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Treatment indication 272
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Predictors of treatment response and pre-therapeutic assessment
Antiviral resistance
275
272
Treatment in 2020 277
Treatment of patients with prior DAA treatment failure 298
Optimisation of HCV treatment 301
Management of side efects and complications 302
Drug-drug interactions
303
Treatment of hepatitis C in special populations 305
Patients with acute hepatitis C 305
Patients with normal aminotransferase levels 306
Patients with compensated versus decompensated liver cirrhosis 306
Patients with hepatocellular carcinoma (HCC) 309
Patients ater liver transplantation 309
Patients with chronic kidney disease 311
Drug use and patients on stable maintenance substitution 312
Patients with co-infections 313
Patients with hemophilia 313
Patients with extrahepatic manifestations 313
Direct-acting antiviral therapy of HCV negative
recipients ater receiving a HCV positive solid organ 314
References 316
13. Extrahepatic manifestations of chronic HCV 325
Albrecht Böhlig, Karl-Philipp Puchner and Thomas Berg
Introduction 325
Mixed cryoglobulinaemia 325
Diagnosis 327
Clinical presentation 328
Malignant lymphoproliferative disorders/NHL 329
Aetiology and pathogenesis of LPDs in patients with HCV infection 330
Treatment of lymphoproliferative disorders 331
Mixed cryoglobulinaemia 332
Systemic vasculitis 333
Peripheral neuropathy 335
Further hematological manifestations 337
HCV-associated thrombocytopenia 337
HCV-related autoimmune hemolytic anaemia 338
HCV-related glomerulonephritis 339
Endocrine manifestations 341
Cardiovascular manifestations 343
Central nervous manifestations 345
Dermatologic manifestations 346
Miscellaneous manifestations 347
References 348
14. Management of HBV/HIV coinfection 355
Stefan Mauss and Jürgen Kurt Rockstroh
Introduction 355
Treatment of chronic hepatitis B in
HBV/HIV-coinfected patients on antiretroviral therapy 357
Conclusion 359
References 360
15. Management of HCV/HIV coinfection 363
Christoph Boesecke, Stefan Mauss, Jürgen Kurt Rockstroh
Epidemiology of HCV/HIV coinfection 363
Diagnosis of HCV in HIV coinfection 365
Natural course of HCV in HIV coinfection 366
Efect of HCV on HIV 367
Efect of AT on HCV 367
Treatment of HCV in HIV coinfection 368
Treatment of HCV for relapse or non-response 372
Treatment of acute HCV in HIV 373
Management of liver cirrhosis and liver transplantation
in people with HCV/HIV coinfection 374
Conclusion 374
References 375
16. HBV/HCV coinfection 379
Raphael Mohr, Carolynne Schwarze-Zander and Jürgen Kurt Rockstroh
Epidemiology of HBV/HCV coinfection 379
Screening for HBV/HCV coinfection 379
Viral interactions between HBV and HCV 380
Clinical scenarios of HBV and HCV infection 381
Acute hepatitis by simultaneous infection of HBV and HCV 381
HCV superinfection 382
HBV superinfection 382
Occult HBV infection in patients with HCV infection 382
Chronic hepatitis in HBV/HCV coinfection 383
Cirrhosis 383
Hepatocellular carcinoma 384
Treatment of HBV and HCV coinfection 384
Conclusion 387
References 387
20 21
17.
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Assessment of hepatic ibrosis and steatosis 391
Frank Grünhage and Frank Lammert
Introduction 391
Mechanisms of liver ibrosis in chronic viral hepatitis 392
Liver biopsy – the “gold standard” for staging of liver ibrosis 393
Surrogate markers of liver ibrosis 394
Ultrasound-based elastography 397
Transient elastography
Acoustic radiation force imaging (ARFI) and shear wave imaging (SSI)
Other imaging techniques for the assessment of liver ibrosis 406
Clinical decision algorithms 407
Population based screening for advanced liver ibrosis 407
Non-alcoholic fatty liver disease 408
Controlled Attenuation Parameter (CAP) 410
398
405
Summary 411
References 411
18. Diagnosis, prognosis & therapy of hepatocellular carcinoma 417
Ulrich Spengler
Classiication of HCC 417
Epidemiology 418
Surveillance of patients at high risk and early HCC diagnosis 420
Diagnosis 420
Stage-adapted therapy for liver cancer 423
Potentially curative therapy in BCLC stages 0-A 423
Palliative therapy in BCLC stages B and C 428
Systemic palliative HCC therapies 432
Prophylaxis of liver cancer 436
References 437
19. Transplant hepatology: a comprehensive update 441
S. Beckebaum, V. R. Cicinnati, A. Radtke
Introduction 441
Timing and indications for liver transplantation 441
Pre-transplant management issues 444
Waiting list monitoring of patients with ALD 446
Waiting list monitoring of hepatitis B
liver transplant candidates 449
Waiting list monitoring and treatment of
hepatitis C liver transplant candidates 450
Adjunct treatment and staging of HCC transplant candidates 454
Liver transplantation in autoimmune hepatitis
and cholestatic liver diseases 455
Living donor liver transplantation:
indications, donor evaluation, and outcome 456
Perioperative complications 457
Long-term complications ater liver transplantation 459
Opportunistic infections 459
Hepatitis E
Chronic rejection (TCM and AMR)
Calcineurin inhibitor-induced nephrotoxicity
and alternative immunosuppressive protocols 464
Other side efects of CNI 467
Corticosteroid minimisation/avoidance protocols
and additional strategies to reduce metabolic complications 468
De novo malignancies 469
Biliary complications 472
Metabolic bone disease
Recurrent diseases ater liver transplantation 476
462
464
475
Pregnancy ater liver transplantation 492
Experiences with liver transplantation in
inherited metabolic liver diseases in adult patients 492
Outcome ater liver transplantation for acute hepatic failure 494
Conclusion 495
References 497
20. End-stage liver disease, HIV and liver transplantation 509
José M. Miró, Fernando Agüero, Pablo Ruiz, Gonzalo Crespo, Alejandro Forner,
Montserrat Laguno, Montserrat Tuset, Juan Ambrosioni, Anna Lligoña,
Constantino Fondevila, Asuncion Moreno, Juan-Carlos García-Valdecasas,
Antonio Rimola and the Hospital Clinic OLT in HIV Working Group
Introduction 509
End-stage liver disease in HIV positive patients 509
Magnitude of the problem and natural history 509
Clinical features of HIV-coinfected patients with ESLD 512
Prognosis ater hepatic decompensation 512
Mortality during the evaluation process for liver transplantation 513
Management of complications of cirrhosis 513
HCV/HBV management 514
Combined antiretroviral therapy (cAT) 516
Hepatocellular carcinoma in HIV positive patients 517
Evaluation process for liver transplantation
in HIV positive patients 518
Donor evaluation 519
Liver transplant (LT) in HIV positive patients 519
Liver disease criteria 519
22 23
HIV criteria 520
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Outcome of LT in HIV positive patients 522
Complications ater LT in HIV positive patients 522
Infectious complications 523
Other complications
Pharmacokinetic interactions in the posttransplant period
Immunosuppression and rejection in HIV positive LT recipients
HCV recurrence ater LT
Pre-DAAs era
DAA era
HBV recurrence ater LT 529
Hepatocellular carcinoma 529
Liver retransplantation 530
528
523
525
526
527
527
Conclusions 530
References 531
21. Metabolic liver diseases: haemochromatosis 537
Claus Niederau
Deinition and classiication of iron overload diseases 537
Type 1 HFE haemochromatosis 538
History 538
Epidemiology 539
Aetiology and pathogenesis 539
Diagnosis 541
Early diagnosis and screening 544
Complications of iron overload 547
Therapy 551
Prognosis
Juvenile hereditary haemochromatosis 554
Transferrin receptor 2 (TFR2)-related type 3 haemochromatosis 555
Type 4 haemochromatosis – Ferroportin Disease 556
554
Secondary haemochromatosis 557
Pathophysiology 557
Use of blood from patients with
HFE haemochromatosis (type 1) for blood donation 558
References 561
22. NAFLD and NASH 565
Claus Niederau
Introduction 565
Prevalence 565
Demographics and risk factors 566
Pathogenesis 566
Human genetic factors 567
Microbiome 568
Natural history 570
Diagnosis 575
Diet, physical exercise and lifestyle recommendations 579
Alcohol and cofee 581
Pharmacological treatment 581
Novel pharmacological approaches 584
Alterations of the intestinal microbiome 592
Surgery for obesity 594
Liver transplantation (LTX) for NASH 595
Follow-up of NAFDL and NASH patients 595
References 596
23. Wilson’s disease 605
Claus Niederau
Introduction 605
Clinical presentation 605
Diagnosis 609
Scoring system 609
Serum ceruloplasmin 609
Serum copper 610
Urinary copper excretion 611
Hepatic copper concentration 611
Radiolabelled copper 611
Liver biopsy indings 612
Neurology and MRI of the CNS 612
Genetic Studies
613
Treatment 613
Monitoring of treatment 618
References 620
24. Autoimmune liver diseases: AIH, PBC and PSC 623
Christian P. Strassburg
Autoimmune hepatitis (AIH) 623
Deinition and diagnosis of autoimmune hepatitis 623
Epidemiology and clinical presentation 625
Natural history and prognosis 627
Who requires treatment? 628
Who does not require treatment? 628
Standard treatment strategy 629
Treatment of elderly patients 632
Alternative treatments 634
24 25
Budesonide 634
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Delazacor t
Cyclosporine A
Tacrolimus
Mycophenolic acid
Cyclophosphamide
Anti-TNF α antibodies
Ursodeoxycholic acid
635
636
636
636
637
637
637
Overlap syndromes and treatment 638
Liver transplantation 639
Recurrence and de novo AIH ater liver transplantation 639
Primary biliary cholangitis 641
Introduction 641
Deinition and prevalence of PBC 642
Diagnostic principles of PBC 643
Therapeutic principles in PBC 644
Primary sclerosing cholangitis 648
Diagnosis of primary sclerosing cholangitis (PSC) 648
Diferential diagnosis: sclerosing cholangitis 650
Association of PSC with inlammatory bowel disease 651
PSC as a risk factor for cancer 652
Medical therapy of PSC 653
Therapy of IBD in PSC 654
References 657
25. Alcoholic hepatitis 663
Claus Niederau
Health and social problems due to alcohol overconsumption 663
Prevention of harmful alcohol use 664
Classiication and natural history of alcoholic liver disease 664
Clinical features and diagnosis of alcoholic hepatitis 666
Course and severity 667
Mechanisms of alcohol-related liver injury 669
Role of PNPLA3 polymorphisms and other
genetic factors in the progression of alcoholic liver disease 673
Treatment 673
Abstinence from alcohol 673
Supportive therapy 674
Corticosteroids 674
Pentoxifylline 675
Comparison and combination of corticosteroids and pentoxifylline 676
N-acetyl cysteine 677
Anti-TNF-α therapy 678
Therapy with granulocyte colony-stimulating factor (G-CSF)
Nutritional support
Other pharmacologic treatments
Liver transplantation
678
679
680
678
Summary 681
References 681
26. Vascular liver disease 687
Matthias J. Bahr
Disorders of the hepatic sinusoid 688
Sinusoidal obstruction syndrome (Hepatic veno-occlusive disease) 688
Peliosis hepatis 693
Disorders of the hepatic artery 695
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) 696
Disorders of the portal vein 699
Portal vein thrombosis 699
Idiopathic non-cirrhotic portal hypertension (INCPH) 704
Disorders of the hepatic veins 706
Budd-Chiari syndrome 706
References 709
27. Acute liver failure 713
Akif Altinbas, Lars P. Bechmann, Hikmet Akkiz, Guido Gerken, Ali Canbay
Introduction and deinition 713
Epidemiology and aetiologies 713
Intoxication 714
Amanita intoxication 716
Viral hepatitis 716
Immunologic etiologies 716
Wilson’s Disease 717
Vascular disorders 717
Pregnancy-induced liver injury 717
Undetermined
718
Molecular mechanisms and clinical presentation 718
Prognosis 720
Treatment 722
General management 722
Hepatic encephalopathy 723
Coagulopathy 723
Liver transplantation 723
Extracorporal liver support systems 724
Speciic treatment options 724
References 726
26 27
1. Hepatitis A
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Sven Pischke and Heiner Wedemeyer
The virus
Hepatitis A is an inlammatory liver disease caused by infection with
the hepatitis A virus (HAV). HAV is a single-stranded 27 nm non-enveloped,
icosahedral RNA virus, which was irst identiied by immune electron
microscopy in 1973 (Feinstone 1973). The virus belongs to the hepadnavirus
genus of the Picornaviridae. Recent structure-based phylogenetic analysis
placed HAV between typical picornavirus and insect picorna-like viruses
(Wang 2015). Recent work suggests a rodent origin of HAV based on a large
screening for hepatoviruses in more than 200 small mammal species
(Drexler 2015). HAV uses host cell exosome membranes as an envelope
which leads to protection from antibody mediated neutralisation (Feng
2013) but also facilitates detection of HAV by plasmacytoid dendritic cells
which are main sources for type I interferon during infection (Feng 2015). Of
note, only blood but not bile HAV shows host-derived membranes.
Seven diferent HAV genotypes have been described, of which four are
able to infect humans (Lemon 1992).
The positive-sense single-stranded HAV RNA has a length of 7.5 kb and
consists of a 5’ non-coding region of 740 nucleotides, a coding region of 2225
nucleotides and a 3’ non-coding region of approximately 60 nucleotides.
Acute hepatitis A is associated with a limited type I interferon response
(Lanford 2011), which may be explained by cleavage of essential adaptor
proteins by an HAV protease-polymerase precursor (Qu 2011). Recently
HAV has been shown to interact with the mitochondrial antiviral signaling
(MAVS) protein resulting in interferon-independent intrinsic hepatocellular
apoptosis and hepatic inlammation (Hirai-Yuki 2016). A dominant role
of CD4+ T cells to terminate HAV infection has been established in HAV
infected chimpanzees (Zhou 2012). However, in human s strong HAV-speciic
CD8 T cells have also been described, potentially contributing to resolution
of infection (Schulte 2011). A failure to maintain these HAV-speciic T cell
responses could increase the risk for relapsing HAV.
Epidemiology
HAV infections occur worldwide, either sporadically or in epidemic
outbreaks. An estimated 1.4 million cases of HAV infections occur each
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1. Hepatitis A
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year. HAV is usually transmitted and spread via the faecal-oral route
(Lemon 1985). Thus, infection with HAV occurs predominantly in areas of
lower socioeconomic status and reduced hygienic standards, especially
in low-income, tropical countries. Not surprisingly, a study investigating
French children conirmed that travel to countries endemic for HAV is
indeed a risk factor for the presence of anti-HAV antibodies (Faillon 2012).
In high-income countries like the US or Germany the number of reported
cases has decreased markedly in the past decades, according to oicial data
published by the Centers for Disease Control and Prevention (CDC, Atlanta,
USA) and the Robert Koch Institute (RKI, Berlin, Germany) (Figure 1). This
decrease is mainly based on improved sanitary conditions as, e.g., recently
demonstrated for Southern Italy (Zuin 2016). Moreover, vaccination
programmes have also resulted in fewer HAV infections in various endemic
countries including Argentina, Brazil, Italy, China, ussia, Ukraine, Spain,
Belarus, Israel and Turkey (Hendrickx 2008).
Despite of the overall decrease in the frequency of hepatitis A in
industrialised countries HAV outbreaks still occur. For example, HAV
outbreaks have been described both in Europe and the US that were linked
to frozen berries (Guzman Herrador 2014, Fitzgerald 2014) or imported
pomegranate arils (Collier 2014). An outbreak of HAV was also described in
Tel Aviv, Israel. Interestingly four of the patients (5%) had been previously
vaccinated. In addition to the observed outbreak, HAV could be detected in
sewage samples from various regions in Israel indicating the presence of
this virus across Israel (Manor 2016).
Transmission
HAV is transmitted faecal-orally either by person-to-person contact
or ingestion of contaminated food or water. Usually HAV is restricted to
humans and is not considered to be a zoonosis. However, experimental HAV
infection of pigs has been demonstrated (Song 2015). HAV transmission is
also possible by blood transfusion but considered to be extremely rare (da
Silva 2016).
Five days before clinical symptoms appear, the HAV can be isolated
from the faeces of patients (Dienstag 1975). The virus stays detectable in
the faeces up to two weeks ater the onset of jaundice. Faecal excretion
of HAV up to ive months ater infection can occur in children and
immunocompromised persons. A recent study from Brazil evaluated the
risk of household HAV transmission within a cohort of 97 persons from 30
families (Rodrigues-Lima 2013). Person-to-person transmission was seen
in six cases indicating a relevant risk for relatives of patients with HAV.
On the other hand, there was no evidence of HAV transmission in another
incident by an HAV-infected food handler in London (Hall 2014). Further
studies are necessary to evaluate the use of HAV vaccination of relatives at
risk in this setting.
Figure 1. Number of reported cases of HAV infections in the US and Germany over the last
decade (Sources: CDC through 2012 and Robert Koch Institute through 12/2015)
Risk groups for acquiring an HAV infection in high-income countries
are health care providers, military personnel, psychiatric patients and
men who have sex with men. Parenteral transmission by blood transfusion
has been described but is a rare event. Mother-to-fetus transmission has
not been reported (Tong 1981). Distinct genetic polymorphisms including
variants in ABCB1, TGFB1, XCC1 may be associated with a susceptibility
to HAV (Zhang 2012).
Recently it was shown that the number of reported HAV infections in
the USA decreased from 6 cases/ 100000 in 1999 to 0.4 cases/ 100000 in
2011, while the percentage of hospitalisations due to HAV increased from
7.3% to 24.5% indicating that HAV is becoming a rare condition but can still
cause serious morbidity, especially in elderly and patients with underlying
liver disorders (Ly 2015). In line with this report the overall immunity to
HAV is declining in United States (Klevens 2015) suggesting that vaccination
coverage needs to be improved.
Clinical course
The clinical course of HAV infection varies greatly, ranging from
asymptomatic, subclinical infections to cholestatic hepatitis or fulminant
liver failure (Figure 2).
30 31
Figure 2. Possible courses of HAV infection
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Most infections in children are either asymptomatic or unrecognised,
while 70% of adults develop clinical symptoms of hepatitis with jaundice
and hepatomegaly.
The incubation time ranges between 15 and 49 days with a mean of
approximately 30 days (Kof 1992). Initial symptoms are usually nonspeciic and include weakness, nausea, vomiting, anorexia, fever, abdominal
discomfort, and right upper quadrant pain (Lednar 1985). As the disease
progresses, some patients develop jaundice, darkened urine, uncoloured
stool and pruritus. The prodromal symptoms usually diminish when
jaundice appears.
Approximately 10% of infections take a biphasic or relapsing course.
In these cases the initial episode lasts about 3–5 weeks, followed by a
period of biochemical remission with normal liver enzymes for 4–5 weeks.
Relapse may mimic the initial episode of the acute hepatitis and complete
normalisation of ALT and AST values may take several months (Tong 1995).
A recent investigation in two HAV-infected chimpanzees demonstrated
that the CD4 count decreased ater clinical signs of HAV disappeared (Zhou
2012). Eventually, an intrahepatic reservoir of HAV genomes that decays
slowly in combination with this CD4 response, may explain the second
phase of disease, but further observations on human patients are required
to verify this.
Cases of severe fulminant HAV leading to hepatic failure occur more
oten in patients with underlying liver disease. Conlicting data on the
course of acute HAV have been reported for patients with chronic hepatitis
C (HCV). While some studies showed a higher incidence of fulminant
hepatitis (Vento 1998), other studies do not conirm these indings and even
suggest that HAV superinfection may lead to clearance of HCV infection
1. Hepatitis A
(Deterding 2006). Other risk factors for more severe courses of acute HAV
are age, malnutrition and immunosuppression. Severity of liver disease
during acute HAV has recently been shown to be associated with a distinct
polymorphism in TIM1, the gene encoding for the HAV receptor (Kim 2011).
An insertion of six amino acids at position 157 of TIM1 leads to more eicient
HAV binding and greater NKT lytic activity against HAV infected liver cells.
In contrast to hepatitis E, there are no precise data on the outcome of
HAV infection during pregnancy. Some data suggest an increased risk of
gestational complications and premature birth (Elinav 2006).
HAV has a lethal course in 0.1% of children, in 0.4% of persons aged
15–39 years, and in 1.1% in persons older than 40 years (Lemon 1985). In
contrast to the other faecal-orally transmitted hepatitis (hepatitis E), no
chronic courses of HAV infection have been reported so far.
Extrahepatic manifestations
Extrahepatic manifestations are uncommon in HAV (Pischke 2007). If
they occur, they usually show an acute onset and disappear upon resolution
of HAV infection in most cases. Possible extrahepatic manifestations of
acute HAV infection are arthralgia, diarrhoea, renal failure, red cell aplasia,
generalised lymphadenopathy, and pancreatitis. Arthralgia can be found in
11% of patients with hepatitis A.
Very uncommon are severe extrahepatic manifestations like pericarditis
and/or renal failure. An association of hepatitis A with cryoglobulinaemia
has been reported but is a rare event (Schif 1992). Furthermore, cutaneous
vasculitis can occur. In some cases, skin biopsies reveal anti-HAV-speciic
IgM antibodies and complements in the vessel walls (Schif 1992). In
contrast to hepatitis B or C, renal involvement is rare, and there are very
few case reports showing acute renal failure associated with HAV infection
(Pischke 2007). Recently it has been shown that approximately 8% of HAV
cases are associated with acute kidney injury (Choi 2011).
Diagnosis
Diagnosis of acute HAV is based on the detection of anti-HAV IgM
antibodies or HAV RNA. The presence of HAV IgG antibodies can indicate
acute or previous HAV infection. HAV IgM and IgG antibodies also become
positive early ater vaccination, with IgG antibodies persisting for at least two
to three decades ater vaccination. Antibodies against HAV and HAV RNA
can also be detected in saliva (Amado Leon 2015). Available serological tests
show a very high sensitivity and speciicity. Recently, a study from Taiwan
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revealed that HIV-infected patients develop protective antibody titres
ater HAV vaccination less frequently than healthy controls (Tseng 2012).
In addition a study examining the immune response to HAV vaccination
in 282 HIV positive patients (Mena 2013) demonstrated that male sex or
HCV coinfection were associated with lower response rates. Furthermore,
it was shown that in people living with HIV, HAV vaccination with three
doses results in an improved durability of antibodies in comparison with
two-dose vaccination (Cheng 2016), while a Nicaraguan study on children
demonstrated that one-dose vaccination resulted in an adequate long-term
immune memory (Mayorga 2016).
A large study investigated 183 adolescents (age 15 to 16 years) who had
been vaccinated with a two-dose HAV vaccination at an age of 6, 12 or 15
months. Seropositivity was lower in children who were vaccinated at
6 months as well as in children where maternal HAV antibodies were
transferred (Spradling 2015). This study demonstrates that HAV vaccination
should usually be performed ater 12 months of age, which is in line with
the current US recommendations. Delayed seroconversion may occur in
immunocompromised individuals, and testing for HAV RNA should be
considered in immunosuppressed individuals with unclear hepatitis. HAV
RNA testing of blood and stool can determine if the patient is still infectious.
However, it has to be kept in mind that various in-house HAV RNA assays
may not be speciic for all HAV genotypes and thus false negative results
can occur.
Elevated results for serum aminotransferases and serum bilirubin
can be found in symptomatic patients (Tong 1995). ALT levels are usually
higher than serum aspartate aminotransferase (AST) in non-fulminant
cases. Increased serum levels of alkaline phosphatase and gamma-glutamyl
transferase indicate a cholestatic form of HAV infection. The increase
and the peak of serum aminotransferases usually precede the increase of
serum bilirubin. Laboratory markers of inlammation, like an elevated
erythrocyte sedimentation rate and increased immunoglobulin levels, can
also frequently be detected.
Recently within a small pilot study, examining 10 patients with acute
HAV, saliva contained HAV RNA in 8/10 (80%) and anti HAV IgM in 10/10
(100%) (Armado Leon 2014). The relevance of this inding and the potential
value of saliva testing needs to be studied in larger cohorts.
Treatment and prognosis
There is no speciic antiviral therapy for treatment of HAV. Of note,
recent work demonstrated that cyclosporine A and silibinin inhibits HAV
replication in vitro (Esser-Nobis 2015). The clinical value of this observation
still needs to be determined.
Recently a study from the Netherlands investigated the use of postexposure HAV vaccination or prophylaxis with immunoglobulins in
patients with household contact with HAV. In this study, none of t he patients
who received immunoglobulins developed acute HAV in contrast to some
patients who received the vaccine. The study revealed that HAV vaccination
post-exposure might be a suicient option in younger patients (<40 years)
while older patients (>40 years) might beneit from immunoglobulins
(Whelan 2013). The disease usually takes a mild to moderate course, which
does not require hospitalisation, and only in fulminant cases is initiation of
symptom focused therapy necessary. Prolonged or biphasic courses should
be monitored closely. HAV may persist for some time in the liver even when
HAV RNA becomes negative in blood and stool (Lanford 2011), which needs
to be kept in mind for immunocompromised individuals. Acute hepatitis
may rarely proceed to acute liver failure; liver transplantation is required
in few cases. In the US, only 4% of all liver transplantations performed for
acute liver failure were due to HAV (Ostapowicz 2002). In a cohort of acute
liver failures at one transplant centre in Germany, approximately 1% of
patients had HAV infection (Hadem 2008). The outcome of patients ater
liver transplantation for fulminant HAV is excellent. Timely referral to liver
transplant centres is therefore recommended for patients with severe or
fulminant HAV.
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Centers for Disease Control and Prevention. Viral Hepatitis Surveillance – United States 2010. Hepatitis A virus, http://www.cdc.gov/
hepatitis/S tatistics/index.htm , accessed 26 Januar y 2013.
Cheng A, Chang SY, Sun HY, et al. Long-term durability of responses to 2 or 3 doses of hepatitis A vaccination in HIV positive adults on
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Choi HK, Son g YG, Han SH, et al . Clinical features and outcomes of acute kidney injury among patients with acute hepatitis A. J Clin Virol
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da Silva SG, Leon LA, Alves G, et al. Rare Case of Transfusion Transmission of Hepatitis A Virus to Two Patients with Haematological
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Deterding K , Tegtmeyer B, Cornberg M, et a l. Hepatitis A virus infectio n suppresses hepatitis C viru s replication and may lead to cle arance of
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Dienstag JL , Feinstone SM, Kap ikian AZ, Purcell RH. F aecal shedding of hep atitis-A antigen. Lanc et 1975;1:765-7.
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Esser-Nob is K, Harak C, Schu lt P, et al. Hepatology 2015, 62 : 397-408.
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Feng Z, Li Y, McKnigh t KL, et al. Human pDCs prefe rentially sense enveloped h epatitis A virions. J Clin Invest .2015;125:169-76.
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Fitzgerald M, Thornton L, O’Gorman J, et al. Outbreak of hepatitis A infection associated with the consumption of frozen berries, Ireland,
2013 - linked to an internatio nal outbreak. Euro Surv eill. 2014;19(43):pii=20942.
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2. Hepatitis B
Kathrin van Bremen, Christoph Boesecke and Jan-Christian Wasmuth
Introduction
Approximately one third of the world’s population has serological
evidence of past or present infection with the hepatitis B vir us (HBV). Despite
the availability of HBV vaccines, the global prevalence of chronic HBV
infection is estimated to be 3.7% (Lok 2016). The World Health Organization
estimates that in 2015 257 million people were living with chronic HBV
(deined as HBsAg positive) resulting in approximately 887.000 deaths
mostly due to cirrhosis and hepatocellular carcinoma (WHO 2017, WHO
2019).
Since the discovery of HBV by Blumberg in 1965, progress has
been impressive, with the availability of vaccines in the 1980s and the
development of potent antiviral drugs two decades later. Nevertheless, the
global burden of chronic HBV remains substantial and healing of chronic
HBV still remains almost impossible.
There is a wide range of HBV prevalence rates in diferent parts of the
world (from 0.1% up to 20%). Low prevalence areas (<2%) represent 12% of
the global population and include Western Europe, the United States and
Canada, Australia and New Zealand. In these regions, the lifetime risk of
infection is less than 20%. Intermediate prevalence is deined as 2% to 7%,
with a lifetime risk of infection of 20–60% and includes the Mediterranean
countries, Japan, Central Asia, the Middle East, and Latin and South
America, representing about 43% of the global population. High prevalence
areas (≥8%) include Southeast Asia, China, and sub-Saharan Africa, where a
lifetime likelihood of infection is greater than 60%. The diverse prevalence
rates are probably related to diferences in age at infection, which correlates
with the risk of chronicity. The progression rate from acute to chronic HBV
infection decreases with age. Approximately 90% of infections acquired
perinatally will progress compared to 5% or less for adult infections
(Stevens 1975, Wasley 2008, Pan 2016).
The incidence of new HBV infections has decreased in most highincome countries, most likely due to the implementation of vaccination
strategies (Rantala 2008, Leroy 2015). However, exact data is diicult to
generate as many cases remain undetected due to the asymptomatic nature
of the infection. In Germany, 4.507 cases (acute or chronic) of HBV were
documented in 2018, corresponding to an incidence rate of 5.4 per 100,000
inhabitants (RKI 2019). From 2001 until 2009 there was a stable decrease in
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2. Hepatitis B
https://t.me/medicina_free
infections which then stagnated until 2014. Since 2015 there has been a rise
in the number of infections mostly due to migration and boosted testing
as well as a change in the deinition of diagnosis (RKI 2019). Likewise, the
incidence of acute HBV in the United States has decreased considerably in
the last two decades (Wasley 2008, CDC 2012). Due to the persisting opioid
crisis the number of acute HBV infections in the US slightly increased
in 2017 (CDC 2017). Moreover, in Germany as well as in the US the major
number of infections is found in foreign born people, presenting 2/3 of all
reported cases in Germany (RKI 2019). Although estimates are diicult
due to a continuously growing migration from high to low prevalence
areas, a further drop in prevalence is expected due to the implementation
of vaccination programmes (Belongia 2008). In Germany, 84,4% of all
children starting school in 2017 were fully vaccinated against HBV, with a
trend toward increasing coverage (RKI 2019).
Thus screening instruments are most important in diagnosing chronic
HBV in migrants, especially facing an increased risk for HCC in those
patients. (ECDC 2019).
Although the incidence of acute HBV infection is decreasing in most
countries, overall HBV-related complications are still on the rise (Gomaa
2008, Hatzakis 2011, Zhang 2013). Reasons for this increase may be the
delay of vaccination efects and the improved diagnosis rate of HBV
cases. When looking at the age-adjusted rate ratios of HBV-related HCC
incidence, a continuous decline can be observed following the launch of
vaccination programmes. Recently published results of a large populationbased controlled trial in Chinese newborns show that HCC incidence was
signiicantly lower in the vaccinated group compared to the control group,
with a hazard ratio of 0.16 (Qu 2014).
Transmission
The predominance of transmission modes varies considerably in
diferent geographic areas. For example, in Western Europe (a low
prevalence area), the main routes are unprotected sexual intercourse and
intravenous drug use. In sub-Saharan Africa (a high prevalence area),
perinatal infection is the predominant mode of transmission. Horizontal
transmission, particularly in early childhood, is regarded as the major
route of transmission in intermediate prevalence areas.
Sexual transmission
Sexual transmission of HBV in people who are unvaccinated largely
occurs among heterosexual men or women who either have multiple sex
partners or contact with sex workers, or among men who have sex with
men (MSM). In low prevalence areas, sexual transmission is the major route
of transmission. In the United States, heterosexual contacts amount up to
40% of newly diagnosed HBV infections, MSM approximately 25% (Wasley
2008), in Germany in 2018 27% of newly diagnosed HBV infections were due
to sexual intercourse with 58% in heterosexual contacts and 42% in MSM
(RKI 2019). Comparatively high rates of HIV/HBV coinfections are observed
in German MSM, as less than half of HIV positive patients are vaccinated
against HBV (Jansen 2015). However, as noted above, infection in adulthood
leads to chronic hepatitis in less than 5% of cases. Measures to prevent
sexual HBV transmission are vaccination – especially of risk groups – and
safer sex practices.
Percutaneous inoculation
Percutaneous inoculation seems to be an efective mode of HBV
transmission, with an estimated risk as up to 30% in individuals without
post-exposure prophylaxis (PEP) or adequate vaccination (Deisenhammer
2006, Hofmann 2002). The most important percutaneous transmission
route is sharing syringes and needles by people who inject drugs (PWID),
representing about 15% of newly diagnosed HBV infections in low prevalence
areas such as Europe and the United States (Wasley 2008). Sharing razors
or toothbrushes are other potential ways of percutaneous transmission,
although absolute risk remains unknown. In addition, practices like
acupuncture, tattooing, and body piercing have been associated with
transmission of HBV. Public health education and the use of disposable
needles or equipment are important methods of prevention.
Perinatal transmission
Perinatal transmission is the major route of HBV transmission in many
parts of the world, and an important factor in maintaining the reservoir
of the infection, particularly in high prevalence areas. In the absence of
prophylaxis, chronic HBV infection will develop in 80 to 90% of infants
born to mothers who are positive for HBV e antigen (HBeAg) (Lee 2006).
Neonatal vaccination has demonstrated high eicacy, indicating that
transmission mostly occurs at or shortly before birth. On the other hand,
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