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Hepatitis E
María Buti Hospital Universitario Valle Hebron
Barcelona
Hepatitis E. Casos clínicos
Varón 52 años Dolor hombros y parestesias
tras viaje a la Cerdaña
Varón 49 años Hepatitis aguda en paciente
con púrpura trombótica trombocitopénica
Caso clínico 1
Varón 52 años
No hábitos tóxicos
Antecedentes: HTA (ramipril, manidipimo) •Sept 2017: dolor hombros bilateral de 48 horas
de duración, con parestesias en EESS
EF: balance muscular y reflejos conservados.
Resto anodino
Antecedente epidemiológico:
Mes previo vacaciones en la Cerdaña
Caso clínico 1
Analítica: TQ 108%, Bilir 0.92 mg/dL, AST 268 UI/mL [12-50], ALT 470
UI/mL [8-50], FA 135 UI/mL [9-55], GGT 147 UI/mL [55-171], albúmina 3.7
mg/dL [3.5-5]
Rx cervical: normal
Ecografía abdominal: normal
EMG: signos incipientes de neuralgia braquial
Varón 52 años con hepatitis aguda
Biliar
Infecciones
Hepatitis autoinmune
Drug-induced liver injury
Hepatitis aguda B o C
Hepatitis E
Ecografía normal
No fármacos salvo antihipertensivos
HBsAg, Ig M antiHBc antiVHC, RNA VHC
NEGATIVOS
Electroforesis IgG
Est. AU NEGATIVO
IgM y RNA VHE POSITIVOS
Hepatitis E Main characteristics:
– Enteric transmission – Epidemic
• Unique viral hepatitis with animal reservoir
Current magnitude of HEV Annual estimation (2005):
20 million acute infections
3 million symptomatic infections
70,000 deaths per year
?? Chronic infections
Rein DB, et al. Hepatology 2012;55:988–997
Data from GT 1 and 2, therefore it took no account of zoonotic HEV
Worldwide distribution of HEV
Purcell RH. J Hepatol, 2008
Hepatitis E. Escenarios
Países subdesarrollados Países desarrollados
August 25, 2016
Genotype 1 and 2 Genotype 3 and 4 Strictly human Human and animals
Link with outbreaks No
Fecal-orally (contaminated water) Zoonosis Blood product transfusion; Transplantation
GT 1- Asia GT 2- Africa and Mexico
GT 3- Europe, Southeast Asia GT 4- France,Italy,Germany, Belgium (pigs), Japan
HEV in developed countries • Main source of infection: zoonosis • Exceptionally: Transfusion, transplantation • HEV RNA have isolated in many animals
(rabbits, pigs, wild boar...) • Associated risk factors:
– Raw/undercooked meat intake – Meat manipulation – Homemade sausages – Game meat intake
Tei S, et al. Lancet. 2003;362:371–373 Riveiro-Barciela M, et al. J Clin Gastroenterol. 2015 ;49:165-8
Acute hepatitis E in developed countries Increasing number of cases in Barcelona
Buti M, et al. J Hepatol 1994 Riveiro-Barciela M, et al. EASL 2015. P0624
HEV is the leading cause of acute hepatitis in Scotland
Kokki I, et al. New Microbes New Infect. 2015 15;10:6-12
Acute hepatitis E Diagnosis
F. Rodríguez-Frias. Enferm Infecc Microbiol Clin, 2012
Meses
Diagnosis acute hepatitis E Ig M antiHEV
ELISA against epitopes: – ORF2: Wantai, In-house assays – ORF2 and ORF3: Adaltis, Mikrogen, Genelabs
Test In-house assays
Wantai [China]
Adaltis [Eurobi,France]
Mikrogen [Menarini, Germany]
Genelabs [Singapore]
Sensitivity 98% G1 85% 87,5% 92% 82%
Specificity 78- 93% G1 99,6% 100% 96% 100%
Drobeniuc J et al. Clin Infec Dis 2010 Aggarwal R. Nat Rev Gastroenterol Hepat 2012
Extrahepatic manifestations of HEV
Riveiro-Barciela M, et al. Ann Hepatol, 2013
Neurologic manifestations of HEV
Dalton HR, et al. J Hepatol 2017;67(5):925-932
Hepatitis E virus-associated neuralgic amyotrophy
Van Eijk JJJ, et al. Neurology 2017 29;89(9):909-917
57 cases with HEV 61 cases without HEV
Majority anicteric All genotype 3 (38 plasma; 1 CSF)
More likely to bilateral involvement
(80.0% vs 8.6%, p < 0.001)
More likely to damage outside the
brachial plexus (58.5% vs 10.5%, p < 0.01)
There was no difference in outcome between the 2 groups at 12 months
Need of HEV testing in all patients with neuralgic amyotrophy??
Varón 52 años con hepatitis aguda E y neuralgia braquial
Evolución analítica y clínica
ALT (UI/mL)
ARN VHE (UI/mL)
21-sep 1-oct 13-oct
Mejoría dolor Desaparición dolor y parestesias
EMG normal
Diagnóstico
Caso clínico 2
Varón 49 años
No hábitos tóxicos
Antecedentes: púrpura trombótica trombocitopénica (PTT)
Desde 2016 EC con caplacizumab
Enero 2017: Último episodio PTT: inducida por gripe A (plasmaféresis)
Febrero 2017: 155.000 Plaquetas/mL [150-500]
Marzo 2017:
Plaquetas 149.000/mL [150-500]
TQ 101%
Bilirrubina 5.35 mg/dL [0.3-1.2]
AST 1515 UI/mL [12-50]
ALT 991 UI/mL [8-50]
Caso clínico 2
Ecografía abdominal: normal
Estudio autoinmunidad: negativo
AntiVHC y RNA VHC, HBsAg, IgM antiHBc: negativos
No ingesta ni manipulación de carne cruda, no viajes al extranjero...
Ingreso previo enero: corticoides, oseltamivir, plasmaféresis,
caplacizumab... DILI?
Not all undiagnosed acute hepatitis cases are related to drugs...
Dalton HR, et al. Aliment Pharmacol Ther. 2007 15;26(10):1429-35
47 cases of hepatotoxicity
6 (13%) HEV RNA +
45 acute hepatitis E
10 (22%) firstly suspicion of hepatotoxicity
DILI HEV
Amoxi-clav. Statins
Flucloxacilin NSAIA
Chinese herbs Amoxicilin
Clorpromazin Cephalosporins
Caso clínico 2
Ecografía abdominal: normal
Estudio autoinmunidad: negativo
AntiVHC y RNA VHC, HBsAg, IgM antiHBc: negativos
IgM VHE y ARN VHE: positivos
Traceback plasmaféresis: 1 de 99 hemoderivados utilizados positivo para ARN VHE
HEV RNA prevalence in blood donors Country Year Author N Subjects HEV RNA
Scotland 2013 Cleland 14520 1/14520
USA 2013 Xu 1939 0/1939
Netherlands 2013 Slot 40176 1/2363
Germany 2014 Juhl 1019 1/4252
Spain 2015 Sauleda 9998 1/3332
China 2015 Ma 816 0/816
USA 2016 Stramer 18829 1/9500
Netherlands 2016 Hogema 59474 1/1321
Cleland A, et al. Vox Sang 2013;105:283-9; Xu C, et al. Transfusion. 2013;53:2505-11; Juhl D, et al. Transfusion. 2014;54:49-56; Slot E, et al. Euro Surveill. 2013 ;18(31); Sauleda S, et al. Transfusion 2015;55:972-9; Ma L, et al. The Journal of international medical research 2015;43:257-262; Stramer SL, et al. Transfusion; 2016;56(2):481-8; Hogema BM, et al. Transfusion 2016;56(3):722-8.
The Lancet. January 2014
Hepatitis E in blood products
Hewitt PE, et al. Lancet 2014 15;384(9956):1766-73
225.000 donations within 1 year in England
78 HEV RNA + (1/2848)
Majority seronegative
16 RBC 10 Plat. (pool)
14 Plat. (aferesis) 2 plasma Transfused
subjects
Infected subjects 4 (25%) 4 (40%) 7 (50%) 2 (100%)
13/18 were immunosuppressed
Caso clínico 2
Coagulación normal
bilirrubina 24.5 mg/dL
Concomitantemente...
Plaquetopenia
50.000/mL
Hb 10 mg/dL
Púrpura en EEII
Aumento LDH
Haptoglobina
indetectable
Actividad ADAMS-13
indetectable Brote de púrpura trombótica
trombocitopénica
Acute hepatitis E Prognosis
• Self-limited infection in the majority of cases Poorer prognosis in developed countries Elderly people Prior liver disease
• High morbidity and mortality rates associated with
acute on chronic liver failure Mortality: 33-76% Underlying alcoholic cirrhosis Genotype 1 and 3
Péron JM. J Hepat, 2011; Dalton HR. Lancet, 2007
Complicaciones asociadas a la infección por VHE
Complicaciones
extrahepáticas
Cronificación de la infección en sujetos inmunosuprimidos
Development of liver fibrosis and rapid progression to cirrhosis
Solid organ and stem cell transplantion
HIV infection Haematological neoplasm and chemotherapy Immunosuppressed therapy
Chronic hepatitis E Clinical relevance
Author, year Organ Incidence
Haagsma EB, 2009 Liver 1,75%
Pischke S, 2010 Liver 2,9%
Legrand-Abravanel F, 2011 Liver, Kidney, Pancreas 5.65%
Pischke S, 2012 Heart 1,5%
Legrand-Abravanel F, 2013 Liver or Kidney 3,1%
Versluis J, 2013 Hematopoietic stem cell 2,4%
Diagnosis of chronic hepatitis E • Cause of persistently increased ALT levels in
transplant patients, immunosuppressed or cirrhotics
• Serological tests are not useful for diagnosis
HEV RNA Transplantation
Cirrhosis HIV
Immunosuppressed
ALT Without etiology
Treatment of chronic hepatitis E Ribavirin in transplantation
Kamar N, el al. NEJM 2014 20;370:1111-20
37 Kidney 10 Liver 5 Heart 5 Kidney-Pancreas 2 Lung
Caso clínico 2
Remisión de la PTT tras tratamiento y curación de la hepatitis aguda e
con Ribavirina (600 mg/d durante 12 semanas)
Plat
elet
s co
unt (
109 /
L)
HEV RNA (IU
/mL)
1,E+00
1,E+01
1,E+02
1,E+03
1,E+04
0
50
100
150
200
250
300
17-3 31-3 4/4 (BL) 11/04 (W1) 18/04 (W2) 03/05 (W4) 30/05 (W8) 27/06 (EOT) 25/07 (FU4) 19/10(FU12)
Platelets count HEV RNA
Ribavirin
Take home messages
Infección por el virus de la hepatitis E
Número creciente de casos
Más frec.: Hepatitis colestásica y pacientes mayores
Manifestaciones extrahepáticas
Normalmente autolimitada
Riesgo de cronificación en sujetos inmunosuprimidos
