections were acquired in the 1960s and 1970s, coming to clinical attention decades later.

78 Chronic Hepatitis C Laboratory features of chronic hepatitis C are similar to those in patients with chronic hepatitis B, but AST/ALT levels tend to fluctuate more (the characteristic episodic pattern of aminotransferase activity) and to be lower, especially in patients with long-standing disease. An interesting and occasionally confusing finding in patients with chronic hepatitis C is the presence of autoantibodies. Rarely, patients with autoimmune hepatitis (see below) and hyperglobulinemia have false-positive immunoassays for anti-hcv. On the other hand, some patients with serologically confirmable chronic hepatitis C have circulating anti-lkm. These antibodies are anti-lkm1, as seen in patients with autoimmune hepatitis type 2 (see below), and are directed against a 33-amino-acid sequence of cytochrome P450 IID6. The occurrence of anti-lkm1 in some patients with chronic hepatitis C may result from the partial sequence homology between the epitope recognized by anti-lkm1 and two segments of the HCV polyprotein. In addition, the presence of this autoantibody in some patients with chronic hepatitis C suggests that autoimmunity may be playing a role in the pathogenesis of chronic hepatitis C.

79 Generally, fatigue is the most common symptom; jaundice is rare. Immune complex mediated extrahepatic complications of chronic hepatitis C are less common than in chronic hepatitis B (despite the fact that assays for immune complexes are often positive in patients with chronic hepatitis C), with the exception of essential mixed cryoglobulinemia. Chronic Hepatitis C In addition, chronic hepatitis C has been associated with extrahepatic complications unrelated to immunecomplex injury. These include Sjögren's syndrome, lichen planus, and porphyria cutanea tarda.

80 Chronic Hepatitis C: natural hystory HCV infection is so prevalent, and because a proportion of patients progress inexorably to end-stage liver disease, hepatitis C is the most frequent indication for liver transplantation Despite this substantial rate of progression the long-term prognosis for chronic hepatitis C in a majority of patients is relatively benign. Mortality over years among patients with transfusion-associated chronic hepatitis C has been shown not to differ from mortality in a matched population of transfused patients in whom hepatitis C did not develop. Hepatic decompensation may occur in ~15% of patients over the course of a decade, The majority (almost 60%) of patients remain asymptomatic and well compensated, with no clinical sequelae of chronic liver disease.

81 Chronic Hepatitis C: risk factors Progression of liver disease in patients with chronic hepatitis C has been reported to be more likely in patients with: older age, longer duration of infection, advanced histologic stage and grade, genotype 1, complex quasispecies diversity, increased hepatic iron, concomitant other liver disorders (alcoholic liver disease, chronic hepatitis b, hemochromatosis, 1 -antitrypsin deficiency, and steatohepatitis), hiv infection, obesity. No other epidemiologic or clinical features of chronic hepatitis C are predictive of eventual outcome..

82 Fibrosis staging by transiet elastography The best prognostic indicator in chronic hepatitis C is hepatic fibrosis

83 HCV infection: genotypes Principal genotypes in Europe

84 HCV proteins and pharmacological targets

85 Chronic Hepatitis C: treatment Approved drugs in Europe Table 2 Indications for treatment of chronic hepatitis C in 2015: Who should be treated and when? EASL Guidelines 2015

86 Chronic Hepatitis C: treatment Treatment recommendations for HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C without cirrhosis, including treatment-naïve patients and patients who failed on a treatment based on PegIFN-α and ribavirin (RBV). Table 2 Indications for treatment of chronic hepatitis C in 2015: Who should be treated and when? EASL Guidelines 2015

87 Chronic Hepatitis C: treatment Treatment recommendations for HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C with compensated (Child- Pugh A) cirrhosis, including treatment-naïve patients and patients who failed on a treatment based on PegIFN-α and ribavirin (RBV). Table 2 Indications for treatment of chronic hepatitis C in 2015: Who should be treated and when? EASL Guidelines 2015

88 Chronic Hepatitis C: retreatment Table 2 Indications for treatment of chronic hepatitis C in 2015: Who should be treated and when? EASL Guidelines 2015

89

90 Chronic Hepatitis C: treatment Features Associated with Reduced Responsiveness Genotype 1 High-level HCV RNA (>2 million copies/ml or >800,000 IU/mL) Advanced fibrosis (bridging fibrosis, cirrhosis) Long-duration disease Age >40 High HCV quasispecies diversity Immunosuppession African American Obesity Hepatic steatosis Reduced compliance

91 Genotype 1& 2 cost of treatment

92 Chronic Hepatitis C: treatment Indications for treatment of chronic hepatitis C in 2015: Who should be treated and when? Table 2 Indications for treatment of chronic hepatitis C in 2015: Who should be treated and when? EASL Guidelines 2015