Historia Natural de la Hepatitis C

Presentación del tema: "Historia Natural de la Hepatitis C"— Transcripción de la presentación:

1 Historia Natural de la Hepatitis C

2 Inconvenientes para establecer la historia natural de la infección por HCV
La infección aguda por el HCV es frecuentemente no reconocida debido a la ausencia de síntomas en la mayoría de los casos por lo cual la historia natural es difícil de establecer. Dificultad en la actualidad para realizar estudios sobre la historia natural en pacientes no tratados. El estudio ideal debería ser prospectivo y con un tiempo de seguimiento prolongado (> 20 años), y a partir de una fuente de infección perfectamente identificada. The silent onset of the acute phase of hepatitis C infection coupled with the frequent lack of symptoms during the early stages of chronic infection has meant that the natural history of hepatitis C virus infection has been very difficult to assess. un estudio ideal que debería ser prospectivo, completo y con tiempo de estudio muy prolongado, al menos superior a 20 años, y partir de una fuente de infección perfectamente identificada en el tiempo.

3 Historia Natural de la infección HCV
Exposición (Fase Aguda) 15% (15) 85% (85) HIV y Alcohol Resuelta Crónica 80% (68) 20% (17) Estable Cirrosis 75% (13) 25% (4) Natural history of HCV Infection The natural history of hepatitis C evolves over the course of decades and can be considered to have three distinct stages. The first is the stage of resolution of recovery. This is seen in approximately 15% of patient with viremia and acute hepatitis followed by resolution of viremia with the persistence of antibody. The second stage is the stable chronic course in which patients have viremia and acute hepatitis with subsequent decrease in ALT. The patient may experience periodic elevations of liver enzymes and persistent viremia for several years. This is the most common stage and is seen in approximately 80% of the patients. During this stage it is believed that patients may experience the emergence of quasispecies and relative ineffectiveness of neutralizing antibodies. The last stage is that of severe progression of the disease and occurs in approximately 20% of the patients. The patient will experience more persistent elevation of liver enzymes, persistent viremia, and a more rapid progression to cirrhosis and possibly even hepatocellular carcinoma. HIV and alcohol should be considered as important cofactors in hepatitis C and the progression to cirrhosis. There is evidence to suggest a greater than 15 fold increase in the incidence of cirrhosis in alcoholic patients and a >5 fold increase with HIV. References: 1. Alter MJ. Epidemiology of Hepatitis C in the West. Semin Liver Dis. 1995; 15: 5-14 2. Management of Hepatitis C. NIH Consensus Statement. 1997; March 24-26: 15(3). Progresión Lenta HCC Trasplante Muerte Alter, MJ. Epidemiology of Hepatitis C in the West. Semin Liver Dis ; 15: Management of Hepatitis C. NIH Consensus Statement ; March 24-26: 15(3).

4 Historia Natural de la infección HCV
Factores asociados a la infección HCV (Alcohol, HBV, HIV, genética, etc) Exposición (Fase Aguda) Crónica Natural history of HCV Infection The natural history of hepatitis C evolves over the course of decades and can be considered to have three distinct stages. The first is the stage of resolution of recovery. This is seen in approximately 15% of patient with viremia and acute hepatitis followed by resolution of viremia with the persistence of antibody. The second stage is the stable chronic course in which patients have viremia and acute hepatitis with subsequent decrease in ALT. The patient may experience periodic elevations of liver enzymes and persistent viremia for several years. This is the most common stage and is seen in approximately 80% of the patients. During this stage it is believed that patients may experience the emergence of quasispecies and relative ineffectiveness of neutralizing antibodies. The last stage is that of severe progression of the disease and occurs in approximately 20% of the patients. The patient will experience more persistent elevation of liver enzymes, persistent viremia, and a more rapid progression to cirrhosis and possibly even hepatocellular carcinoma. HIV and alcohol should be considered as important cofactors in hepatitis C and the progression to cirrhosis. There is evidence to suggest a greater than 15 fold increase in the incidence of cirrhosis in alcoholic patients and a >5 fold increase with HIV. References: 1. Alter MJ. Epidemiology of Hepatitis C in the West. Semin Liver Dis. 1995; 15: 5-14 2. Management of Hepatitis C. NIH Consensus Statement. 1997; March 24-26: 15(3). Cirrosis HCC Trasplante 4

5 Incidencia acumulada de HCC (%) Años después de la inclusión
882 pacientes con F3 / F4 NR (6 meses IFN) NR = No respondedores RP = Respondedores parcial (ALT < x 2.5 n.v.) RVS = Respuesta virológica sostenida 15 No tratados 12 9 RP (12 meses IFN) 6 RP (24 meses IFN) 3 RVS 1 2 3 4 5 Años después de la inclusión Alberti, 2000

6 Características de la infección HCV
Periodo de incubación Infección aguda (ictericia) Frecuencia de casos fatales Infección crónica Hepatitis crónica Cirrosis Muerte por enfermedad hepática Promedio 6 – 7 semanas (rango 2 – 26) Leve (< 20%) Bajo 75 – 85% 70% 10 – 20% 1 – 5%

7 El HCV es la Indicación más frecuente de trasplante por Cirrosis
Coincidiendo con todos los reportes locales e internacionales el HCV es la etiología más prevalente y lamentablemente una que tiene pocas chances de ser tratada en el pre Tx. En órden de frecuencia le siguen la HAI, el OH, la hemocromatosis, la CBP y lamentablemente dentro de las menos prevalentes está la HBV (en un 8%) ya que tiene muy buenos resultados con el tratamiento médico. Hospital Universitario Austral: período 7

8 Prevalencia en Bancos de Sangre Comunicaciones al CNRL-ANLIS “Dr. C. G
Prevalencia en Bancos de Sangre Comunicaciones al CNRL-ANLIS “Dr.C.G.Malbràn” Año Donantes controlados anti-HCV (+) (%) Rango Menor Mayor 2000 444182 0.78 Chaco Formosa 2001 430890 La Pampa T. del Fuego 2002 363658 0.74 San Juan 2003 380793 Tucuman 2004 147475 0.64 2005 109432 0.79 Entre Rios Jujuy 2006 422916 0.69 0,78 0,17-1,83 Consenso de HCV AAEEH, Descalzi V. et al

9 Estudios en “Población General” en Áreas de Alta Prevalencia
Provincia Ciudad Prevalencia anti-HCV(+) Prevalencia en Población años Genotipo n % Bs. As (1999) O Brien 102/1632 5.6 23.4% 1b (100%) Santa Fe (2005) Rufino 10/452 2.2 9.2% 1b (67%) Wheelwright 89/1814 4.9 17% 1b (89%) Cordoba (2005) Cruz del Eje 108/1840 5.8 32% 2(90%) Capital 35/1131 3.09 NA 2 (64%) Villa Maria 47/420 11.2 Rio Cuarto 14/361 4 Las características de la infección por HCV en O’Brien, Rufino,Wheelwright y Cruz del Eje son idénticas al patrón descripto en Italia y Japón con una prevalencia de anti-HCV muy baja en menores de 40 años y un pico máximo entre 9% y 23% en individuos entre los 60 y 70 años de edad. Es decir que el mayor riesgo para la transmisión del HCV probablemente haya ocurrido hace más de 30 años a través de prácticas inyectables no seguras Rey J, Mengarelli S, Bessone F, Ramadán A, y Descalzi V. Consenso AAEH 2007 9 9

10 Estudios por “Consulta Espontánea” en Población General en Argentina
Fuente Fecha N Prevalencia FAPLHE 1996 7109 2.8% Cap. Fed 666 5.6% CTSP 5460 3.4% Salta 2000 722 3.3% Derqui, Bs As* 2003 1472 0.87% Como podemos ver en esta tabla encuestas epidemiologicas por demanda espontànea estimuladas por difusión publica han permitido conocer algunos datos de prevalencia en algún sector de la población gral...FAPLHE….SALTA El ultimo de ellos, relizado en la población de Derqui pcia de BA referenciado en el consenso de coinfección 2005, sin embargo mostro una prevalencia de 0.87% porcentaje similar al reportado al CNRL por los bancos de sangre de lapcia de BA en el mismo año de la relizacion del estudio (2003) Rey J, Mengarelli S, Bessone F, Ramadán A, y Descalzi V. Consenso AAEEH, 2007 10

11 Porcentaje de evolución a la cirrosis según la población analizada
Evaluación de 57 estudios Estudio % casos con cirrosis a los 20 años de infección Unidades de hepatología 21,5% (7,5-25,6) Postransfusional 23,8% (11,0-36,6) Donantes de sangre 4,1% (0,0-8,3) HCV adquirida en la comunidad 6,4% (3,5-9,4) HEPATOLOGY 2000;32: Estimates based upon referred patients from liver clinics had a 20-year rate of cirrhosis of 22% (95% confidence interval [CI], 18%–26%), whereas studies in blood donors and community cohorts were lower, with cirrhosis estimated to occur in 4% (95% CI, 1%–7%) and 7% (95% CI, 4%–10%), respectively, after 20 years of disease [78]. Community cohorts probably provide the most accurate estimates of HCV disease progression in the general population of HCV-infected individuals. En 2001 se publicó un metaanálisis sobre 57 estudios que evaluaban la historia natural de la hepatitis C. Incluyó 5 cohortes de pacientes con hepatitis postransfusional, 10 de donantes de sangre y 4 de infecciones adquiridas en la comunidad. La progresión estimada a cirrosis después de 20 años en estos grupos de pacientes fue del 24, el 4 y el 7%, respectivamente, y del 22% en el resto de los estudios. Estos índices fueron mayores en los estudios transversales, probablemente por la existencia de sesgos en la selección de los pacientes. Freeman A et al. Hepatology 2001;34:

12 Historia natural de una población dadora de sangre
45 40 35 30 25 20 15 10 5 Tiempo desde la infección (años) 1.0 0.8 0.6 0.4 0.2 0.0 Probabilidad de sobrevida Sobrevida general Sobrevida libre de tx n = 485 ♂ = 439 Edad a la donación = 22.6 ± 5.6 años Gt 1 = 477 Seguimiento = 31.2 ± 3.96 años HCC = 21 Muerte relacionada a enfermedad hepática = 25 Tx = 36 In conclusion, our study supports earlier data that although there is no significant mortality in the first 20 years after infection, later follow-up shows that both morbidity and mortality increase substantially. Of the 485 plasma donors studied, 439 were male, 46 female. The age at plasma donation was 22.6 ± 5.6 years, the follow up was 31.2 ± 3.96 years. Of the 485 donors, six cleared the virus spontaneously (all were anti-HCV positive), 2 were infected with HCV genotype 2, the remaining 477 with genotype 1. Ferenci et al J. Hepatol 2007

13 Historia Natural de la infección HCV
Factores asociados a la infección HCV (Alcohol, HBV, HIV, etc) Exposición (Fase Aguda) Crónica Natural history of HCV Infection Aunque la infeccion aguda ha disminuido en los ultimos años pueden observarse nuevos casos y siempre debe estar presente en el diagnostico diferencial. The majority of persons who have acute HCV infection develop chronic infection. Es un punto relevante en la HN de la enfermedad. This is seen in approximately 15% of patient with viremia and acute hepatitis followed by resolution of viremia with the persistence of antibody. The second stage is the stable chronic course in which patients have viremia and acute hepatitis with subsequent decrease in ALT. Cirrosis HCC Trasplante 13

14 Caso Clínico 35 años, ♂ UDI Presenta astenia en Febrero 2008
Anictérico Sin antecedentes de ol, ni drogas ALT 1570 (VN 31 UI/L) Anti HCV (-) HBsAg (-) antiHBc IgM (-) Anti HAV IgM (-)

15 Caso Clínico Abril 2008, Anti HCV + Asintomático ALT 850 (VN 31 UI/L)
Proteinograma normal Autoanticuerpos negativos PCR HCV RNA (+)

16 Características Clínicas HCV aguda
Periodo de incubación semanas La mayoría de los pacientes la infección aguda cursa de manera asintomática (50 – 90%). Los síntomas se presentan en 20 al 30%: Ictericia = en 10-20% “Síndrome gripal”, astenia Anorexia Dolor abdominal Artralgias Pasaje a la cronicidad  50 – 90%. HCV RNA detectable at 7-21 days after exposure Antibodies at days, mean 50 days LFTs usu rise after 4 weeks Because acute hepatitis C is often asymptomatic, detection and diagnosis are usually difficult.

17 Resolución de una hepatitis aguda HCV
Sintoms +/- anti-HCV HCV RNA Título ALT Early identification of acute hepatitis C is important, but may be difficult as the disease may be relatively silent. Patients with acute hepatitis C should be considered for antiviral therapy in order to prevent progression to chronic hepatitis C. High SVR rates (up to 90% or even higher) have been reported with pegylated IFN-a monotherapy, essentially in a series of symptomatic patients, regardless of the HCV genotype. Antibody development occurs at 9 weeks after exposure on average, but cases are described in which antibody development occurred more than 12 months after the first detection of viremia [61]. Normal 1 2 3 4 5 6 1 2 3 4 Meses Años Tiempo después de la exposición

18 Tratamiento de la HCV aguda según síntomas y genotipo
Gt 1, 4 Asintomáticos Gt 1, 4 Sintomáticos Gt 2, 3 Sintoms +/- Título HCV RNA anti-HCV ALT ALT It has also been suggested to follow these patients with HCV RNA quantification every 4 weeks and to treat only those still positive at 12 weeks after initial presentation [157]. Some clinicians may prefer to start treatment earlier if the HCV RNA is high and not declining. The usual treatment of acute hepatitis C should be based on pegylated IFN-a monotherapy, i.e. either pegylated IFN-a2a, 180 lg/week, or pegylated IFN-a2b, 1.5 lg/kg/week, for 24 weeks. There is currently no indication for administering IFN-a as post-exposure prophylaxis in the absence of documented HCV transmission. Normal 1 2 4 6 8 Meses Tiempo después de la exposición

19 Marcadores para el HCV + - Anti-HCV HCV RNA Interpretación
Infección aguda o crónica dependiendo del contexto clínico - Resolución de la infección Infección aguda durante el periodo de baja viremia Infección aguda Infección crónica en estado de inmunosupresión Falso positivo Ausencia de infección Diagnosis of HCV infection is based on detection of anti-HCV antibodies by enzyme immunoassay and detection of HCV RNA by a sensitive molecular method (lower limit of detection <50 IU/ml), ideally a real-time PCR assay. The diagnosis of chronic hepatitis C is based on the detection of HCV infection (positive anti-HCV antibodies and HCV RNA) in a patient with signs of chronic hepatitis. Rarely, in profoundly immunosuppressed patients, anti-HCV antibodies are not detected and HCV RNA is present alone.

20 HCV aguda. Resolución espontánea según IL28B
Polimorfismo IL28B muestra una fuerte relación con la resolución espontánea n =190 mujeres % METHODS: We analyzed the SNP rs in 190 women from the German anti-D cohort (infected with HCV genotype 1b via contaminated rhesus prophylaxis) Inmunoglobulina anti-D and its association with spontaneous clearance. Clinical data were available in 136 women with acute infection who were also evaluated for IL28B genotype. El gen IL28B codifica la interleucina 28, también conocido como interferón (IFN) lambda tipo III (IFN-lambda-3). La IL28B es un mensajero químico de las reacciones inmunológicas que presenta actividad antiviral (citocina relacionada al IFN-alfa). En 136 casos se pudo disponer de los datos clínicos y del genotipo de la IL28B. El aclaramiento viral espontáneo fue más común en las pacientes portadoras del genotipo CC (64%), frente al CT (24%) o el TT (6%). Además, la ictericia fue más frecuente en el primer grupo. En estos casos no hubo relación entre ictericia y curación, pero entre las pacientes CT y TT la ictericia durante el episodio agudo se asoció a mayores probabilidades de curación espontánea. TILLMANN H et al. GASTROENTEROLOGY 2010;139:1586–1592

21 Cronicidad seguida de la infección aguda
20 40 60 80 100 3 24 28 49 Edades medias de cuatro cohortes (años) Proporción con infección crónica (%) Se relaciona con la edad These data suggested that young age at the time of infection is an important determinant of the likelihood of spontaneous recovery. Chronicity Following Acute Infection May Relate to Age Early studies had estimated that 85% of acute infections became chronic. These were mostly studies of older patients. Subsequent studies of cohorts of patients infected at younger ages point strongly to the conclusion that younger age at infection increases the likelihood of spontaneous resolution. Vogt M et al. New Engl J Med 1999;341:866 Wiese M et al. Hepatology 2000;32:91 Kenny-Walsh E et al. New Engl J Med 1999;340:1228 Seeff LB et al. New Engl J Med 1992;327:1906 Vogt, 1999; Wiese, 2000; Kenny-Walsh, 1999; Seeff LB, 1992

22 HCV aguda. Historia Natural
Alta probabilidad de curación espontanea: Edad < 40 años Sexo femenino Ictericia Genotipo C/C IL28B Riesgo de progresión a la cronicidad: Sexo masculino Co-infección HIV o HBV Consumo de alcohol

23 Historia Natural de la infección HCV
Factores asociados a la infección HCV (Alcohol, HBV, HIV, etc) Exposición (Fase Aguda) Crónica Natural history of HCV Infection Infected persons whose acute HCV infection does not resolve are at risk for progressive liver disease, characterized by continuing hepatocellular inflammation and an increase in fibrosis from mild to advanced (bridging), followed by cirrhosis, first compensated then decompensated, and, finally, HCC. These developments occur over periods of two to four decades, however, so that investigators have used differing strategies to evaluate the frequency and rate of progression of the chronic liver disease (31) (Fig. 1). Cirrosis HCC Trasplante 23

24 Recientemente identificados
Factores que contribuyen con la progresión de la fibrosis en HCV crónica Factores establecidos Recientemente identificados Duración de la infección Edad al adquirir la infección Sexo masculino Magnitud de la fibrosis al diagnóstico Co-infección HIV o HBV Consumo de alcohol (> 20 – 50 gr/día) Edad del paciente a la biopsia Infección con el genotipo 3 Presencia de resistencia insulínica Polimorfismo IL28 HLA DRB1*1201-3 Etnicidad Latina Esteatosis Uso de cannabis Aquí podemos observar factores que son modificables y otros que no. JACOBSON I et al CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010.

25 Hígado ligeramente aumentado de tamaño e hiperecogénico
EC, sexo masculino, 66 años Motivo de consulta Febrero (2011) Hipertransaminasemia diagnosticada hace 8 meses. Antecedentes Dislipidemia: Rosuvastatina 20 mg/día Sedentario Ingesta de alcohol 40 gr/día Sin historia de transfusiones, cirugías o uso de drogas ilícitas. Asintomático. Ecografía (Dic 10) Hígado ligeramente aumentado de tamaño e hiperecogénico

26 EC, sexo masculino, 66 años Examen físico
Peso: 87 Kg - Talla: 178 cm - IMC: 27,5 Hígado: 2 cm RC, firme, indoloro Bazo: no palpable Sin estigmas de hepatopatía crónica

27 Laboratorio Hto. (%) / Hb (g/dl) 42 /13,9 GB (cel/ml) 4.700
Plaquetas (cel/ml) Urea (mg/dl) 31 Glucemia (mg/dl) 84 Colesterol 128 Albúmina (g/dl) 3,8 BT/BD (mg/dl) 1,1/0,4 AST (UI/l) 2,7 xVN ALT (UI/l) 1,9 xVN FAL (UI/l) 1,1 xVN GGT (UI/l) 2 xVN Concentración de protrombina (%) 75 CPK(UI/l) 3,7 xVN Alfafetoproteína 13

28 Laboratorio (Abril 2011) Hto. (%) / Hb (g/dl) 41 /12,9 GB (cel/ml)
5.600 Plaquetas (cel/ml) Urea (mg/dl) 27 Glucemia (mg/dl) 92 Colesterol 132 BT/BD (mg/dl) 0,9/0,3 AST (UI/l) 1.9 xVN ALT (UI/l) 2 xVN FAL (UI/l) 1,3 xVN GGT (UI/l) 1,1 xVN Concentración de protrombina (%) 79 Alfafetoproteína 9

29 Laboratorio (Abril 2011)  globulina Ferritina (xVN) 1,1
Saturación Transferrina 18 Albúmina (g/dl) 3.6  globulina 1,61 Anti HAV IgG Pos HBsAg Neg Anti-HBc Anti HCV FAN Pos (1:80) ASMA (-) Atc antitransglutaminasa (-)

30 Endoscopía digestiva

31 Ecografía abdominal Hígado: aumento de volumen y ecogenicidad en forma difusa. Superficie ligeramente irregular. Lesión nodular de 3 cm en LI.

32 TAC contrastada de abdomen
Hígado ligeramente aumentado de tamaño y de superficie irregular y esplenomegalia leve. Se observó una intensa captación del contraste por la lesión (4cm) en fase arterial, seguido de un lavado rápido en fase venosa portal (“wash out”). hígado de tamaño normal y superficie irregular, esplenomegalia moderada

33 Diagnostico temprano a través del “screening”
Diagnostico de cirrosis El paciente tiene posibilidades de ser tratado si el diagnóstico de HCC es establecido ? Vigilancia: ECO / 6 meses Criterios diagnósticos de cirrosis Child-Pugh C Evaluación para Tx Enfermedades asociadas Aspectos para considerar

34 Efecto de la edad en el momento de la infección sobre la progresión a la cirrosis
˂ 20 años años ˃ 30 años Porcentaje de cirrosis The factors most consistently associated with development of chronicity are age at the time of infection and immune status at the time of exposure. Both age and age at the time of infection are associated with risk of cirrhosis development [100–102]. Años luego de la exposición al HCV Hla-Hla Thein et al. HEPATOLOGY 2008;48:

35 Historia Natural HCV post transfusional
Intervalos estimados infección-enfermedad Edad de la transfusión=35 años (1 – 76) Años Tong et al NEJM 1995

36 El sexo masculino tiene mayor probabilidad de desarrollar cirrosis
1.00 Hombres 0.75 p = 0.05 Probabilidad 0.50 Mujeres Male gender is consistently associated with higher risk of fibrosis progression (w 2.5-fold) [101] and higher rates of cirrhosis and HCC than seen in females. The effect is independent of alcohol consumption, higher body mass index, and iron overload. 0.25 0.00 10 20 30 40 Duración de la infección an años Poynard T et al., J. Hepatol. 2001;34:

37 Influencia del alcohol sobre la progresión a la cirrosis
n = > HCV + OL = 210 a 560 g/semana Strasser, 1995 Serfay, 1997 Roudot-Thoraval, 1997 Verbaan, 1988 Pol, 1998 Wiley, 1998 Bellentani, 1999 Khan, 2000 Loguercio, 2000 Thomas, 2000 Poynard, 2001 Di Martino, 2001 Harris, 2002 Monto, 2004 Total A recent meta-analysis of 20 studies including 15,000 persons chronically infected with HCV, reported a pooled relative risk of cirrhosis associated with heavy alcohol intake of 2.33 (95% CI, 1.67–3.26) [107]. In this analysis, heavy alcohol intake was defined by a range of at least 210 to 560 g of alcohol per week (equivalent to 2.3–5.6 drink equivalents per day). 2.33 ( ) Hutchinson SJ, et al. Clin Gastroenterol Hepatol 2005;3(11):1150–9.

38 Interacción entre ingesta de alcohol y riesgo en desarrollar cirrosis
O.R. (95% C.I.) Studies indicate that at levels of 50 g/d or higher, the effects of HCV and alcohol are additive, but at very high levels (125 g/d or more), the effects are synergistic [109]. Ingesta de alcohol gr/día Corrao G et al. Hepatology 1998;27:

39 Interacción entre ingesta de alcohol y riesgo en desarrollar cirrosis
O.R. (95% C.I.) Studies indicate that at levels of 50 g/d or higher, the effects of HCV and alcohol are additive, but at very high levels (125 g/d or more), the effects are synergistic [109]. Ingesta de alcohol gr/día Corrao G et al. Hepatology 1998;27:

40 Infección Crónica HCV Progresión a la Cirrosis
Proporción de pacientes que desarrollan Cirrosis según el nivel de fibrosis inicial Pacientes con Cirrosis Percentaje de 100 80 En puente 60 Portal Lesión histológica como parámetro evolutivo de la infección crónica por virus C What happens to these minimally symptomatic individuals as we follow them over time? The majority of individuals will develop progressive fibrosis and eventually cirrhosis from hepatitis C. The liver biopsy helps predict the risk of developing cirrhosis over a 20-year period in patients with hepatitis C. For individuals who do not have any evidence of fibrosis on their initial biopsy, the risk of developing cirrhosis over the next 20 years is only about 25% to 30%. On the other hand, once a patient has fibrosis, he or she will develop progressive fibrosis and eventually cirrhosis, it will just take time. According to this study, 100% of individuals with portal fibrosis develop cirrhosis, but it takes years. However, individuals with high levels of fibrosis on initial biopsy will develop cirrhosis sooner, in only about 8-10 years. That initial biopsy can be very helpful in providing feedback to the patient on why they should embark on therapy even though they are asymptomatic or minimally symptomatic. The biopsy provides information in three major areas. Firstly, it can elucidate cause; for example marked accumulation of iron in the hepatic parenchyma suggests hemachromatosis, whereas biliary duct damage associated with granulomas raises the suspicion of primary biliary cirrhosis. Secondly, it provides information on underlying pathologic processes (eg, steatosis, necroinflammation and fibrosis) and provides the opportunity to stage the severity of disease (eg, presence of cirrhosis). Thirdly, it can also act as a prognostic indicator. For example, in the context of hepatitis C, 3 Necroinflammation in the biopsy suggests future fibrosis. 40 Ausencia 20 5 10 15 20 Tiempo (años) Yano M, et al. Hepatology. 1996;23:

41 Efecto de la coinfección HIV/HCV sobre la progresión de la Fibrosis
4 3 Grado de Fibrosis METAVIR 2 HIV+/HCV+ (n = 122) HCV+ (n = 122) 1 HIV/HCV Coinfection on Fibrosis Among persons who have chronic HCV infection, HIV coinfection is associated with more advanced stages of fibrosis and higher risk of cirrhosis. In a French study, the median time to cirrhosis was estimated to be 26 years (95% CI, 22–34) in HIV-HCV coinfected patients, versus 38 years (95% CI, 32–47) in monoinfected patients [114]. Prior to the work of Benhamou Y, et al, the natural history of hepatitis C virus (HCV) infection in HIV infected patients had never been studied according to the concept of liver fibrosis progression. The aim of this work was to assess the fibrosis progression rate in HIV-HCV coinfected patients and in patients infected by HCV only. A cohort of 122 HIV-HCV coninfected patients was compared with a control group of 122 HIV-negative HCV-infected patients. The fibrosis progression rate was defined as the ratio between fibrosis stage (METAVIR scoring system) and the HCV duration. The prevalence of extensive liver fibrosis (METAVIR fibrosis scores 2, 3 and 4) and moderate or severe activity were higher in HIV-infected patients (60% and 54%, respectively) than in control patients (47% and 30%, respectively; P < .05 and P < .001, respectively). HIV seropositivity (P < .0001), alcohol consumption (> 50 g/d, P=.0002), age at HCV infection (< 25 years old, P < .0001), and severe immunosuppression (CD4 count < 200 cells/µL, P < .0001) were associated with an increase in the fibrosis progression rate. In coinfected patients, alcohol consumption ( > 50 g/d), CD4 count (< 200 cells/µL), and age at HCV infection ( < 25 years old) (P < .0001, respectively) were associated with a higher fibrosis progression rate. HIV seropositivity accelerates HCV-related liver fibrosis progression. In coninfected patients, a low CD4 count, alcohol consumption rate, and age at HCV infection are associated with a higher liver fibrosis progression rate. Reference: 1. Benhamou Y, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients ;30: 10 20 30 40 Duración de la infección HCV (años) con CD4<200/mm3,+ OH, edad Benhamou Y ,et al. Hepatology. 1999;30:

42 HCC en pacientes cirróticos coinfectados con HBV/HCV
HCC 32/290 cirróticos Seguimiento 87.8 ± 35.9 meses % de pacientes These investigators also assessed the risk of hepatocellular carcinoma in 290 patients with cirrhosis, 5.5% of whom had dual HBV and HCV infection and 68% of whom had HCV infection alone. Hepatocellular carcinoma developed in significantly more patients with dual HBV and HCV infection than in those with only HCV infection (p < 0.02; Fig. 1). The development of hepatocellular carcinoma also correlated with an age of more than 59 years (p < 0.005) and a longer duration of cirrhosis (p < 0.005). Benvegnu L et al. J Hepatol Koff RS. J Clin Gastroenterol. 2001;33:20-26.

43 ALT en la infección crónica por HCV
Diferentes curvas evolutivas de la ALT VN

44 HCV y progresión de la fibrosis
100 ALT elevada (n=31) ALT normal (n=30) 80 60 % de fibrosis avanzada p = 0.02 40 No obstante que los estudios son limitados, existen evidencias de que la enfermedad es progresiva, aunque a más lenta que en aquellos que tienen enzimas anormales. 20 2 4 6 8 10 12 14 16 Tiempo (años) Hui CK et al. J Hepatol 2003

45 Fibrosis de acuerdo al nivel de ALT
Significant fibrosis is less common in persons with normal than with abnormal serum enzymes, but is reportedly present in 5–30% of them (60, 61). There has been some controversy as to whether persons with persistently normal enzymes do have potentially progressive liver disease. Studies of paired biopsies spaced 1.5–5 years apart have reported no fibrosis progression (62–66), while other studies of paired biopsies spaced 2.8–7 years apart have reported fibrosis progression in 17–28% (67–69). ALT persistentemente elevada ALT persistentemente normal Shiffman M y col JID 2000

46 La resistencia a la insulina está asociada a una más rápida progresión de la fibrosis en pacientes HCV N = 260 OR: 1.3; P < .001 por tendencia HOMA-IR Score de fibrosis 5 4 3 2 1 F0 F1 F2 F3 F4 HCV, hepatitis C virus; HOMA-IR, homeostasis model assessment of insulin resistance; OR, odds ratio. Insulin resistance is another important factor in the progression of fibrosis and may or may not be related to steatosis. This study of 260 HCV‑infected persons identified insulin resistance as independently associated with stage of fibrosis. This figure shows that the HOMA‑IR, a convenient and simple measure of insulin resistance, increased in patients with more advanced fibrosis (P < .001). In addition, this correlation was seen even for those patients with noncirrhotic forms of fibrosis, which helps to discount the potential confounder that cirrhosis itself can increase hepatic insulin resistance. Therefore, the suggestion here is that insulin resistance is already operative in intermediate states of fibrosis, suggesting then that insulin resistance could be the cause, rather than the effect, of advanced fibrosis. Hui JM, et al. Gastroenterol. 2003;125:

47 Esteatosis y progresión de la fibrosis
N = 135 HCV (+) no tratados Intervalo de las biopsias = 61 meses (18-158) 1 0,8 0,6 0,4 0,2 P < .0001 Esteatosis > 30% Probabilidad de progresión de la fibrosis entre pares de biopsias hepáticas Esteatosis % Cumulative probability of progression of fibrosis according to the percentage of steatosis at initial liver biopsy. Probability of progression of fibrosis was significantly related to the percentage of hepatocytes with steatosis. In conclusion, steatosis is a major determinant of the progression of fibrosis in mild hepatitis C, regardless of the genotype. Our results argue for antiviral treatment in the subgroup of patients with mild hepatitis and steatosis. Esteatosis % Esteatosis < 5% 10 20 30 40 50 60 70 80 90 meses Fartoux et al Hepatology 2005

48 La diabetes como factor de riesgo de enfermedad hepática y HCC
14 12 10 8 6 4 2 1.00% 0.80% 0.60% 0.40% 0.20% Años 1.40% 1.20% 0.25% 0.15% 0.10% 0.05% Enfermedad hepática Hepatocarcinoma No diabéticos n = 650,620 (control) Diábeticos n = 173,643 (no ol, no virus) El-Serag HB et al. Gastroenterology 2004

49 Historia Natural de la infección HCV
Factores asociados a la infección HCV (Alcohol, HBV, HIV, etc) Exposición (Fase Aguda) Crónica Natural history of HCV Infection The natural history of hepatitis C evolves over the course of decades and can be considered to have three distinct stages. The first is the stage of resolution of recovery. This is seen in approximately 15% of patient with viremia and acute hepatitis followed by resolution of viremia with the persistence of antibody. The second stage is the stable chronic course in which patients have viremia and acute hepatitis with subsequent decrease in ALT. The patient may experience periodic elevations of liver enzymes and persistent viremia for several years. This is the most common stage and is seen in approximately 80% of the patients. During this stage it is believed that patients may experience the emergence of quasispecies and relative ineffectiveness of neutralizing antibodies. The last stage is that of severe progression of the disease and occurs in approximately 20% of the patients. The patient will experience more persistent elevation of liver enzymes, persistent viremia, and a more rapid progression to cirrhosis and possibly even hepatocellular carcinoma. HIV and alcohol should be considered as important cofactors in hepatitis C and the progression to cirrhosis. There is evidence to suggest a greater than 15 fold increase in the incidence of cirrhosis in alcoholic patients and a >5 fold increase with HIV. References: 1. Alter MJ. Epidemiology of Hepatitis C in the West. Semin Liver Dis. 1995; 15: 5-14 2. Management of Hepatitis C. NIH Consensus Statement. 1997; March 24-26: 15(3). Cirrosis HCC Trasplante 49

50 Consecuencias al año según el estadio de cirrosis
0,5% NO VARICES NO ASCITIS Estadio 1 COMPENSADA 1% 4% VARICES NO ASCITIS 2 % Estadio 2 MUERTE 7% 4% ASCITIS 24% Estadio 3 25% DESCOMPENSADA SANGRADO 35% Estadio 4a 18% SANGRADO & ASCITIS Estadio 4b 60% D’Amico Barcelona 2011

51 Probabilidad de sobrevida en pacientes HCV con Cirrosis
Probabilidad Sobrevida 100 N = 384 80 60 Pacientes (%) 40 Compensada 20 Luego de la primera complicación mayor Once any of these decompensating events occurs, patients fall down a slippery slope, as this study of the natural history of patients with HCV‑related cirrhosis clearly demonstrates. As shown, survival rates for patients with compensated liver function (shown in blue) remained quite high over a 10‑year period. By contrast, once a first complication occurred, the survival dropped off dramatically, such that the survival rate was only 50% at 5 years in this group of patients (shown in orange). Therefore, the onset of any decompensating event is clearly an ominous sign for persons with HCV‑related cirrhosis. 12 24 36 48 60 72 84 96 108 120 Meses Pacientes Riesgo Fattovich G et al. Gastroenterology 112; , 1997. 51

52 Historia natural de la cirrosis
En presencia de cirrosis cada año: 3-8 % desarrollarán HCC 1-2% presentarán falla hepática El trasplante hepático será necesario entre 5-10% por año.

53 Progresión de la hepatitis C
lenta ≥ 30 años después de la infección Sexo Femenino, edad jóven Descompensación (~ 20%) HCC (1-4% por año) Hígado normal Infecciónaguda Infeccióncrónica (80%) Hepatitis crónica Cirrosis (20%) Progresión de la enfermedad Infección resuelta espontáneamente (20%) hepatitis estable (80%) Lentamente progresiva (~ 75%) In persons who have chronic HCV infection, disease progression is variable, and only aproportion of infected patients develop the serious complications of chronic infection, including cirrhosis and hepatocellular carcinoma (HCC). rápida ≤ 20 años después de la infección Sexo masculino, consumo de alcohol, esteatosis hepática, RI, co-infecciones HIV o HBV, HCV postrasplante Lauer & Walker. N Engl J Med 2001

54 Conclusiones I/II La edad a la infección, duración, ingesta de alcohol, coinfección con HIV, coinfección con HBV y el sexo masculino son factores asociados con un mayor riesgo de progresar a la cirrosis. La esteatosis hepática, la resistencia insulínica y la genética han sido identificados como nuevos factores de progresión.

55 Conclusiones II/II La historia natural es variable y solamente una proporción de pacientes desarrollarán cirrosis y hepatocarcinoma: Entre 4 – 24% de los pacientes evolucionaran a cirrosis luego de 20 años. Se estima una incidencia anual de hepatocarcinoma en cirrosis de ~ 3%.

56 Importancia del tratamiento: Progresión de la enfermedad desde la cirrosis
1.5%/anual 1.1%/anual 0.4%/anual 2.5%/anual Carcinoma hepatocelular Hemorragia Variceal Encefalopatía Hepática Ascitis 86%/anual 40%/anual 68%/anual 11%/anual Mortalidad Buti M et al. J Hepatol 2000

57 HISTORIA NATURAL DE LA CIRROSIS POR HCV
Estudio Prospectivo de 404 casos (media de 85.7 ± 36 meses) % Casos que desarrollan complicaciones TASA ANUAL 2.7% 2.4% 0.7% 0.3% Al menos una 28% HCC 19% Ascitis 17% Child B/C 17% Sangrado Variceal 5% EPS 2% 10% 20% 30% 40% Benvegnù et al, 2000

58 Historia Natural de la Cirrosis
Cada año: 3-8 % desarrollaran HCC 1- 2% desarrollaran insuficiencia hepática 5 -10% necesitaran un trasplante

59 Dificultades para establecer la historia natural de la infección por HCV
La infección aguda por HCV es raramente reconocida debido a la ausencia de síntomas en el 70% de los casos por lo tanto un grupo control es muy difícil de seleccionar. Dificultad de realizar estudios actuales sobre la historia natural en pacientes no tratados. Los resultados deberían analizarse luego de 3 a 4 décadas de seguimiento. The silent onset of the acute phase of hepatitis C infection coupled with the frequent lack of symptoms during the early stages of chronic infection has meant that the natural history of hepatitis C virus infection has been very difficult to assess. un estudio ideal que debería ser prospectivo, completo y con tiempo de estudio muy prolongado, al menos superior a 20 años, y partir de una fuente de infección perfectamente identificada en el tiempo.

60 Impacto del Alcohol y nivel de CD4 sobre la progresión a la cirrosis en pacientes coinfectados HCV/HIV 50 40 < > 50 g/d > > 50 g/d 30 < < 50 g/d Progresión estimada (años) > < 50 g/d 20 >50g/d Impact of Alcohol Use and CD4 on Progression to Cirrhosis Among HIV/HCV coinfected patients, alcohol consumption (>50 g/day), CD4 counts (<200 cells/l), and age at infection (>25 years old) were independent factors associated with the fibrosis progression rate. Median expected times from HCV infection to cirrhosis in the 2 groups of patients according to the daily alcohol intake and CD4 cell count at liver biopsy is shown in the graph above. An HIV-infected patient with 200 CD4 cells/l or less and drinking more than 50 g of alcohol daily had a liver fibrosis progression rate of fibrosis units per year (median expected time to cirrhosis 16 years), whereas it was fibrosis units per year (median expected time to cirrhosis 36 years) for an HIV-infected patients with greater than 200 CD4 cells/l, drinking 50 g or less of alcohol daily. On the other hand, a nondrinker and non-HIV infected patient had fibrosis progression rate of fibrosis units per year (expected time to cirrhosis 40 years.) Reference: 1. Benhamou Y, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients ; 30: <50g/d 10 HCV + / HIV + HIV- Benhamou Y, et al. Hepatology 1999; 30: 1054

61 Infección Crónica HCV Progresión a la Cirrosis
Leve 15%-33% Moderada Severa Cirrosis A 20%-33% The schematic in this slide looks collectively at these natural history data. Some patients with mild hepatitis C will have mild hepatitis C for their entire life—30-50 years—and never develop scarring in their liver, and hepatitis C does not significantly impact their life expectancy. This likely applies to about 15% to 30% of patients. Another 20% to 30% of patients develop rapidly progressing hepatitis C with cirrhosis, decompensated cirrhosis, and liver cancer within years of exposure. The remaining 50% to 65% of patients develop fibrosis progression to cirrhosis, but at variable rates—some individuals will develop cirrhosis after 25 years, some after 30 years, some after 40 years, and so on. Cirrosis C HCC 10 20 30 40 50 Años Shiffman ML. Viral Hepatitis Rev. 1999;5:27-43.

62 Probabilidad acumulada
HCV en pacientes con cirrosis Sobrevida y porcentaje de descompensación Sobrevida acumulada 10- Años Probabilidad acumulada 50 100 Descompensación Estable Descompensación 40 80 HCC 30 60 Porcentaje de pacientes Sobrevida (%) Survival in HCV-infected patients depends upon whether they have stable or decompensated cirrhosis. Individuals with stable cirrhosis who have never developed a complication of their cirrhosis have a good 10-year survival of about 80%. By contrast, individuals who have decompensated cirrhosis have a 10-year survival of approximately 30%. The rate at which individuals develop decompensated liver disease is approximately 3% to 5% per year, cumulatively, and this continues to increase as patients with cirrhosis are followed over 10 years. The rate at which individuals develop HCC is on the average about 1% to 3% per year, cumulatively. Thus, after 10 years, the risk of patients with cirrhosis developing liver cancer is approximately 12% to 14%. 20 40 10 20 2 4 6 8 10 Años Fattovich G, et al. Gastroenterology. 1997;112:

63 Efecto de la edad sobre el riesgo de progresión
Effect of age on the risk of progression of hepatic fibrosis in the 4 years subsequent to initial liver biopsy. The impact of age though is marked, the risk of progression in a 50-year-old being almost three times the risk of progression in a 20-year old (Fig. 1). Edad Ryder SD. Gut 2004;53:451–455.

64 Efecto protectivo de los estrógenos sobre la progresión de la enfermedad
* ** ** * p < 0,001 ** p < 0, 02 ** ** * 10-3 METAVIR unidad/año Di Martino et al Hepatology 2004

65 Factores que influyen en la historia natural
Factores bien establecidos Factores probables Factores controvertidos Raza Actividad necroinflamatoria basal H U E S P D Edad al adquirir la infección Duración Sexo masculino ALT elevada Presencia de fibrosis Insulina resistencia Esteatosis HLA II (polimorfismo genéticos) V I R U S HBV HIV Carga viral Genotipos HCV Alcohol Esquistosomiasis Tabaquismo Cannabis F E A X T T O E R R E N S O S

66 Características de acuerdo al nivel de ALT
ALT elevada n = 58 ALT normal n = 37 p Edad 45.2 ± 1.2 40.2 ± 1.3 NS N° (%) ♂ 32 (55.2%) 15 (40.5%) Genotipo 1 43 (74.1%) 28 (25.9%) Log HCV RNA, copias/mL 5.50 ± 0.07 5.42 ± 0.13 Shiffman M y col JID 2000

67 Summary of Key Conclusions
Several weight-related factors associated with liver disease outcomes in patients with advanced HCV infection Insulin resistance Histologic features of fatty liver disease Weight change Greater steatosis strongly associated with higher risk for liver disease progression among patients with bridging fibrosis, whereas greater steatosis associated with lower risk for liver disease progression among patients with cirrhosis Everhart JE, et al. Gastroenterol. 2009;137:

68 Progresión según la ˃ 20 años 10 – 20 años ˂ 10 años
Porcentaje de cirrosis Años luego de la exposición al HCV

69 Pacientes con HCV y transaminasas persistentemente normales
Datos obtenidos de 15 estudios n= 2,012 casos Fibrosis (METAVIR) Actividad (METAVIR) A1 F0 F1 A0 49% 44% A2 F2 33% 34% F3 A3 F4 16% 5% 18% 1% 1% Alberti et al. EASL, 2004

70 Asociación de esteatosis con fibrosis
Hepatocitos afectados (%): Grado 0  ausencia Grado 1-2  30% a 60% Grado 3-4  ≥ 60% Grado de Fibrosis METAVIR These investigators also assessed the risk of hepatocellular carcinoma in 290 patients with cirrhosis, 5.5% of whom had dual HBV and HCV infection and 68% of whom had HCV infection alone. Hepatocellular carcinoma developed in significantly more patients with dual HBV and HCV infection than in those with only HCV infection (p < 0.02; Fig. 1). The development of hepatocellular carcinoma also correlated with an age of more than 59 years (p < 0.005) and a longer duration of cirrhosis (p < 0.005). Adinolfi L et al. Hepatology 2001.

71 Curso de la HCV postransfusional
Pacientes transfundidos: HCV + = 924 (seguimiento 11,1 (8,2-20,6)) Control = 475 (seguimiento 11,8 (8,3-25)) Sobrevida 924 transfusion recipients infected with the hepatitis C virus (HCV) traced during the HCV lookback retrospectivo programme and 475 transfusion recipients who tested negative for antibodies to HCV (control Años Mayor mortalidad en aquellos pacientes con consumo de alcohol Harris H et al Gut 2002

72 ¿Cómo conocer la historia natural de la hepatitis C?
Conocer la fecha de infección Estudiar a la totalidad de los infectados para establecer la proporción con la evolución más favorable o desfavorable Analizar la presencia de cofactores Estudiar la evolución de la enfermedad en ausencia de tratamiento Seguimiento a largo plazo Los estudios realizados NO cumplen estos requisitos

73 Probabilidad de desarrollar cirrosis según la edad de la infección
>50 1.00 31–40 41–50 0.75 Probabilidad 21–30 0.50 Slide 73. Probability of Fibrosis Progression to F4 According to Age at Infection The METAVIR scoring system classifies the stage of fibrosis on a 5-point scale: F0 = no fibrosis; F1 = portal fibrosis without septa; F2 = few septa; F3 = numerous septa without cirrhosis; F4 = cirrhosis.1 Without treatment, as many as one third of HCV-infected patients will progress to cirrhosis within 20 years, and almost one third will never progress to cirrhosis or will do so after 50 years.1 A variety of factors are predictive of enhanced risk of decompensation and rate of progression to F4 cirrhosis. (See Slide 14.) Patients more than 50 years of age at the time of infection are almost certain to progress to cirrhosis, generally within 15 years. Patients in their 40s at the onset of infection have a 75% probability of progressing to F4 cirrhosis within 25 years.2 The effects of age at onset of infection and duration of infection on fibrosis progression support the importance of treating older patients (ie, aged >50 years) with HCV infection. 1. Poynard T et al. Lancet. 1997;349: Poynard T et al. J Hepatol. 2001;34: 0.25 <21 0.00 10 20 30 40 Duración de la infección (años) Poynard T et al., J. Hepatol. 2001;34:

74 HCV aguda –Resolución espontánea
% Gerlach Fifty-one of 60 (85%) patients presented with symptomatic acute hepatitis C virus. In the natural (untreated) course of acute symptomatic hepatitis C (n = 46), spontaneous clearance was observed in 24 patients (52%), usually within 12 weeks after the onset of symptoms, whereas all asymptomatic patients (n = 9) developed chronic hepatitis C. Kamal Results: Whereas 5 of 15 patients with HCV alone recovered from acute HCV, all (17 of 17) patients with S. mansoni coinfection progressed to histologically proven chronic hepatitis. Coinfected patients had either absent or transient weak HCV-specific CD4+ responses with Th0/Th2 cytokine production. Gerlach et al. Gastroenterology 2003;125:80-8. Santantonio T et al. Clin Infect Dis 2006;43: Kamal et al. Gastroenterology 2001;121: Zakaria et al. Clin Infect Dis 2007;44:30-6

75 HCV Progresión de la Fibrosis Efecto del Alcohol
< 10 11-20 21-30 31-40 > 40 4.0 3.0 2.0 1.0 Ingesta de Alcohol Score de fibrosis > 50 g/día < 50 g/día Another factor that affects fibrosis progression is alcohol use; individuals with hepatitis C who drink alcohol on a regular basis have a higher mean fibrosis score according to time of infection compared with individuals who do not drink alcohol. The impact of consuming alcohol continues to increase stepwise over the decades. Studiesindicatethatatlevelsof50g/dorhigher,thee?ectsof HCVandalcoholareadditive,butatveryhighlevels(125g/dormore),the e?ectsaresynergistic [109]. Duración de la Infección (años) Poynard T, et al. Lancet. 1997;349:

76 Resistencia insulínica
HCV crónica Genotipo 3 Genotipos 1 y 4 Obesidad Resistencia insulínica ? An important emerging risk factor for fibrosis progression and cirrhosis is steatosis and factors related to the metabolic syndrome (body mass index or obesity). Esteatosis “metabólica” Esteatosis “viral”

77 Esteatosis y progresión de la fibrosis
N = 135 HCV (+) no tratados Intervalo de las biopsias = 61 meses (18-158) 1 0,8 0,6 0,4 0,2 P < .0001 Esteatosis > 30% Probabilidad de progresión de la fibrosis entre pares de biopsias hepáticas Esteatosis % Probability of progression of fibrosis was significantly related to the percentage of hepatocytes with steatosis. Esteatosis % Esteatosis < 5% 10 20 30 40 50 60 70 80 90 meses Fartoux et al Hepatology 2005

78 Infección Aguda HCV HCV RNA + + + + + + + + + - - - + + + + +
200 HCV RNA 150 ALT (IU/l) 100 This next slide looks at the biochemical and virologic response of patients exposed to HCV. In the green line you can see acute elevation in liver transaminases within the first couple of weeks after exposure to the virus, indicating acute HCV infection. Notice in the red bar I have indicated presence or absence of HCV RNA. During the acute phase of HCV infection, if you test for HCV, sometimes the virus will be detectable, but at other times the virus is undetectable. Because of this intermittent viremia, virologic assays are not the best assays to screen for acute hepatitis C. Over the next couple of weeks of infection, liver transaminases decline and then go into an undulating pattern over the next years, when the serum alanine aminotransferase (ALT) can fall into the normal range for either brief or prolonged periods of time, only to elevate again. This shows that individuals with chronic hepatitis C can have both elevated liver enzymes and normal liver enzymes, and sometimes they can have persistently normal liver enzymes for long periods of time. However, these individuals will test positive for antibodies to hepatitis C and, if they have chronic infection, will be viremic. The blue line indicates an individual who had spontaneous resolution from hepatitis C. Again, you see acute elevation of liver transaminases during the acute phase, intermittent viremia in the first couple of weeks after the infection, and then the liver transaminases coming down and remaining persistently normal. It is important to recognize that individuals who have been exposed to HCV but develop spontaneous resolution will also develop antibodies to hepatitis C. This is the type of individual who may go and donate blood to a blood bank and have a positive antibody for hepatitis C or be noted as having a positive antibody on life or health insurance physical exams. However, they have persistently normal liver enzymes, and when tested for HCV RNA, they are virus undetectable. 50 Cronicidad 6 12 Meses