558
Originalarbeit
Prevalence of Risk Factors for Liver Disease in a Random Population Sample in Southern Germany
Authors
M.-L. Huetter1, M. Fuchs2, M. M. Hänle3, R. A. Mason4, A. S. Akinli3, A. Imhof5, W. Kratzer, R. Lorenz3 for the EMIL study group.*
Affiliations
Affiliation addresses are listed at the end of the article.
Schlüsselwörter
Zusammenfassung
Abstract
"
!
!
Hintergrund: Chronische Lebererkrankungen führen zur Fibrose und Zirrhose der Leber: Dies kann wiederum zum chronischen Leberversagen oder zur Entwicklung eines hepatozellulären Karzinoms führen (HCC). Hauptrisikofaktoren für chronische Lebererkrankungen sind virale Hepatitis und Alkoholkonsum. In der vorliegenden Studie wurde die Prävalenz von Hepatitis B und C ermittelt sowie Risikofaktoren für chronische Lebererkrankungen wie Fettleber, virale Hepatitis und Lifestyle-Faktoren in einer zufälligen Bevölkerungsstichprobe untersucht. Methoden: An der Studie nahmen 2256 Probanden (1182 Frauen, 1074 Männer) im Alter von 18 − 65 Jahren teil. Bei allen Probanden wurden standardisierte Ultraschalluntersuchungen und Laboruntersuchungen durchgeführt sowie anthropometrische Größen bestimmt. Die Probanden wurden von November bis Dezember 2002 zufällig aus einer Kleinstadt in Südwestdeutschland ausgewählt. Ergebnisse: Die Ergebnisse zeigen, dass mehrere Faktoren mit einer chronischen Lebererkrankung assoziiert sind. Insgesamt 18,1 % der Probanden gaben einen Alkoholkonsum von über 20 g/Tag an. Das Metabolische Syndrom wurde bei 5,9 % (n = 132) der Probanden diagnostiziert. Insgesamt 45,1 % (n = 1017) der Teilnehmer hatten einen BMI über 25 kg/m². Die Prävalenz von chronischer Hepatitis B lag bei 0,7 % (n = 15), die von Anti-HCV bei 0,6 % (n = 15). Erhöhte gGT-Werte wurden bei 10,4 % (n = 14) der Probanden beobachtet. Die Prävalenz der Steatosis hepatis betrug 25 % (n = 564). Schlussfolgerungen: In vielen Fällen könnten chronische Lebererkrankungen durch gesunde Ernährung, durch Präventionsstrategien wie routinemäßige Impfung, insbesondere gegen Hepatitis-B-Virus (HBV), verhindert werden.
Background: Chronic liver disease leads to fibrosis and cirrhosis of the liver. This may, in turn, result in chronic liver failure or the development of hepatocellular carcinoma (HCC). Main risk factors for chronic liver disease are viral hepatitis and alcoholism. The present study assessed a randomly selected population in southern Germany for risk factors for chronic liver disease such as fatty liver disease, viral hepatis infection and life-style factors. In addition, the potential association with elevated liver enzymes was investigated. Methods: A total of 2256 subjects (1182 females, 1074 males), aged 18 − 65 years, participated in the study. Each subject underwent a standardized ultrasound examination, and anthropometric and biochemical assessments. Test subjects were randomly selected from the general population of a town in southwestern Germany. Data were acquired from November to December 2002 without further follow-up. Results: Several factors were found to be associated with chronic liver disease in the study population. Alcohol consumption > 20 g/d was seen in 18.1 % (n = 409). Metabolic syndrome was diagnosed in 5.9 % (n = 132). The number of people with a BMI greater than 25 kg/m² was 45.1 % (n = 1017). The prevalence of subjects with chronic hepatitis B was 0.7 % (n = 15), that of anti-HCV positive patients, 0.6 % (n = 15). Elevated gGT was seen in 10.4 % (n = 14) of the patients. Prevalence of hepatic steatosis was 25.0 % (n = 564). Conclusions: Many cases of chronic liver disease could be prevented by healthy nutrition, optimized medical treatment of associated disorders, and prevention strategies such as routine vaccination, in particular, against hepatitis B virus (HBV).
● Querschnittsstudien ● Ultraschall ● Fettleber ● Hepatitis B ● Hepatitis C " " " "
Key words
● cross-sectional-studies ● ultrasonography ● fatty liver ● hepatitis B ● hepatitis C " " " " "
received accepted
8.8.2013 13.1.2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1366017 Z Gastroenterol 2014; 52: 558–563 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0044-2771 Correspondence Prof. Dr. Wolfgang Kratzer Department of Internal Medicine I, Albert-EinsteinAllee 23, University Hospital Ulm 89081 Ulm Germany Tel.: ++ 49/7 31/50 04 47 30 Fax: ++ 49/7 31/50 04 46 20 [email protected]
Huetter M-L et al. Prevalence of Risk … Z Gastroenterol 2014; 52: 558–563
* These authors contributed equally
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Prävalenz von Risikofaktoren für eine Lebererkrankung in einer zufälligen Bevölkerungsstichprobe in Süddeutschland
Originalarbeit
!
Chronic liver disease (CLD) can result from a variety of causes. Most significant among these are viral hepatitis (hepatitis B or C) and alcohol abuse. Other important causes of CLD include autoimmune and metabolic diseases. Over time, CLD progresses to fibrosis and ultimately cirrhosis of the liver. The mortality rate is very high in patients suffering from liver cirrhosis or hepatocellular carcinoma (HCC) [1]. In the German population, CLD is most often the result of chronic alcohol abuse, with viral hepatitis (mainly hepatitis C) constituting a second major cause [2 – 4]. The extent of liver damage is directly associated with the duration and amount of alcohol abuse. According to the German Centre Against the Dangers of Addiction (DHS) and sample surveys, the estimated number of adults with alcohol-related liver disease in Germany is estimated at 2.0 to 3.2 million, 80 % of whom are men. Alcohol-related liver diseases in Germany are about as frequent as in other countries with high alcohol consumption, such as France [5]. The World Health Organization (WHO) estimates that about onethird of the world’s population, or two billion persons, have been infected with the hepatitis B virus (HBV), with about 5 % of the world’s population (350 million people) suffering from chronic HBV infection. In contrast, only about 3 % of the global population has had contact with the hepatitis C virus (HCV): an estimated 170 million people, however, are believed to be chronically infected [6]. A striking heterogeneity characterizes the distribution of HBV (0.1 − 8 %) and HCV (0.1 − 6.0 %) in European nations. The incidence of HCV infections has continued to increase in Europe, while that of HBV has tended to decline [7]. More recent studies of HCV prevalence in Germany report an HCV seroprevalence of 2.6 %. It should be noted, however, that these data stem from highly selected emergency room patients from large cities with a large proportion of high-risk patients and patients with an immigrant background [8]. Data from the German Health Interview and Examination Survey for Adults (DEGS1) show falling prevalence figures for HBV and HCV [9]. The studies of Cornberg et al. for Europe, Canada and Israel appear to confirm this trend toward low prevalence figures, especially for Germany [10]. HBV and HCV infections represent important risk factors worldwide for the development of cirrhosis of the liver, accounting for about 30 % of cases. Hepatocellular carcinoma (HCC) is caused by HBV in 50 % of cases; a further 25 % are associated with HCV. Worldwide, it is estimated that up to one million persons die annually as a result of liver cirrhosis or HCC secondary to HBV or HCV infection [11, 12]. HBV infection in Germany is mainly associated with unsafe sexual intercourse. Some people acquire HBV by receiving infusions or injections, specifically through intravenous drug abuse. The transmission pathway is clear in only 50 %. The risk of HBV and HCV transmission was reduced drastically as a result of the implementation of highly sensitive methods for identifying contaminated blood products. Non-alcoholic fatty liver disease (NAFLD) is an increasing problem in Western nations and is mainly associated with metabolic syndrome. It is characterized as a pathological accumulation of fat in the liver in the absence of excessive consumption of alcohol. The prevalence of NAFLD is about 20 − 30 % in developed countries [13, 14]. The progression of NAFLD to inflammation of the hepatic parenchyma leads to non-alcoholic steatohepatitis (NASH). In contrast to NAFLD, NASH may lead to liver cirrhosis and liver failure. NASH is seen in 2 − 3 % of cases of NAFLD [15 – 17].
The present study examined a randomly selected population in southwestern Germany for risk factors for chronic liver disease such as fatty liver disease, viral hepatis infection and life-style factors. A secondary objective was to obtain liver enzyme levels in these subjects.
Methods !
Study population In 2002, we conducted a population-based cross-sectional health survey in the southwestern German city of Leutkirch (EMIL Study: Echinococcus Multilocularis and Internal Diseases in Leutkirch). A total of 4000 of 12 475 residents of an urban population were randomly selected from the registry of inhabitants and invited to participate in the study. Out of the 4000 subjects, 107 were excluded for various reasons (unknown current address, n = 68; not giving informed consent, n = 39). Of 3893 eligible subjects, 2445 persons aged 10 – 65 years participated in the study (participation rate: 62.8 %). The proportion of subjects with an immigrant background was 9.9 %. The largest group was the ethnic Turkish population (4.7 %). Age and gender distribution of the " Fig. 1. inhabitants and the study population are shown in ● We excluded from the present study those subjects for whom the recorded historical, anthropometric, laboratory or sonographic data were incomplete. These exclusions resulted in a cohort of 2256 persons. A more detailed description of subject recruitment has been published elsewhere [18]. Subjects participated in a structured interview (questionnaire) and underwent anthropometric measurements, blood sample collection and an ultrasound examination. Each interview was conducted by a trained interviewer. The questionnaire included personal data (e. g., date of birth, gender, education, medical history), health behaviour (e. g., exercise) and other risk factors for disease (e. g., smoking, blood transfusion). In order to validate the results, multiple cross-checked questions on the same topic were addressed to the participants. The interview was partially based on validated instruments from other studies (e. g., alcohol questions from the MONICA study, [19]).
Anthropometry Based on recommendations of the World Health Organization (WHO), subjects’ height, body weight, hip and waist circumference were determined [20].
Abdominal ultrasound For detection of NAFLD and other pathologies, all participants underwent a real-time ultrasonographic examination of the liver (HDI 5000, Advanced Technology Laboratories Ultrasound, Philips Medical Systems, Bothell, WA, USA). Liver size and contour, focal liver lesions and differences in diameter of the hepatic veins were recorded. The diagnosis of fatty liver (hepatic steatosis) was based on the finding of “bright” liver tissue with fine, tightly packed echoes, making it significantly more echogenic than the adjacent right kidney [21, 22].
Laboratory tests and procedures About 25 mL of venous blood were obtained from a cubital vein. Laboratory testing was performed using standardized procedures. Blood samples for virus serology and determination of liver enzyme concentrations (gGT) were obtained using one serum
Huetter M-L et al. Prevalence of Risk … Z Gastroenterol 2014; 52: 558–563
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Introduction
559
Originalarbeit
Fig. 1 Age and gender distribution of the inhabitants and study population
tube (10 mL) and one lithium-heparin tube (10 mL). For the determination of HCV serology the test Axsym® by Abbott (Abbott GmbH & Co. KG, Wiesbaden, Germany) was used. For the determination of HBV serology the test Elecsys 2010 by Roche (Roche Diagnostics Int., Risch, Switzerland) was used. For transport to the laboratory, serum tubes were stored at –20 °C, while lithium-heparin tubes were stored at 4 °C.
Table 1 Amount of alcohol intake in g/day in subjects with and without steatosis hepatis.
hepatic steatosis no [n (%)] ex-consumer 0g
total [n (%)] yes [n (%)]
47 (2.8)
20 (3.6)
67 (3.0)
678 (40.1)
185 (32.8)
863 (38.3)
0 − 20 g
702 (41.5)
215 (38.1)
917 (40.7)
Metabolic syndrome
21 − 40 g
185 (10.9)
86 (15.3)
271 (12.0)
For purposes of the present study, metabolic syndrome was diagnosed when subjects met at least three of the following five criteria modified from ATP III: obesity with a BMI > 30 kg/ m², serum triglycerides > 1.7 mmol/L, HDL < 1.0 mmol/L (men) or < 1.2 mmol/L (women), history of arterial hypertension, random blood glucose > 8.9 mmol/L and/or history of diabetes mellitus. Data on hypertension and diabetes were assessed from subjects' past medical history.
> 40 g
80 (4.7)
58 (10.3)
138 (6.1)
were assessed using the χ² test, when the number of cases was too small, Fisher’s exact test were used. All statistical tests were two tailed. The significance level was set at α = 5 % (p < 0.05).
Results Ethics and informed consent
!
The study met the requirements of the World Medical Association Declaration of Helsinki on ethical principles for medical research involving human subjects in the version current at the time of the study (2000) and was approved by the research ethics committee of the Baden-Württemberg Medical Association. Each participant provided his or her informed written consent.
Population characteristics
Statistics Statistical calculations were performed using the SAS 9.2 statistics software (SAS Institute Inc., Cary, North Carolina, USA). Data were first analyzed descriptively. Categorical data were presented with absolute and relative frequencies. Potential risk factors
Huetter M-L et al. Prevalence of Risk … Z Gastroenterol 2014; 52: 558–563
A total of 2256 participants took part in this prospective trial, of whom 1074 (47.6 %) were males and 1182 (52.4 %) females. The median age of the participants was 39.4 ± 14.9 years.
Alcohol consumption and hepatic steatosis The total prevalence of hepatic steatosis was 25.0 % (17.3 % women, 33.5 % men). A daily alcohol consumption of 1 − 20 g was reported by 40.7 % of subjects, while 12.0 % reported drinking 21 − 40 g/d. Only 6.1 % admitted more than 40 g per day. gammaGlutamyl transpeptidase (gGT) elevation was seen in 5.8 % of people reporting no alcohol consumption. By contrast, elevated gGT levels were observed in 10 % of those drinking 1 − 20 g/d; in
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560
Originalarbeit
Body-mass index (BMI) A normal body mass index (< 25) was observed in 54.9 % of the study population, while 30.1 % of subjects were overweight (BMI 25 − 30). Obesity was observed in 15.0 %. GGT elevation was reported in 26.4 % of subjects with a BMI < 25. Subjects with a BMI of 25 − 30 showed elevation of GGT in 43.0 % of cases, while 30.6 % of those with a BMI > 30 had an elevation in gGT. Occurrence of " Table 2. hepatic steatosis in obese people is shown in ●
Metabolic syndrome Criteria for metabolic syndrome were met in 5.9 %. In 16.2 % of these subjects, there was elevation of gGT.
Hepatitis B serology At screening, a total of 56 subjects tested positive for anti-HBc antibodies. This represents 2.5 % of the studied population " Table 3). Five of these 56 subjects (8.9 %) showed evidence of (● past HBV infection (antibodies to both HBsAg and HBeAg). In 15 subjects (26.8 %), the presence of HBsAg indicated chronic HBV infection. Thus, chronic HBV infection was present in 0.7 % of the total population. In 36 subjects (64.3 %), only anti-HBc was isolated. Only one of the 15 HBsAg positive subjects was aware of their status: hence, 93.3 % had an unrecorded chronic HBV infection. Concentration of gGT above the respective reference range was documented in one HBsAg positive subject. The occurrence of hepatic steatosis in HBsAg-positive subjects in correlation with " Table 4. elevated liver enzymes is shown in ● " Table 1). Anti-HCV was detected in the sera of 14 subjects (0.6 %; ● Findings were confirmed by subsequent immunoblot in 14 subjects; immunoblot results were questionably positive in the remaining four subjects. Only three of the 14 anti-HCV positive sub-
Hepatic steatosis depending on weight.
hepatis steatosis
p-value
no [n (%)]
yes [n (%)]
1592 (94.1)
326 (57.8)
30 − 35
79 (4.7)
169 (30.0)
35 − 40
14 (0.8)
52 (9.2)
7 (0.4)
17 (3.0)
weight (BMI) < 30
> 40
Table 3
< 0.0001
Hepatitis serology.
n
Discussion !
Individuals suffering from liver cirrhosis or hepatocellular carcinoma (HCC) have a very high mortality rate. Recent years have seen an increased incidence of HCC not only in the USA and Japan but also in European populations [23 – 27]. One explanation of this trend could be that obesity increases the risk of HCC. A recent meta-analysis described an increased HCC risk of 17 % in overweight persons and of 90 % among those with a BMI greater than 30 [28, 29]. In our study population 30.1 % of subjects were overweight (BMI 25 − 30), with 16 % of subjects being obese. This reflects data from the year 2002. Since then, the number of people in Germany struggling with obesity has steadily grown. The reasons for this include a lack of exercise and an unhealthy diet. New data show that 66 % of men and 51 % of women aged 18 − 80 years are overweight; 20 % of all Germans are obese. These individuals are at high risk for developing type-2 diabetes mellitus, hypercholesterolemia and hypertension. An additional problem is that younger people aged 14 − 18 years suffer from obesity in 7 − 11 % [30].
Table 4
Hepatic steatosis depending on hepatitis serology.
variables
Hepatitis C serology
Table 2
jects were aware of their status: hence, 78.6 % had a previously unrecorded HCV infection. Concentration of gGT above the respective reference range was documented in two HCV positive subjects. The occurrence of hepatic steatosis in anti-HCV positive subjects in " Table 4. correlation with elevated liver enzymes is shown in ●
anti-HBc isolated
anti-HBs
HBsAg
anti-HCV
[n (%)]
[n (%)]
[n (%)]
[n (%)]
female 1182 19 (1.6 %)
1 (0.1 %)
8 (0.7 %)
7 (0.6 %)
male
1074 17 (1.6 %)
4 (0.4 %)
7 (0.7 %)
7 (0.7 %)
total
2256 36 (1.6 %)
5 (0.2 %)
15 (0.7 %)
14 (0.6 %)
Among 56 subjects of the EMIL study positive for anti-HBc at hepatitis B screening, HBsAg was identified in 15 subjects (26.8 %). Past HBV infection was diagnosed in five subjects (positive for both anti-HBc and anti-HBs; 8.9 %). Anti-HBc was detected as an isolated finding in 36 subjects (64.3 %). Anti-HCV was detected in 14 subjects.
hepatic steatosis
p-value
no [n (%)]
yes [n (%)]
no viral infection
(n = 1673)
(n = 554)
ALT normal elevated
1565 (80.8 %) 108 (37.1 %)
371 (19.2 %) 183 (62.9 %)
Originalarbeit
Prevalence of Risk Factors for Liver Disease in a Random Population Sample in Southern Germany
Authors
M.-L. Huetter1, M. Fuchs2, M. M. Hänle3, R. A. Mason4, A. S. Akinli3, A. Imhof5, W. Kratzer, R. Lorenz3 for the EMIL study group.*
Affiliations
Affiliation addresses are listed at the end of the article.
Schlüsselwörter
Zusammenfassung
Abstract
"
!
!
Hintergrund: Chronische Lebererkrankungen führen zur Fibrose und Zirrhose der Leber: Dies kann wiederum zum chronischen Leberversagen oder zur Entwicklung eines hepatozellulären Karzinoms führen (HCC). Hauptrisikofaktoren für chronische Lebererkrankungen sind virale Hepatitis und Alkoholkonsum. In der vorliegenden Studie wurde die Prävalenz von Hepatitis B und C ermittelt sowie Risikofaktoren für chronische Lebererkrankungen wie Fettleber, virale Hepatitis und Lifestyle-Faktoren in einer zufälligen Bevölkerungsstichprobe untersucht. Methoden: An der Studie nahmen 2256 Probanden (1182 Frauen, 1074 Männer) im Alter von 18 − 65 Jahren teil. Bei allen Probanden wurden standardisierte Ultraschalluntersuchungen und Laboruntersuchungen durchgeführt sowie anthropometrische Größen bestimmt. Die Probanden wurden von November bis Dezember 2002 zufällig aus einer Kleinstadt in Südwestdeutschland ausgewählt. Ergebnisse: Die Ergebnisse zeigen, dass mehrere Faktoren mit einer chronischen Lebererkrankung assoziiert sind. Insgesamt 18,1 % der Probanden gaben einen Alkoholkonsum von über 20 g/Tag an. Das Metabolische Syndrom wurde bei 5,9 % (n = 132) der Probanden diagnostiziert. Insgesamt 45,1 % (n = 1017) der Teilnehmer hatten einen BMI über 25 kg/m². Die Prävalenz von chronischer Hepatitis B lag bei 0,7 % (n = 15), die von Anti-HCV bei 0,6 % (n = 15). Erhöhte gGT-Werte wurden bei 10,4 % (n = 14) der Probanden beobachtet. Die Prävalenz der Steatosis hepatis betrug 25 % (n = 564). Schlussfolgerungen: In vielen Fällen könnten chronische Lebererkrankungen durch gesunde Ernährung, durch Präventionsstrategien wie routinemäßige Impfung, insbesondere gegen Hepatitis-B-Virus (HBV), verhindert werden.
Background: Chronic liver disease leads to fibrosis and cirrhosis of the liver. This may, in turn, result in chronic liver failure or the development of hepatocellular carcinoma (HCC). Main risk factors for chronic liver disease are viral hepatitis and alcoholism. The present study assessed a randomly selected population in southern Germany for risk factors for chronic liver disease such as fatty liver disease, viral hepatis infection and life-style factors. In addition, the potential association with elevated liver enzymes was investigated. Methods: A total of 2256 subjects (1182 females, 1074 males), aged 18 − 65 years, participated in the study. Each subject underwent a standardized ultrasound examination, and anthropometric and biochemical assessments. Test subjects were randomly selected from the general population of a town in southwestern Germany. Data were acquired from November to December 2002 without further follow-up. Results: Several factors were found to be associated with chronic liver disease in the study population. Alcohol consumption > 20 g/d was seen in 18.1 % (n = 409). Metabolic syndrome was diagnosed in 5.9 % (n = 132). The number of people with a BMI greater than 25 kg/m² was 45.1 % (n = 1017). The prevalence of subjects with chronic hepatitis B was 0.7 % (n = 15), that of anti-HCV positive patients, 0.6 % (n = 15). Elevated gGT was seen in 10.4 % (n = 14) of the patients. Prevalence of hepatic steatosis was 25.0 % (n = 564). Conclusions: Many cases of chronic liver disease could be prevented by healthy nutrition, optimized medical treatment of associated disorders, and prevention strategies such as routine vaccination, in particular, against hepatitis B virus (HBV).
● Querschnittsstudien ● Ultraschall ● Fettleber ● Hepatitis B ● Hepatitis C " " " "
Key words
● cross-sectional-studies ● ultrasonography ● fatty liver ● hepatitis B ● hepatitis C " " " " "
received accepted
8.8.2013 13.1.2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1366017 Z Gastroenterol 2014; 52: 558–563 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0044-2771 Correspondence Prof. Dr. Wolfgang Kratzer Department of Internal Medicine I, Albert-EinsteinAllee 23, University Hospital Ulm 89081 Ulm Germany Tel.: ++ 49/7 31/50 04 47 30 Fax: ++ 49/7 31/50 04 46 20 [email protected]
Huetter M-L et al. Prevalence of Risk … Z Gastroenterol 2014; 52: 558–563
* These authors contributed equally
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Prävalenz von Risikofaktoren für eine Lebererkrankung in einer zufälligen Bevölkerungsstichprobe in Süddeutschland
Originalarbeit
!
Chronic liver disease (CLD) can result from a variety of causes. Most significant among these are viral hepatitis (hepatitis B or C) and alcohol abuse. Other important causes of CLD include autoimmune and metabolic diseases. Over time, CLD progresses to fibrosis and ultimately cirrhosis of the liver. The mortality rate is very high in patients suffering from liver cirrhosis or hepatocellular carcinoma (HCC) [1]. In the German population, CLD is most often the result of chronic alcohol abuse, with viral hepatitis (mainly hepatitis C) constituting a second major cause [2 – 4]. The extent of liver damage is directly associated with the duration and amount of alcohol abuse. According to the German Centre Against the Dangers of Addiction (DHS) and sample surveys, the estimated number of adults with alcohol-related liver disease in Germany is estimated at 2.0 to 3.2 million, 80 % of whom are men. Alcohol-related liver diseases in Germany are about as frequent as in other countries with high alcohol consumption, such as France [5]. The World Health Organization (WHO) estimates that about onethird of the world’s population, or two billion persons, have been infected with the hepatitis B virus (HBV), with about 5 % of the world’s population (350 million people) suffering from chronic HBV infection. In contrast, only about 3 % of the global population has had contact with the hepatitis C virus (HCV): an estimated 170 million people, however, are believed to be chronically infected [6]. A striking heterogeneity characterizes the distribution of HBV (0.1 − 8 %) and HCV (0.1 − 6.0 %) in European nations. The incidence of HCV infections has continued to increase in Europe, while that of HBV has tended to decline [7]. More recent studies of HCV prevalence in Germany report an HCV seroprevalence of 2.6 %. It should be noted, however, that these data stem from highly selected emergency room patients from large cities with a large proportion of high-risk patients and patients with an immigrant background [8]. Data from the German Health Interview and Examination Survey for Adults (DEGS1) show falling prevalence figures for HBV and HCV [9]. The studies of Cornberg et al. for Europe, Canada and Israel appear to confirm this trend toward low prevalence figures, especially for Germany [10]. HBV and HCV infections represent important risk factors worldwide for the development of cirrhosis of the liver, accounting for about 30 % of cases. Hepatocellular carcinoma (HCC) is caused by HBV in 50 % of cases; a further 25 % are associated with HCV. Worldwide, it is estimated that up to one million persons die annually as a result of liver cirrhosis or HCC secondary to HBV or HCV infection [11, 12]. HBV infection in Germany is mainly associated with unsafe sexual intercourse. Some people acquire HBV by receiving infusions or injections, specifically through intravenous drug abuse. The transmission pathway is clear in only 50 %. The risk of HBV and HCV transmission was reduced drastically as a result of the implementation of highly sensitive methods for identifying contaminated blood products. Non-alcoholic fatty liver disease (NAFLD) is an increasing problem in Western nations and is mainly associated with metabolic syndrome. It is characterized as a pathological accumulation of fat in the liver in the absence of excessive consumption of alcohol. The prevalence of NAFLD is about 20 − 30 % in developed countries [13, 14]. The progression of NAFLD to inflammation of the hepatic parenchyma leads to non-alcoholic steatohepatitis (NASH). In contrast to NAFLD, NASH may lead to liver cirrhosis and liver failure. NASH is seen in 2 − 3 % of cases of NAFLD [15 – 17].
The present study examined a randomly selected population in southwestern Germany for risk factors for chronic liver disease such as fatty liver disease, viral hepatis infection and life-style factors. A secondary objective was to obtain liver enzyme levels in these subjects.
Methods !
Study population In 2002, we conducted a population-based cross-sectional health survey in the southwestern German city of Leutkirch (EMIL Study: Echinococcus Multilocularis and Internal Diseases in Leutkirch). A total of 4000 of 12 475 residents of an urban population were randomly selected from the registry of inhabitants and invited to participate in the study. Out of the 4000 subjects, 107 were excluded for various reasons (unknown current address, n = 68; not giving informed consent, n = 39). Of 3893 eligible subjects, 2445 persons aged 10 – 65 years participated in the study (participation rate: 62.8 %). The proportion of subjects with an immigrant background was 9.9 %. The largest group was the ethnic Turkish population (4.7 %). Age and gender distribution of the " Fig. 1. inhabitants and the study population are shown in ● We excluded from the present study those subjects for whom the recorded historical, anthropometric, laboratory or sonographic data were incomplete. These exclusions resulted in a cohort of 2256 persons. A more detailed description of subject recruitment has been published elsewhere [18]. Subjects participated in a structured interview (questionnaire) and underwent anthropometric measurements, blood sample collection and an ultrasound examination. Each interview was conducted by a trained interviewer. The questionnaire included personal data (e. g., date of birth, gender, education, medical history), health behaviour (e. g., exercise) and other risk factors for disease (e. g., smoking, blood transfusion). In order to validate the results, multiple cross-checked questions on the same topic were addressed to the participants. The interview was partially based on validated instruments from other studies (e. g., alcohol questions from the MONICA study, [19]).
Anthropometry Based on recommendations of the World Health Organization (WHO), subjects’ height, body weight, hip and waist circumference were determined [20].
Abdominal ultrasound For detection of NAFLD and other pathologies, all participants underwent a real-time ultrasonographic examination of the liver (HDI 5000, Advanced Technology Laboratories Ultrasound, Philips Medical Systems, Bothell, WA, USA). Liver size and contour, focal liver lesions and differences in diameter of the hepatic veins were recorded. The diagnosis of fatty liver (hepatic steatosis) was based on the finding of “bright” liver tissue with fine, tightly packed echoes, making it significantly more echogenic than the adjacent right kidney [21, 22].
Laboratory tests and procedures About 25 mL of venous blood were obtained from a cubital vein. Laboratory testing was performed using standardized procedures. Blood samples for virus serology and determination of liver enzyme concentrations (gGT) were obtained using one serum
Huetter M-L et al. Prevalence of Risk … Z Gastroenterol 2014; 52: 558–563
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Introduction
559
Originalarbeit
Fig. 1 Age and gender distribution of the inhabitants and study population
tube (10 mL) and one lithium-heparin tube (10 mL). For the determination of HCV serology the test Axsym® by Abbott (Abbott GmbH & Co. KG, Wiesbaden, Germany) was used. For the determination of HBV serology the test Elecsys 2010 by Roche (Roche Diagnostics Int., Risch, Switzerland) was used. For transport to the laboratory, serum tubes were stored at –20 °C, while lithium-heparin tubes were stored at 4 °C.
Table 1 Amount of alcohol intake in g/day in subjects with and without steatosis hepatis.
hepatic steatosis no [n (%)] ex-consumer 0g
total [n (%)] yes [n (%)]
47 (2.8)
20 (3.6)
67 (3.0)
678 (40.1)
185 (32.8)
863 (38.3)
0 − 20 g
702 (41.5)
215 (38.1)
917 (40.7)
Metabolic syndrome
21 − 40 g
185 (10.9)
86 (15.3)
271 (12.0)
For purposes of the present study, metabolic syndrome was diagnosed when subjects met at least three of the following five criteria modified from ATP III: obesity with a BMI > 30 kg/ m², serum triglycerides > 1.7 mmol/L, HDL < 1.0 mmol/L (men) or < 1.2 mmol/L (women), history of arterial hypertension, random blood glucose > 8.9 mmol/L and/or history of diabetes mellitus. Data on hypertension and diabetes were assessed from subjects' past medical history.
> 40 g
80 (4.7)
58 (10.3)
138 (6.1)
were assessed using the χ² test, when the number of cases was too small, Fisher’s exact test were used. All statistical tests were two tailed. The significance level was set at α = 5 % (p < 0.05).
Results Ethics and informed consent
!
The study met the requirements of the World Medical Association Declaration of Helsinki on ethical principles for medical research involving human subjects in the version current at the time of the study (2000) and was approved by the research ethics committee of the Baden-Württemberg Medical Association. Each participant provided his or her informed written consent.
Population characteristics
Statistics Statistical calculations were performed using the SAS 9.2 statistics software (SAS Institute Inc., Cary, North Carolina, USA). Data were first analyzed descriptively. Categorical data were presented with absolute and relative frequencies. Potential risk factors
Huetter M-L et al. Prevalence of Risk … Z Gastroenterol 2014; 52: 558–563
A total of 2256 participants took part in this prospective trial, of whom 1074 (47.6 %) were males and 1182 (52.4 %) females. The median age of the participants was 39.4 ± 14.9 years.
Alcohol consumption and hepatic steatosis The total prevalence of hepatic steatosis was 25.0 % (17.3 % women, 33.5 % men). A daily alcohol consumption of 1 − 20 g was reported by 40.7 % of subjects, while 12.0 % reported drinking 21 − 40 g/d. Only 6.1 % admitted more than 40 g per day. gammaGlutamyl transpeptidase (gGT) elevation was seen in 5.8 % of people reporting no alcohol consumption. By contrast, elevated gGT levels were observed in 10 % of those drinking 1 − 20 g/d; in
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Body-mass index (BMI) A normal body mass index (< 25) was observed in 54.9 % of the study population, while 30.1 % of subjects were overweight (BMI 25 − 30). Obesity was observed in 15.0 %. GGT elevation was reported in 26.4 % of subjects with a BMI < 25. Subjects with a BMI of 25 − 30 showed elevation of GGT in 43.0 % of cases, while 30.6 % of those with a BMI > 30 had an elevation in gGT. Occurrence of " Table 2. hepatic steatosis in obese people is shown in ●
Metabolic syndrome Criteria for metabolic syndrome were met in 5.9 %. In 16.2 % of these subjects, there was elevation of gGT.
Hepatitis B serology At screening, a total of 56 subjects tested positive for anti-HBc antibodies. This represents 2.5 % of the studied population " Table 3). Five of these 56 subjects (8.9 %) showed evidence of (● past HBV infection (antibodies to both HBsAg and HBeAg). In 15 subjects (26.8 %), the presence of HBsAg indicated chronic HBV infection. Thus, chronic HBV infection was present in 0.7 % of the total population. In 36 subjects (64.3 %), only anti-HBc was isolated. Only one of the 15 HBsAg positive subjects was aware of their status: hence, 93.3 % had an unrecorded chronic HBV infection. Concentration of gGT above the respective reference range was documented in one HBsAg positive subject. The occurrence of hepatic steatosis in HBsAg-positive subjects in correlation with " Table 4. elevated liver enzymes is shown in ● " Table 1). Anti-HCV was detected in the sera of 14 subjects (0.6 %; ● Findings were confirmed by subsequent immunoblot in 14 subjects; immunoblot results were questionably positive in the remaining four subjects. Only three of the 14 anti-HCV positive sub-
Hepatic steatosis depending on weight.
hepatis steatosis
p-value
no [n (%)]
yes [n (%)]
1592 (94.1)
326 (57.8)
30 − 35
79 (4.7)
169 (30.0)
35 − 40
14 (0.8)
52 (9.2)
7 (0.4)
17 (3.0)
weight (BMI) < 30
> 40
Table 3
< 0.0001
Hepatitis serology.
n
Discussion !
Individuals suffering from liver cirrhosis or hepatocellular carcinoma (HCC) have a very high mortality rate. Recent years have seen an increased incidence of HCC not only in the USA and Japan but also in European populations [23 – 27]. One explanation of this trend could be that obesity increases the risk of HCC. A recent meta-analysis described an increased HCC risk of 17 % in overweight persons and of 90 % among those with a BMI greater than 30 [28, 29]. In our study population 30.1 % of subjects were overweight (BMI 25 − 30), with 16 % of subjects being obese. This reflects data from the year 2002. Since then, the number of people in Germany struggling with obesity has steadily grown. The reasons for this include a lack of exercise and an unhealthy diet. New data show that 66 % of men and 51 % of women aged 18 − 80 years are overweight; 20 % of all Germans are obese. These individuals are at high risk for developing type-2 diabetes mellitus, hypercholesterolemia and hypertension. An additional problem is that younger people aged 14 − 18 years suffer from obesity in 7 − 11 % [30].
Table 4
Hepatic steatosis depending on hepatitis serology.
variables
Hepatitis C serology
Table 2
jects were aware of their status: hence, 78.6 % had a previously unrecorded HCV infection. Concentration of gGT above the respective reference range was documented in two HCV positive subjects. The occurrence of hepatic steatosis in anti-HCV positive subjects in " Table 4. correlation with elevated liver enzymes is shown in ●
anti-HBc isolated
anti-HBs
HBsAg
anti-HCV
[n (%)]
[n (%)]
[n (%)]
[n (%)]
female 1182 19 (1.6 %)
1 (0.1 %)
8 (0.7 %)
7 (0.6 %)
male
1074 17 (1.6 %)
4 (0.4 %)
7 (0.7 %)
7 (0.7 %)
total
2256 36 (1.6 %)
5 (0.2 %)
15 (0.7 %)
14 (0.6 %)
Among 56 subjects of the EMIL study positive for anti-HBc at hepatitis B screening, HBsAg was identified in 15 subjects (26.8 %). Past HBV infection was diagnosed in five subjects (positive for both anti-HBc and anti-HBs; 8.9 %). Anti-HBc was detected as an isolated finding in 36 subjects (64.3 %). Anti-HCV was detected in 14 subjects.
hepatic steatosis
p-value
no [n (%)]
yes [n (%)]
no viral infection
(n = 1673)
(n = 554)
ALT normal elevated
1565 (80.8 %) 108 (37.1 %)
371 (19.2 %) 183 (62.9 %)
