Skip to main content
main-content

01.12.2017 | Minireview | Ausgabe 1/2017 Open Access

BMC Medicine 1/2017

Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals

Zeitschrift:
BMC Medicine > Ausgabe 1/2017
Autoren:
Thomas F. Baumert, Frank Jühling, Atsushi Ono, Yujin Hoshida

Background

Chronic infection of hepatitis C virus (HCV), estimated to affect more than 150 million individuals globally, has proven a major health problem by causing liver cirrhosis and cancer. Hepatocellular carcinoma (HCC), the major liver cancer histological type, is the second leading cause of cancer mortality worldwide [1]. Interferon-based regimens have been the mainstay of anti-HCV therapy, yielding HCV cure, or sustained virologic response (SVR), in approximately 50% of patients [2]. Recently developed direct-acting antivirals (DAAs), which directly target the viral protease, polymerase, or non-structural proteins, have enabled interferon-free anti-HCV therapies with a revolutionary improvement of SVR rate, approaching or surpassing 90% [3]. Despite the unprecedentedly high antiviral efficacy, access to therapy remains limited, at less than 10% of the total number of HCV-infected individuals, especially in developing countries, due to the high drug costs [4, 5]. In addition, the high frequency of unrecognized HCV infection in the general and specific (e.g., inmates and homeless) populations, estimated at 50% or above of infected individuals, hampers control of the virus even with the commercialization of DAAs [5, 6]. With the 3–4 million newly infected cases each year, it is estimated that the HCV-associated disease burden will remain high in the next decade, even in developed countries [79].
Wider use of DAAs has revealed several limitations, including more refractory genotype 1a or 3 virus, emergence of resistant HCV stains with characteristic resistance-associated substitutions, and poorer response in prior non-responders to interferon-based therapies [10]. These findings warrant further development of alternative strategies such as the application of specific DAA combination therapies to target resistant HCV strains, host targeting agents/viral entry inhibition, and the development of diagnostic tools to monitor therapeutic progress and success [1114]. Even after SVR, re-infection can occur in up to 10–15% of patients, especially in high-risk populations such as injection drug users [1517]. Post-transplantation graft re-infection is also a critical issue given that most liver explants (67%) remain HCV RNA positive in the liver despite undetectable blood HCV RNA [18]. In these clinical scenarios, a prophylactic vaccine is likely to be an effective option. Although HCV vaccine development is challenging due to the high viral genetic variability, promising progress has been made to date [16]. Thus, complementary antiviral approaches including improved and more accessible therapies as well as the development of a prophylactic vaccine will be necessary to achieve impactful global control of infection that leads to HCV eradication, namely a reduction of regional incidence close to zero.

Effect of HCV cure on HCC development

HCV-induced progressive liver fibrosis and aging are well-established high-risk conditions for HCC development (Fig. 1) [1]. Of note, the highly carcinogenic “field effect” in fibrotic/cirrhotic livers leads to repeated recurrence of de novo HCC tumors even after curative treatment of the initial primary tumors. The effect of achieving an SVR on HCC risk has been reported in multiple retrospective cohorts of patients who were mostly treated with interferon-based therapies (Table 1); these studies consistently showed significant reduction of HCC incidence in SVR patients. A pooled analysis of 12 observational studies with a total of 25,497 patients showed that interferon-induced SVR resulted in an approximately four-fold reduction of HCC risk irrespective of liver disease stage (hazard ratio, 0.24; P < 0.001) [19]. Annual HCC incidence in patients with advanced liver fibrosis or cirrhosis and active HCV infection is reported to range from 1% to 8% [1], reducing to 0.07% to 1.2% after achieving an SVR by interferon-based therapies (Table 1). SVR is also implicated in reduction of all-cause mortality, which may alter patient prognosis to the level of the general population, although this is yet to be established [20, 21]. In cirrhotic patients who failed to achieve SVR, subsequent maintenance low-dose interferon treatment reduced annual HCC incidence to 1.2% when compared to 4.0% in untreated patients (hazard ratio, 0.45; P = 0.01) [22]. This result suggests that the anti-inflammatory and/or immunomodulatory effects of interferon may have HCC-preventive effects irrespective of HCV presence, although the adverse effects (flu-like symptoms, neuropsychiatric and myelosuppressive effects) hamper its wider use [1]. DAAs are shown to be less toxic, and are expected to overcome the limitations of interferon-based therapies. DAAs were indeed well-tolerated even in compensated and decompensated cirrhosis patients in recent clinical trials [23, 24]. However, their HCC preventive effect is still only partially understood.
Table 1
Incidence of post-sustained virologic response (SVR) hepatocellular carcinoma (HCC) development and recurrence
Author (year), Reference
Major race
Country
Type of anti-HCV therapy
n
Follow-up, median, years
Male sex, n (%)
Age, median, years
Advanced fibrosis/cirrhosis, n (%)
Treatment for previous HCC
Reported HCC incidence in SVR, % (interval in years)
Annual HCC incidence in SVR, %
Reported HCC incidence in non-SVR, % (interval in years)
Annual HCC incidence in non-SVR, %
Study design
HCC development
              
Akuta (2011) [34]
Asian
Japan
IFN-based
1273
1.1
783 (61.5)
53
109 (8.6)
3.2 (5)
0.65
Retrospective
Chang (2012) [51]
Asian
Taiwan
IFN-based
1271 (including 400 non-SVR)
3.4
661 (75.9)
55.4a
355 (27.9)
1.2 (3)
0.4
Retrospective
Huang (2014) [52]
Asian
Taiwan
IFN-based
642
4.4
302 (54.3)
51.4a
86 (13.4)
5.8 (5)
1.2
Retrospective
Yamashita (2014) [53]
Asian
Japan
IFN-based
562
4.8
311 (55.3)
57
129 (23.0)
3.1 (5)
0.63
Retrospective
Oze (2014) [54]
Asian
Japan
IFN-based
1425
3.3
727 (51.0)
54.5
118 (11.6)
2.6 (5)
0.53
11.7 (5)
2.49
Prospective
Toyoda (2015) [55]
Asian
Japan
IFN-based
522
7.2
292 (55.9)
50.6
27 (5.5)
1.2 (5)
0.24
Retrospective
Wang (2016) [56]
Asian
Taiwan
IFN-based
376
7.6
185 (49.2)
54.1
127 (33.8)
1.4 (5)
0.28
Retrospective
Kobayashi (2016) [57]
Asian
Japan
IFN-based
528
7.3
308 (58.4)
54
78 (14.8)
2.2 (5)
0.44
Retrospective
El-Serag (2016) [36]
Caucasian
USA
IFN-based
10,738
2.8
10,232 (95.3)
53.1a
1548 (14.4)
0.33 (5)
0.07
Retrospective
Nagaoki (2016) [58]
Asian
Japan
IFN-based
1094
4.2
585 (53.5)
60
208 (1.9)
4.0 (5)
0.82
Retrospective
Tada (2016) [59]
Asian
Japan
IFN-based
587
14.0
324 (55.2)
50
4.4 (10)
0.45
14.7 (10)
1.59
Retrospective
Tada (2016) [60]
Asian
Japan
IFN-based
170
14.2
106 (62.4)
52.5
7.1 (10)
0.74
Retrospective
van der Meer (2016) [61]
Caucasian
Europe and Canada
IFN-based
1000
5.7
676 (68.0)
52.7
842 (85.0)
7.6 (8)
0.99
Retrospective
Kobayashi (2016) [57]
Asian
Japan
DAAs
77
4.0
34 (44.2)
63
23 (29.9)
3.0 (5)
0.62
Retrospective
HCC development or recurrence
              
Conti (2016) [39]
Caucasian
Italy
DAAs
344 (59 had previous HCC, including 30 non-SVR)
0.5
207 (60.1)
63
39 (11.3)
Resection, ablation, TACE
3.2 (0.5)d
6.3d
Retrospective
Cheung (2016) [24]
Caucasian
UK
DAAs
317 (18 had previous HCC)
1.3
NA
54
254 (80.1)
Resection, ablation, TACE
5.4 (1.3)
4.27
11.2 (1.3)
9.14
Prospective
HCC recurrence
              
Saito (2014) [62]
Asian
Japan
IFN-based
14
3.9
13 (92.9%)
72
12 (85.7)
Resection, ablation
18.0 (3)
6.62
75.3 (3)
46.61
Retrospective
Huang (2015) [63]
Asian
Taiwan
IFN-based
56
4.4
36 (64.3)
61.6
21 (37.5)
Resection, ablation
43.2b
84.8b
Retrospective
Kunimoto (2016) [64]
Asian
Japan
IFN-based
40
5.1
35 (87.5%)
65
14 (35.0)
Resection, ablation
23.0 (3)
8.71
56.0 (3)
27.37
Retrospective
Petta (2016) [65]
Caucasian
Italy
IFN-based
57
2.8
41 (72.0)
62
0
Resection, ablation
15.2 (2)
8.24
Retrospective
Minami (2016) [66]
Asian
Japan
IFN-based
38
27 (71.0)
66
0
Ablation
52.9 (2)
37.6
Retrospective
Conti (2016) [39]
Caucasian
Italy
DAAs
59 (including 6 non-SVR)
0.5
40 (67.8)
72
10 (16.9)
Resection, ablation, TACE
28.8d (0.5)
49.3d
Retrospective
Reig (2016) [40]
Caucasian
Spain
DAAs
58
0.5
40 (69.0)
66.3
5 (8.6)
Resection, ablation, TACE
27.6d (0.5)
47.6d
Retrospective
ANRS study group (2016) [42]
Caucasian
France
DAAs
189 (including 41 non-SVR)
2.2
147 (78.0)
62a
152 (80.0)
Resection, ablation, LT
0.73b,d
8.76c,d
0.66b,e
7.92c,e
Prospective
ANRS study group (2016) [42]
Caucasian
France
DAAs
13
1.8
11 (85.0)
61a
13 (100)
Resection, ablation
1.1b
13.3c
1.7b,e
20.76c,e
Prospective
ANRS study group (2016) [42]
Caucasian
France
DAAs
314
257 (82.0)
61a
49 (15.6)
LT
2.2 (0.5)
4.4
Prospective
Petta (2016) [65]
Caucasian
Italy
DAAs
58
1.5
40 (69.0)
66.3
2 (4.0)
Resection, ablation
26.3 (2)
15.3
Retrospective
Minami (2016) [66]
Asian
Japan
DAAs
27
18 (67.0)
71
0
Ablation
29.8 (2)
17.7
Retrospective
When not reported, annual HCC incidence was estimated by using the declining exponential approximation of life expectancy [67]
aMean
b100 person-month
c100 person-year
dIncidence in patients including non-SVR patients
eIncidence in patients not treated by anti-HCV therapy
DAA direct-acting antiviral, HCC hepatocellular carcinoma, HCV hepatitis C virus, IFN interferon, LT liver transplantation, SVR sustained virologic response, TACE transarterial chemoembolization

Projected trend of HCV HCC incidence with new generation anti-HCV therapies

HCC is the most rapidly increasing cause of cancer death, with HCV as the major etiology affecting generally more than half of HCC patients in developed countries such as the USA [25]. HCV incidence increases are more prominent in specific subpopulations such as the 1945–1965 birth cohort (baby boomers) in the USA, in whom a 64% incidence was observed between 2003 and 2011; such an incidence is estimated to result in more than one million HCV-related cirrhosis and/or HCC by 2020, with increasing HCC incidence until 2030 [2628]. In US veterans, HCC incidence has increased by 2.5-fold and mortality has tripled since 2001, driven overwhelmingly by HCV [29]. In a regional population in Australia, in contrast to the decreased incidence of hepatitis B virus (HBV)-related HCC due to clinical implementation of the antivirals, anti-HCV therapies had no impact on HCV-related HCC risk between 2000 and 2014 [30]. Despite the anticipated improvement in SVR rate with wider use of DAAs, model-based simulation studies have predicted further increases of HCC incidence over the next decade – even with SVR rates of 80–90% by DAAs, predicted HCC incidence will continue to increase until 2035 unless the current annual treatment uptake rate (1–3%) is increased by more than five-fold by 2018 [9, 31, 32]. These studies clearly highlight the urgent need for identification of undiagnosed HCV infection by implementing HCV screening programs targeting high-risk populations as well as improved access to new generation anti-HCV therapies with reduced costs and streamlined treatment intake and follow-up [33].

Post-SVR HCC risk factors

It is noteworthy that SVR does not necessarily mean elimination of HCC risk despite the substantially decreased incidence. In fact, HCC can occur even more than 10 years after successful HCV clearance (Table 1). The annual post-SVR HCC incidence of approximately 1% is still higher than the cancerous conditions in other organs, and the volume of HCC-developing patients will remain substantial given the vast size of the HCV-infected population [1].
Retrospective interrogation of previously treated patients mostly by interferon-based regimens revealed several post-SVR HCC-associated clinical variables, most of which are known HCC risk factors in patients with active HCV infection (Table 2). More advanced liver fibrosis as well as biochemical or imaging surrogates of histological fibrosis (e.g., serum albumin, platelet count, fibrosis-4 index, aspartate aminotransferase-to-platelet ratio index, elastography-based liver stiffness) before and/or after antiviral treatment are the most prominent features associated with higher post-SVR HCC risk. Older age, alcohol abuse, accompanying metabolic disorders (especially diabetes), and persisting hepatic inflammation, e.g., high aspartate aminotransferase, were also associated with HCC risk. Serum alpha-fetoprotein levels pre- and post-SVR have also been implicated as a risk indicator, with relatively low cut-off values ranging from 5 to 20 ng/mL. In addition to the host factors, post-SVR HCC-associated pre-treatment viral factors have been identified, suggesting that HCV leads to irreversible changes in cellular signaling via mechanisms such as epigenetic activation or imprinting, which continue to drive carcinogenesis even after viral clearance. A variant in genotype 1b HCV core protein, Gln70(His70), was associated with increased HCC incidence post-SVR, with a hazard ratio of 10.5, in a cohort of 1273 interferon-treated Japanese patients [34]. Interestingly, the variant can induce cancer-related transcriptional dysregulation in an HCV-infectious cell system [35]. HCC risk association of genotype 3 was also found in a cohort of 10,817 US veterans [36]. A further study suggested differences in molecular aberrations in HCC tumors from SVR livers compared to tumors in livers with active HCV infection, which may represent SVR-specific mechanisms of carcinogenesis [37].
Table 2
Host and viral risk factors for post-sustained virologic response (SVR) hepatocellular carcinoma (HCC) development (summarized from multivariable Cox regression models)
Risk factor
 
Variable
n
Country
Follow-up, median, years
Hazard ratio
95% CI
P value
Reference
Host factor
Fibrosis
        
 
Pre-SVR
        
  
Histological stage F2-4
562
Japan
4.8
10.7
2.2–192.1
<0.001
[53]
  
Histological stage, F3-4
1273
Japan
1.1
9.0
2.3–35.2
0.002
[34]
  
Histological stage, F3-4
1094
Japan
4.2
3.2
1.6–7.2
<0.001
[58]
  
Histological stage, F3-4
376
Taiwan
7.6
12.8
1.6–101.9
0.021
[56]
  
Histological stage, F3-4
871
Taiwan
3.4
4.0
1.5–10.7
0.007
[51]
  
Platelet, < 150 × 103/mm3
1056
Japan
4.7
2.8
1.1–7.2
0.04
[68]
  
Platelet, < 150 × 103/mm3
871
Taiwan
3.4
2.8
1.2–6.4
0.015
[51]
  
Platelet, < 150 × 103/mm3
1000
Europe and Canada
5.7
1.1
1.0–1.1
0.029
[61]
  
Albumin, < 35 g/dL
399
Sweden
7.8
4.4
1.3–14.7
0.016
[69]
  
Liver cirrhosis, yes
1351
Taiwan
4.0
8.4
4.1–17.0
<0.001
[70]
  
Liver cirrhosis, yes
4663
Canada
5.6
3.2
1.2–9.0
[71]
 
Post-SVR
        
  
FIB-4 index, high
522
Japan
7.2
1.7
1.1–2.9
0.02
[55]
  
APRI ≥ 0.7
1351
Taiwan
4.0
2.9
1.5–5.7
0.002
[70]
  
Elastography liver stiffness > 12 kPa
376
Taiwan
7.6
6.3
2.1–19.5
0.001
[56]
  
Liver cirrhosis, yes
10,738
USA
2.8
6.7
4.3–10.4
<0.001
[36]
  
Platelet, < 130 × 103/mm3
571
Japan
9.0
3.9
1.5–10.1
0.004
[72]
 
Age, years
≥50
562
Japan
4.8
4.1
1.4–17.4
<0.01
[53]
  
≥55
571
Japan
9.0
3.6
1.4–9.6
0.009
[72]
  
≥60
642
Taiwan
4.4
3.7
1.3–10.2
0.012
[52]
  
≥60
871
Taiwan
3.4
3.8
1.7–8.4
0.001
[51]
  
≥60
4663
Canada
5.6
4.4
1.3–15.3
[71]
  
>60
1094
Japan
4.2
3.1
1.3–6.6
0.009
[58]
  
>60
1056
Japan
4.7
3.1
1.3–7.4
0.01
[68]
  
>60
1000
Europe and Canada
5.7
9.8
1.2–77.8
0.031
[61]
  
≥65
1425
Japan
3.3
5.8
1.1–30.1
0.036
[54]
  
≥65
1351
Taiwan
4.0
2.7
1.2–6.3
0.017
[70]
  
≥65
10,738
USA
2.8
4.5
2.0–10.4
<0.001
[36]
  
Older
589
Taiwan
4.7
1.1
1.0–1.1
0.046
[73]
 
Sex
Male
1094
Japan
4.2
12.0
2.8–50.0
<0.001
[58]
  
Male
4663
Canada
5.6
3.3
1.1–9.6
[71]
  
Male
571
Japan
9.0
7.6
1.7–33.1
0.007
[72]
 
Diabetes
Yes
522
Japan
7.2
2.1
1.1–4.0
0.045
[55]
  
Yes
376
Taiwan
7.6
4.0
1.3–12.1
0.021
[56]
  
Yes
399
Sweden
7.8
3.2
1.1–9.6
0.035
[69]
  
Yes
10,738
USA
2.8
1.9
1.2–2.9
0.005
[36]
  
Yes
1000
Europe and Canada
5.7
2.3
1.0–5.3
0.057
[61]
  
Yes
4663
Canada
5.6
1.6
0.6–4.0
[71]
  
Yes
589
Taiwan
4.7
3.8
1.4–10.1
0.008
[73]
 
Elixhauser comorbidity index
Yes (≥1)
4663
Canada
5.6
2.2
1.0–5.1
[71]
 
Alpha-fetoprotein, ng/mL
        
 
Pre-SVR
≥8
562
Japan
4.8
2.6
1.2–6.1
<0.05
[53]
  
≥15
1351
Taiwan
4.0
1.9
1.0–3.6
0.038
[70]
  
≥20
871
Taiwan
3.4
3.2
1.6–6.2
0.001
[51]
 
Post-SVR
≥5
1425
Japan
3.3
8.1
2.7–23.9
<0.001
[54]
  
≥5
571
Japan
9.0
3.6
1.4–9.6
0.009
[72]
  
≥15
1351
Taiwan
4.0
2.3
1.0–5.3
0.043
[70]
  
≥10
1094
Japan
4.2
7.8
2.9–16.8
<0.001
[58]
 
Race/ethnicity
Hispanic
10,738
USA
2.8
2.3
1.1–4.8
0.032
[36]
 
Alcohol abuse
Yes
562
Japan
4.8
3.9
1.7–9.0
<0.01
[53]
  
Yes
10,738
USA
2.8
1.7
1.1–2.6
0.021
[36]
  
Yes
4663
Canada
5.6
1.1
0.34–3.3
[71]
 
Illicit drug use
Yes
4663
Canada
5.6
3.7
1.0–14.3
[71]
 
AST
>100 IU/L
1056
Japan
4.7
3.1
1.3–7.3
0.01
[68]
 
AST/ALT ratio
>0.72
1000
Europe and Canada
5.7
1.0
1.0–1.1
0.068
[61]
 
GGT
>75 U/L
642
Taiwan
4.4
6.4
2.2–18.9
0.001
[52]
Viral factor
Genotype 1b with Gln70 (His70) variant
 
1273
Japan
1.1
10.5
2.9–38.2
<0.001
[34]
 
Genotype 3
 
10,738
USA
2.8
1.6
1.0–2.7
0.071
[36]
 
Genotype 3
 
4663
Canada
5.6
1.4
0.58–3.4
[71]
All data are from interferon-based studies
APRI aspartate aminotransferase-to-platelet ratio index, ALT alanine aminotransferase, AST aspartate aminotransferase, FIB-4 fibrosis-4, GGT gamma-glutamyl transpeptidase, HCV hepatitis C virus, HCC hepatocellular carcinoma, SVR sustained virologic response
Current practice guidelines recommend regular biannual HCC screening for cirrhotic patients with active HCV infection, but it is still undetermined whether and how post-SVR patients should be monitored for future HCC development and if any of the risk-associated variables has clinical utility [1]. Molecular hallmarks of persisting HCC risk in post-SVR livers may serve as biomarkers to identify a subset of patients still at risk and should be therefore monitored by regular HCC screening. A pan-etiology HCC risk-predictive gene signature in the liver, which was shown to predict post-SVR HCC development, may serve as a biomarker to identify a subset of SVR patients who should be regularly monitored for future HCC [38].

Post-DAA HCC development and recurrence

Accumulating clinical experience of DAA-based treatment has suggested that post-SVR HCC development and recurrence may be more frequent compared to interferon-based treatment (Table 2). In a small series of HCC patients who achieved an SVR by all-oral DAAs after HCC treatment, tumor recurrence rates of approximately 30% within 6 months were reported; these rates are alarmingly high, however, the observation period was short, a proper control group was lacking, and the finding was not replicated in a subsequent study [3943]. Further studies are needed to clarify whether DAAs increase HCC incidence and to determine the natural history and baseline post-SVR HCC incidence according to the type of anti-HCV therapy in each specific patient population. Interestingly, chronic hepatitis B patients treated with directly-acting anti-HBV drugs, entecavir or other nucleos(t)ide analogues, showed higher HCC incidence compared to peg-interferon-treated patients, suggesting that the difference in HCC-suppressive effect may be a common phenomenon across different hepatitis viruses [44].
Several studies suggested a possibly distinct difference in host immune modulation between interferon and DAAs. Rapid decline of HCV viral load by DAAs was experimentally or clinically associated with restored HCV-specific, often exhausted, CD8+ T cell function, memory T cell re-differentiation and lymphocyte deactivation, and normalized NK cell function [4548], all of which may indicate a quick loss of anti-HCV immune responses. Interestingly, reactivation of other co-infected viruses, such as herpes virus, was observed after DAA-based anti-HCV therapy [49], suggesting simultaneous loss of bystander immune response to the viruses and possibly to neoplastic cells, which may lead to higher HCC recurrence after DAA treatment. On the other hand, complete remission of follicular lymphoma after DAA-based therapy was reported, suggesting that the influence of DAA-based SVR on cancer may vary according to cancer types and biological/clinical contexts [50].

Conclusions

HCV-related HCC will remain a major health problem in the coming decades despite the clinical deployment of DAAs. Access to the new generation antiviral therapies should be substantially improved to achieve meaningful prognostic benefit at the population level. The development of a vaccine remains an important goal for global control and eradication of infection. Post-SVR HCC is an emerging problem, with urgent unmet needs for the clinical strategy of early tumor detection and intervention, as well as elucidation of its molecular mechanisms for therapeutic target and biomarker discovery. Prolonged clinical observation should be further accumulated to determine the impact of DAA-induced SVR on HCC development and recurrence as well as on other cancer types.

Acknowledgements

The authors acknowledge grant support of the European Union (ERC-2014-AdG-671231HEPCIR (TFB, YH), H2020-667273-HEPCAR (TFB), ANRS (TFB), the French Cancer Agency (ARC IHU201301187 (TFB)), the IdEx program of the University of Strasbourg (TFB), the Foundation University of Strasbourg (TFB), U.S. NIH/NIDDK R01 DK099558 (YH), Irma T. Hirschl Trust (YH), and U.S. Department of Defense (W81XWH-16-1-0363 YH, TFB). This work has been published under the framework of the LABEX ANR-10-LAB28 and benefits from a funding from the state managed by the French National Research Agency as part of the Investments for the future program.

Availability of data and materials

Not applicable.

Authors’ contributions

TFB, FJ, AO, and YH drafted and revised the manuscript. TFB and YH supervised the review process. All authors read and approved the final manuscript.

Competing interests

The authors do not have any conflict of interest and did not receive writing assistance.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.
Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2017

BMC Medicine 1/2017 Zur Ausgabe


 

Neu im Fachgebiet Allgemeinmedizin

Meistgelesene Bücher aus dem Fachgebiet

2018 | Buch

Repetitorium Geriatrie

Geriatrische Grundversorgung - Zusatz-Weiterbildung Geriatrie - Schwerpunktbezeichnung Geriatrie

Das vorliegende Werk orientiert sich an den Fort-bzw. Weiterbildungsinhalten der Zusatz-Weiterbildung „Geriatrie“ , der Schwerpunktbezeichnung „Geriatrie“ sowie der strukturierten curricularen Fortbildung „Geriatrische Grundversorgung“ und wendet …

Herausgeber:
Dr. Rainer Neubart

2012 | Buch

Häufige Hautkrankheiten in der Allgemeinmedizin

Klinik Diagnose Therapie

Patienten mit Hautkrankheiten machen einen großen Anteil der Patienten in der Allgemeinarztpraxis aus. Prägnante Texte und zahlreiche Abbildungen zu Klinik, Pathogenese, Diagnose und Therapie helfen, die häufigsten dermatologischen Probleme zu lösen.

Autor:
Prof. Dr. med. Dietrich Abeck

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Allgemeinmedizin und bleiben Sie gut informiert – ganz bequem per eMail.

Bildnachweise