The Liver Care Trial: Screening for Liver Disease in Individuals Attending Treatment for Alcohol Use Disorder - a Randomized Controlled Study
Phase: NA
Conditions: Alcoholic Liver Disease, Alcohol Use Disorder, Alcohol Abuse, Alcoholism, Fibrosis, Liver, Alcohol-Related Disorders
Sponsor: Zealand University Hospital

 
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Official title: Screening for liver disease in individuals attending treatment for alcohol use disorder – a 
randomized controlled study  
 
Document date: 05th of January 2023  
 

 
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Protocol  
0 TITLE IN ENGLISH AND DANISH 
4 
1 INTRODUCTION AND OBJECTIVES 
4 
2 HYPOTHESES, ENDPOINTS AND RATIONALE 
5 
2A HYPOTHESES AND ENDPOINTS 
5 
2B THE RATIONALE 
5 
3 SCIENTIFIC BACKGROUND 
6 
3A ALCOHOL-RELATED LIVER DISEASE IS OFTEN DIAGNOSED TOO LATE 
6 
3B A NON-INVASIVE MEASUREMENT OF LIVER STIFFNESS CAN DETECT LIVER DISEASE IN ITS EARLY STAGE 
7 
3C AN EVALUATION FOR LIVER DISEASE IS NOT ROUTINELY OFFERED TO INDIVIDUALS IN TREATMENT FOR ALCOHOL USE 
DISORDERS 
7 
3D SCREENING FOR DISEASE MAY LEAD TO BEHAVIOR CHANGE – THE TEACHABLE MOMENT HYPOTHESIS 
8 
3E PRIOR STUDIES 
9 
4 METHODS 
9 
4A STUDY DESIGN 
9 
4B PRACTICALITIES 
10 
4C: DEVIATIONS FROM STANDARD CARE 
16 
5 STATISTICS AND SAMPLE SIZE 
17 
6 STUDY OUTCOMES 
18 
7 PARTICIPANTS 
20 
7A INCLUSION CRITERIA 
20 
7B EXCLUSION CRITERIA 
20 
8 RISKS AND ADVERSE EFFECTS 
21 
9 BLOOD SAMPLES AND THE RESEARCH BIOBANK 
21 
10 DATA OBTAINED FROM MEDICAL RECORDS 
25 
11 ECONOMY 
27 

 
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12 ECONOMIC COMPENSATION TO PARTICIPANTS 
27 
13 RECRUITMENT OF PARTICIPANTS AND PROCEDURE FOR OBTAINING INFORMED CONSENT 
27 
14 PUBLICATION OF RESULTS 
29 
15 ETHICS 
29 
16 PARTICIPATING INSTITUTIONS 
29 
17 COLLABORATORS 
30 
18 REFERENCES 
32 
 
 
 

 
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0 Title in English and Danish 
The Liver Care Trial: Screening for liver disease in individuals attending treatment for alcohol use 
disorder – a randomized controlled study 
(Danish: Screening for leversygdom hos personer i alkoholbehandling – et lodtrækningsstudie) 
1 Introduction and objectives 
Individuals with alcohol use disorders are less likely to receive preventive healthcare such as 
outpatient follow-up and screening examinations compared to the general population.1 Evidence 
indicates that information and screening for disease may lead to a positive change in health risk 
behaviors. For example, a screening for lung cancer with detection of scan abnormalities seems to 
increase smoking cessation.2,3 However, if no disease is detected by a screening examination some 
research indicates a risk for a negative influence on health risk behaviors such as decrease in 
physical activity.2 Therefore, it is important to study if and how screening for liver disease influence 
alcohol consumption among individuals with alcohol use disorders.4 
 
Objective 
 To evaluate the efficacy of screening for liver disease with liver stiffness measurement on 
abstinence or light consumption after 6 months in individuals who are receiving treatment 
for alcohol use disorder and without a history of liver disease. We will conduct a randomized 
controlled trial with concealed allocation and blinded outcome assessment comparing A) an 
invitation to a liver stiffness measurement, blood sampling and leaflet on alcohol-related 
disease (intervention) with B) an invitation to blood sampling (control). The primary 
outcome is ‘abstinence or light consumption’ (≤ 10 units/week) throughout the last months, 

 
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and with one unit containing 12 gram of pure alcohol) and assessed 6 months after 
randomization. 
2 Hypotheses, endpoints and rationale 
2a Hypotheses and endpoints 
 Null-hypothesis: We hypothesize that among individuals attending treatment for alcohol use 
disorders, a screening for liver disease with liver stiffness measurement will not change the 
proportion that is abstinent or with light controlled consumption after 6 months of follow-
up compared to standard care. 
 Alternative hypothesis: We hypothesize that among individuals attending treatment for 
alcohol use disorders, a screening for liver disease with liver stiffness measurement will 
increase the proportion that are abstinent or with light controlled consumption with 15% 
after 6 months of follow-up compared to standard care. 
 
2b The rationale 
Early diagnosis of alcohol-related liver disease is key to survival, in particular if it leads to alcohol 
abstention.5 Technological advances have made it possible to detect liver fibrosis as a sign of 
disease in its early stage by an easy and non-invasive approach called a liver stiffness 
measurement.6 Among individuals in attending treatment for alcohol use disorders without a 
history of liver disease, 17% had either significant hepatic fibrosis or cirrhosis identified with a liver 
stiffness measurement.6 

 
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Until now, it has not been established whether having a screening for liver disease 
with liver stiffness measurement, irrespectively of its result, could motivate alcohol abstention 
among individuals with alcohol use disorders. One could fear that a liver scan indicating low 
likelihood of liver disease could be interpreted as a license to continue drinking alcohol (a 
phenomenon called the “certificate of health effect” that has been observed for physical activity 
and weight gain in an RCT of colon cancer screening).7 No randomized controlled trials have been 
conducted. We have conducted a successful pilot study (ClinicalTrials.gov identifier NCT05244720) 
showing that a full study is feasible regarding recruitment and participation. 
3 Scientific background 
3a Alcohol-related liver disease is often diagnosed too late 
Today, around 35% of patients with alcohol-related liver disease die within the first year after 
diagnosis.8 This high mortality is mainly caused by the liver disease being diagnosed in its late stage, 
when complications of liver failure such as ascites, variceal bleeding or hepatic encephalopathy 
have developed. Alcohol-related liver disease develops over many years prior to diagnosis, but the 
disease is usually asymptomatic until complications develop. If alcohol-related liver disease were to 
be diagnosed before the development of liver disease complications, the liver has the potential to 
regenerate if alcohol consumption is reduced, which increases the survival associated with alcohol-
related liver disease significantly.5 Early diagnosis of alcohol-related liver disease improves the 
likelihood for better treatment options for the life-threatening complications of varices and 
hepatocellular carcinoma.5 
 

 
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3b A non-invasive measurement of liver stiffness can detect liver disease in its early stage  
Patients with the early stages of alcohol-related liver disease are asymptomatic and they therefore 
less frequently seek healthcare for liver disease.5 Blood samples and clinical examination can even 
be unaffected, so investigations done by general practitioners are not sufficient to detect fibrosis of 
the liver.9 Technological advances have made it possible to detect the disease in its early stage by 
an easy and non-invasive approach called a liver stiffness measurement (FibroScan©).6 This  
measurement takes around 10 minutes and is without adverse effects.9 International guidelines 
recommend that individuals with long-lasting heavy drinking such as individuals attending alcohol 
misuse treatment should be offered an evaluation for liver disease such as a liver stiffness 
measurement.5,10 Indeed, among Danish asymptomatic individuals attending treatment for alcohol 
use disorders, 17% had significant alcohol-related liver disease defined as significant liver fibrosis or 
cirrhosis (liver stiffness measurement 8kPa).6 
 
3c An evaluation for liver disease is not routinely offered to individuals in treatment for alcohol use 
disorders 
Individuals attending treatment for alcohol use disorders have a much higher risk of several medical 
conditions such as anemia that can be caused by vitamin deficiencies (folate or B12) or 
gastrointestinal bleed.11 The English National Institute for Health and Care Excellence recommends 
blood sampling to diagnose deficiencies in vitamins and minerals and anemia in individuals with 
alcohol use disorders to be able to give vitamin supplements to individuals with deficiencies.12 If 
anemia is diagnosed, this should be further ruled out with current guidelines and may include 
endoscopies to look for ulcers, malignancy, or other causes of gastrointestinal bleeding.13 Today, no 

 
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routine blood sampling is done in Danish specialized alcohol treatment centers, although blood 
sampling may be performed in case of prescriptions of pharmacotherapy.14 
 
3d Screening for disease may lead to behavior change – the teachable moment hypothesis 
Observational studies have found increased smoking cessation rates after myocardial infarction, 
cancer diagnosis, and prior to surgery.15 A similar pattern is seen for alcohol: Health problems and 
perceived consequences of heavy drinking motivate reduced alcohol consumption in treatment-
seeking individuals with alcohol use disorders.16,17 It remains unknown whether screening for 
alcohol-related disease before health problems occur is enough to induce a reduction in alcohol 
consumption. A systematic review of randomized controlled trials from 2011 concluded that the 
literature was too sparse to draw a conclusion on whether screening for a somatic disease had 
effects on health behavior.2 Results from an observational study indicate that appropriate 
behavioral advice in the context of screening for liver disease can reduce heavy drinking.4 
However, an important issue to consider is the “certificate-of-health effect” with the 
observation that individuals who had a negative screening result are more likely than controls to 
practice an unhealthy lifestyle in the months after their screening. In that sense a negative screening 
result may be regarded as a “licence to drink/smoke/eat unhealthy”. This has been observed for a 
RCT with a colon cancer screening program in which the screened individuals had a lower 
improvement in smoking, exercise habits and eating healthy after 3 years compared to the controls.7 
We believe that ‘individuals in alcohol treatment’ is a suitable study population to offer 
an evaluation of liver disease since these people are more likely to be motivated for alcohol 
abstinence than are, for instance, heavy drinkers in primary care not seeking alcohol treatment.4  

 
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Motivational interviewing is an evidence-based approach to increase patient 
compliance and reduce alcohol consumption in individuals with alcohol use disorders.18 Motivational 
interviewing is based on empathy and seek to increase patient engagement  - and therefore it may 
be a good approach for patients with alcohol use disorders who often feel stigmatized in the 
hospital.19 We therefore developed an intervention with delivering the liver stiffness measurement 
based on motivational interviewing. 
 
3e Prior studies 
No randomized controlled studies of a liver stiffness measurement versus no intervention have 
been conducted to study if such a liver stiffness measurement could increase abstinence or light 
controlled consumption, in addition to what can be obtained by motivational interviewing/brief 
advice.20,21 
4 Methods 
4a Study design 
See the study flowchart for a graphical presentation of the study design. This is a randomized 
controlled study aiming to clarify if a liver stiffness measurement in the spirit of motivational 
interviewing can increase cutting down to light consumption or abstinence after 6 months among 
individuals attending treatment for alcohol use disorders. Participants are randomized 2:1 to 
intervention (invitation to blood samples and liver stiffness measurement and leaflet) or standard 
care including an invitation to blood samples. If those in the control group have the liver stiffness 
measurement performed elsewhere it could introduce a bias because some participants 

 
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randomized as controls had the intervention as well. Therefore, study participants randomized as 
controls will be invited to have a screening for liver disease based on blood samples (the Fib-4 
index), this is in line with the current recommended practice from the European Association of the 
Study of Liver Diseases, at what participants could be offered from their general practitioneer.22 
The study period for recruitment and follow-up will proceed from December 2022 until November 
2032. There is follow-up for each individual participant at 6 months conducted by 1) telephone 
contact, 2) electronic health record, and 3) information on compliance with and untimely treatment 
drop-out of specialized treatment for alcohol use disorders. 
 
4b Practicalities 
See SPIRIT DIAGRAM below 
 
Baseline assessment 
Questionnaires with baseline data will be filled by the participant and collected by the alcohol 
therapist and include: Severity of alcohol use disorders (AUDIT questionnaire),23 years with heavy 
drinking (exceeding the national guidelines for sensible drinking anno 2022: > 10 units/week), 
current alcohol consumption, day for last alcohol consumption, sociodemographic variables, and 
smoking. Moreover, we will ask for motivation to decrease alcohol consumption and the belief in 
this change using ”Spørg til alkoholvaner” from the guideline to general practitioners.24 A unit of 
alcohol is equivalent to 12 g of pure alcohol in this study. Further, we will ask for health-related 
quality of life with the validated Short-form 12 questionnaire, version 2.25 
 

 
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Randomization 
The randomization of the sequence of participants to intervention or control group will be 
computer generated using REDCap by the researchers before enrollment to the study begins, so 
that each participant number/sequence number has a determined randomization outcome before 
enrollment to the study begins. Participants are randomized 2:1 to an invitation to blood samples, 
leaflet and a liver stiffness measurement at Sjællands Universitetshospital (intervention) or to 
standard care with an invitation to blood samples. We will use Sequentially numbered opaque 
sealed envelopes with the sequence number provided. The physician or alcohol therapist will hand 
this envelope to the participant after obtaining informed consent for study participation and after 
the collection of the baseline variables, and by this approach assigning participants to 
randomization group. 
 
The intervention: Invitation to a liver stiffness measurement 
The intervention will be delivered with motivational interviewing meaning that the researcher 
delivering the intervention has participated in a course in motivational interviewing for alcohol use 
disorders. There will be a semi-structured manual to follow for delivering of the intervention and 
this is prepared in conjunction with a certified motivational interviewing coach. The intervention 
consists of 1) a liver stiffness measurement using FibroScan©, 2) clinical examination for signs of 
liver disease, 3) routine blood samples, and 4) leaflet with description of alcohol-related disease 
and benefits of cutting down and with the result of the liver stiffness measurement (Appendix 
“spørgeskemaer”).  

 
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The researchers will contact the study participants by phone for an appointment within few days 
after the enrolment and will aim for an appointment for a liver stiffness measurement within 4 
weeks and preferably within 2 weeks. If not reached the first time by phone, they will be called up 
to 10 times until they are reached. The researchers will explain about the liver stiffness 
measurement (the same information as the “deltagerinformation”). The researchers will explain to 
the participant that they need to fast for 4 hours before they meet at the hospital for blood 
sampling and liver stiffness measurement (morning sessions will be prioritized).26 At the hospital, 
routine blood samples and optionally blood samples for biobank will be taken. A measurement of 
liver stiffness will be performed using FibroScan©. The FibroScan© (transient elastography) works 
by measuring shear wave velocity with an ultrasound probe. A FibroScan© assesses liver stiffness 
which correlates with liver fibrosis. The FibroScan© is safe, without adverse events and used in 
daily clinical practice. Early liver disease (“significant liver fibrosis”) will be defined as a test result of 
8.0-15 kPa with 10 successful measurements and an IQR of the median < 30 %.27 Late liver disease 
(“liver cirrhosis”) will be defined as a test result of 15.1 kPa with 10 successful measurements and 
an IQR of the median < 30 %. 27 
The participant attending the liver stiffness measurement, will have the test result of the 
FibroScan© explained promptly by the healthcare professional performing the FibroScan©. 
Moreover, the result will be written on the leaflet. If the FibroScan© suggests early liver disease or 
the blood samples reveal anemia or vitamin deficiencies, the participant will be offered routine 
assessment for this at the hospital department where the study takes place. When the results of 
the blood samples are available they will be explained to the participant by a physician.  
We will collect blood used for routine care analyses (for more details see table 1) and for a research 
biobank. We will analyse blood for biomarkers of liver disease and inflammation including 

 
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apolipoproteinA1, haptoglobin, alpha-2-macroglobulin, and hyaluronate, which are not yet used in 
daily clinical practice.22 For example, the Fibrotest is a commercially available algorithm that 
combines age, gender, alpha-2- macroglobulin, haptoglobin, apolipoprotein, bilirubin, and gamma-
glutamyl transferase (GGT).28 Moreover, The Enhanced Liver Fibrosis (ELF) test is a commercially 
available algorithm that combines 3 direct serum markers of extracellular matrix remodeling and 
fibrogenesis: hyaluronic acid, the N-terminal pro-peptide of collagen type III, and tissue inhibitor of 
metalloproteinase-1.21,28 
We will also analyse phosphatidyl ethanol, a marker of chronic alcohol consumption. 
 
Control group 
Participants randomized as controls will be offered: 1) routine blood samples including AST, ALT and 
platelet count to calculate the FIB-4 index.22 Participants randomized as controls will need 
themselves to call for an appointment for blood samples. If the FIB-4 index suggests early liver 
disease ( 1.30) or the blood samples reveal anemia or vitamin deficiencies, the participant will be 
offered routine assessment for this at the hospital department where the study takes place. 
Participants will only be contacted by physicians after blood sampling if the blood samples indicate 
abnormalities and a need for follow-up. 
 
Follow-up  
We offer one follow-up assessment to all participants who were randomized and no matter 
intervention or not, and no matter the result of the liver stiffness measurement. Follow-up data is 
collected at 6 months by a research nurse who is blinded to whether or not the participant had the 

 
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intervention. Follow-up data include: Severity of alcohol use disorders (AUDIT), motivation to cut 
down, alcohol consumption/heavy drinking days the last 6 months, smoking status and health-
related quality of life (Short-Form 12, version 2).25 
The follow-up data will be collected by three methods: 1) by phone interview with the validated 
Timeline Follow-Back method.29 In these interviews, the research nurse will tell the participant not 
to reveal the information about if they had a liver stiffness measurement, 2) from participants’ 
electronic health record to look for data on alcohol consumption, and 3) we will obtain information 
on compliance with and untimely treatment drop-out of treatment for alcohol use disorders from 
the municipal specialized alcohol treatment center (Novavi Køge and Roskilde). We expect loss to 
follow-up to be negligible because we include information from medical chart review and 
compliance with alcohol misuse treatment. However, if study participants emigrate they will be 
regarded as loss to follow-up. 
If participants are unavailable for the telephone-interview on alcohol consumption after 6 months, 
we will use multiple imputation to construct missing values. In a sensitivity analysis we will analyse 
whether the results change if unavailability for the telephone-interview is regarded as relapse to 
heavy drinking (treatment failure). 
We will also collect information on hospital evaluation of liver disease outside the project, this 
information will come from medical charts review. 
SPIRIT DIAGRAM 
 
Enrolme
nt 
Allocation 
Close-out 
TIMEPOINTS 
-t1 
Baseline 
Within 1 
month 
6 months 
>2 years 

 
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ENROLMENT: 
 
 
 
 
 
Eligibility screen 
X 
 
 
 
 
Informed consent  
X 
 
 
 
 
Allocation 
 
X 
 
 
 
INTERVENTIONS: 
 
 
 
 
 
Liver screening with liver 
stiffness measurement 
 
 
X 
 
 
Standard care with offer of 
blood tests 
 
 
X 
 
 
ASSESSMENTS: 
 
 
 
 
 
Baseline: AUDIT, motivation 
to cut down, units/week, last 
alcohol consumption, SF-12, 
smoking 
X 
 
 
 
 
Follow-up: Alcohol 
abstinence/light consumption 
last month, AUDIT, motivation 
to cut down, SF-12, smoking 
 
 
 
X 
 
Longer follow-up: healthcare 
use, liver disease incidence, 
death 
 
 
X 
X 
X 
 

 
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4c: Deviations from standard care 
All participants at the specialized alcohol misuse treatment centers will receive their usual standard 
treatment for alcohol use disorder. If patients choose to take part in this study they will be offered 
blood samples with screening for liver fibrosis with the FIB-4 index. If they are randomized to the 
intervention, they will be offered a liver stiffness measurement and a leaflet in addition to blood 
samples. The intervention may increase the rate of abstinence in the intervention group compared 
to the control group, but we don’t know. 
 
Baseline assessment at 
alcohol abuse treatment
center and randomization
Intervention
• In the spirit of motivatioal
interviewing
• Liver stiffness measurement
• Blood samples
• Leaflet
Standard care (control)
• Blood samples 
and calculation of FIB-4
Follow-up on 
alcohol consumption
(6 months since
intervention)
Follow-up on 
alcohol consumption
(6 months since
randomization)
33,33%
66,66%
Study flow chart

 
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5 Statistics and sample size 
A final statistical protocol will be uploaded on clinicaltrials.gov before enrolment begins. The 
analyses of data will be based on the intention-to treat approach meaning that our primary analysis 
will include all participants who were randomized. The primary outcome (alcohol abstinence or 
light consumption (≤ 10 units alcohol/week throughout the last month)) will be analyzed using a 
logistic regression model with adjustment for average number of units per week at inclusion. 
Multiple imputation will be used to account for missing information on outcome and average 
number of units per week at inclusion. In addition, the primary outcome will be investigated using 
the per protocol principle, where only those participants randomized to the intervention who 
actually met at the hospital and had the liver stiffness measurement will be included in the analysis 
in addition to the controls. We will use inverse probability of treatment weighting in those analyses 
to account for measured confounding of age, sex, average number of drinks per week and months 
in alcohol misuse treatment.30 Further, we will analyse whether “time on unsuccessful” treatment 
for alcohol use disorder is an intervention moderator analysed as interaction with randomization 
group and primary outcome. Secondary and supportive outcomes will be investigated using the 
same principles used for the primary outcome, however for continuous outcomes linear regression 
will be used and for count data, Poisson regression models. 
We plan to include 408 individuals in the study: 272 will be offered the intervention and 136 will be 
controls. This number is based on a sample size calculation with the assumption of a favourable 
alcohol outcome at follow-up of abstinence or light consumption in 66% in the intervention group 
and 51% in the control group and with a power of 80% and a two-sided significance level of 5%.31 
The number of 272 in the intervention group will also allow a comparison between those who are 
screen positive (fibroscan indicate liver fibrosis) that is expected in about 20% (data from pilot trial 

 
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and this reference: 32) and those who are screen negative (80%) with a difference in the outcome of 
abstinence or light consumption of 24% (75% vs. 51% will be light drinkers/abstinent at 6 months). 
We expect loss to follow-up to be negligible because of the three follow-up methods applied 
(described in the follow-up section above). The specialized alcohol treatment center of Novavi Køge 
has around 200 and Novavi Roskilde around 150 individuals attending treatment for alcohol use 
disorders every year. We expect to include 408 participants during a period of 30 months. 
  
6 Study outcomes   
Primary outcome: Alcohol abstinence or light consumption (≤ 10 units/week) throughout the last 
month and assessed after 6 months since the intervention of an evaluation of liver disease (yes/no). 
Evaluation of primary 
outcome of alcohol 
abstinence or light 
consumption throughout the 
last month 
Interpreted as not fulfilling 
alcohol abstinence/light 
consumption if indicated by 
just one of the outcomes 
measures below 
Interpreted as fulfilling 
alcohol abstinence/light 
consumption the last month if 
indicated by all three of the 
outcomes measures below 
1) Telephone interview with 
timeline follow-back method 
Interview reveals alcohol 
intake above the light 
consumption level the last 
month 
Interview reveals alcohol 
abstinence or light 
consumption the last month 
2) Electronic health record 
Hospital contact the last 
month with history that 
Either no hospital contacts or 
hospital contact without 

 
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Secondary outcomes: 1) Reduction in number of heavy drinking days throughout last month (yes or 
no), 2) reduction in AUDIT score (yes or no), 3) improvement or no decrease in motivation to cut 
down on alcohol (yes or no), improvement or no decrease in health-related quality of life (yes or 
no), calculated as the difference between baseline and follow-up. 4) Continuous treatment for 
alcohol use disorder among participants exceeding light consumption levels. One could fear that a 
liver stiffness measurement indicating low likelihood of liver disease could be interpreted as a 
license to continue drinking alcohol (a phenomenon called the “certificate-of-health effect”). This 
will be evaluated by comparing likelihood of abstinence or light consumption at six months 
between those in intervention group with a screen negative result (liver stiffness measurement< 
8kPa) with those in the control group. 
indicates current drinking: 
alcohol intoxication, ethanol 
measurement or told by the 
patient. 
mentioning of alcohol  
consumption above the light 
consumption  level 
3) Untimely treatment drop-
out of treatment for alcohol 
use disorder from Novavi 
Untimely treatment drop-out 
the last month as judged by 
Novavi alcohol treatment 
center or death with obvious 
involvement of alcohol during 
the 6 months since baseline 
Not untimely dropout the last 
month 

 
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Supportive outcomes: Evaluation of liver disease by liver stiffness measurement, ultrasound or CT 
scan at the hospital not as part of the study among participants randomized as controls (cross-
over). Also, we will evaluate further investigations at the hospital if a transient elastography 
measurement result indicates early liver disease (significant fibrosis (8kPa)) to assess the health-
care burden. Longer follow-up (3 years) is planned to be conducted through health care registries to 
look for incidence of alcohol-related liver disease and death, visits to general practitioner and 
hospital contacts.25,26 
 
7 Participants 
7a Inclusion criteria 
 Attending outpatient treatment for alcohol use disorder (international classification of 
disease version 10: F102: alcohol dependence or F101: harmful alcohol use) at Novavi Køge 
or Roskilde 
 
Age ≥ 18 years 
 
Informed written consent 
7b Exclusion criteria 
 
Not speaking Danish 
 
Severe liver disease (known by the participant) 

 
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8 Risks and adverse effects 
The known risks for venepuncture are bleeding and hematoma at the point of puncture. A transient 
elastography is a non-invasive test and the technique is based on ultrasound. The transient 
elastography is considered safe without adverse events to the patient.9 The emotional impact of 
further clinical investigations seems to be negligible, at least after four weeks.33 
 
9 Blood samples and the research biobank 
From each participant we will collect blood only one time. All blood samples are outlined in Table 1 
and in the following points. Part of the blood is destroyed within few days and is not considered as 
a research biobank; another part of the blood is stored in a research biobank.  
A: Blood samples (not stored) 
Section A shows the amount of blood samples taken at inclusion with routine analyses of markers 
of liver disease, anemia and selected vitamins. These blood samples will be analysed immediately 
by the laboratory at Zealand University Hospital, Køge. The blood will be destroyed within few days 
after analysis. This is not considered as a research biobank.  
 B: Phosphatidylethanol (stored in a research biobank for maximum 1 year) 
Section B shows the amount of blood used for the alcohol biomarker analysis (phosphatidylethanol) 
taken at inclusion. Sygehus Lillebælt, Vejle is the only place in Denmark making this analysis. The 
blood will be stored in a research biobank at Department of Internal Medicine, Zealand University 
Hospital, Køge before it is sent to Sygehus Lillebælt. During the study period, the blood will be 
collected for each study patient, stored in the research biobank and continuously in groups sent to 

 
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Sygehus Lillebælt for analysis. The blood will be stored for maximum 1 year and will be destroyed 
immediately after the analysis in Sygehus Lillebælt.  
 C: The blood for biomarkers of liver disease (stored in research biobank) 
Section C shows the amount of blood used for analyses of biomarkers of liver disese. The blood will 
be stored in a research biobank at Region Sjællands Biobank i Næstved, Sygehusene i Næstved, 
Slagelse og Ringsted. The blood samples will be stored in the research biobank during the study 
period of 10 years. After the end of the study we will apply the Danish Data Protection Agency for 
permission to store the excess amount of blood from section C in a new biobank for future 
unspecified research. In case of permission the blood will not be destroyed or anonymized, it will be 
stored in a new research biobank and still handled according to the Law of Data Protection. In case 
of rejection we will destroy the blood after 10 years.  
The volume of blood collected for blood samples without the research biobank: 17 ml  
The volume of blood collected for the research biobank: 29 ml 
The total volume of blood collected during the study period: 46 ml  
 Table 1. Blood samples 
  
Type of analyses 
Sampling 
time 
points 
Sampling volume 
and destruction 
Location 
 
Routine blood samples (not a research biobank) 
A 
Hæmoglobin;B 
Erythrocyt middelcellevolume;B 
MHCH; B 
One time  
Total amount of 
blood: 17 ml 
 
Laboratories of 
clinical 
biochemistry, 

 
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Ferritin; B 
Leukocytter;B 
CRP;P 
Trombocytter;B 
Koagulationsfaktor II+VII+X [INR];P 
Aspartattransaminase [ASAT];P 
Alanintransaminase (ALAT);P 
Albumin; P, 
Bilirubin;P 
Kreatinin;P 
Natrium;P 
Kalium;P 
Basisk fosfatase;P 
Gammaglutamyltransferase(GGT); P 
B12; P 
Folate; P 
Glucose; P 
Insulin; P 
Cortisol; P 
Samples will be 
destroyed 
immediately after 
analysis (maximum 2 
days) 
 
 
Zealand University 
Hospital, Køge 
 
Blood samples for the research biobank 
B 
Phosphatidylethanol 
One time 
 
 
Total amount of 
blood: 4 ml 
 
Stored at 
Laboratories of 
clinical 
biochemistry, 
Zealand 
University 
Hospital, Køge  

 
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Samples will be 
stored and sent to 
Sygehus Lillebælt for 
analysis. 
It will destroyed 
immediately after 
analysis (maximum 1 
year) 
 
 
 
Analysed at 
Region Midt, 
Sygehus Lillebælt, 
Vejle (only place 
in Denmark who 
does this analysis) 
C 
 
ApolipoproteinA1, haptoglobin, 
alpha2macroglobulin, hyaluronate and a little 
extra in case of failure analyses. 
 
 
 
One time 
Total amount of 
blood: 25 ml 
Samples will be 
stored in the 
research biobank of 
Region Sjællands 
Biobank i Næstved, 
Sygehusene i 
Næstved, Slagelse og 
Ringsted. 
Samples will be 
analysed at clinical 
biochemistry, 
Sygehusene i 
Næstved, Slagelse og 
Ringsted. Afterwards 
they will be 
destroyed. 
 
Stored at Region 
Sjællands Biobank 
i Næstved, 
Sygehusene i 
Næstved, Slagelse 
og Ringsted. 
 
 

 
Protokol_V2_05.01.2023 
 
 
 
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10 Data obtained from medical records and health registries 
We will not obtain information from medical records before informed consent. 
Data obtained from medical records after obtained written informed consent: 
 Information on alcohol-related hospital contacts: if patients are not responding to our 
phone call we will investigate whether they have been admitted to the hospital with alcohol 
problems. 
 Results of assessments for liver disease 
 Results of blood samples (those mentioned in Table 1) 
 Information on death: to clarify if the patient died, including causes of death 
 
We (the researchers) will ask participants for permission to look in participants’ medical records to 
obtain information on health that is necessary in order to conduct the present research project and 
for quality control, self-control, and monitoring. The information will be collected 6-36 months after 
study enrolment. 
Data obtained from specialized alcohol treatment centers: 
From municipal specialized alcohol treatment centers (Novavi Køge and Roskilde), we will obtain 
data on finishing date of treatment for alcohol use disorder and whether it was untimely 
(unplanned), after we have obtained written informed consent. The information will be collected 6-
12 months after study enrolment. 
Data from health registries 

 
Protokol_V2_05.01.2023 
 
 
 
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Two years after start of inclusion to the study, we will seek permission to get data from Danish 
nationwide healthcare registries including: Landspatientregisteret (information on hospital 
contacts, diagnosis of liver disease and other alcohol-related diseases), CPR-registeret (vital status), 
uddannelsesregisteret (education), registerbaserede arbejdsstyrkestatistik (employment history), 
familieregisteret (children and cohabitation status) and dødsårsagsregisteret (cause of death). This 
information will be used to analyse whether there are differences for intervention and control 
group in this study with regard to: diagnosis of liver disease, hospital contacts for liver disease, 
survival, cause of death, employment history. Also we will investigate any differences according to 
educational level and employment status. 
 
11 Processing of personal data 
The processing of personal data in the current study will be handled in accordance with the law of 
data protection (in Danish: Databeskyttelsesforordningen og Databeskyttelsesloven). It is the 
responsibility of the primary investigator (Lone Galmstrup Madsen) to ensure that handling of 
personal data will comply with the law of data protection. Baseline information and the informed 
consent will be handled in paper form at Novavi Køge, and Roskilde where it will be locked safely in 
a room, where Tine Lunding Bergenhagen (the manager of Novavi Køge) or Tina Skoubo Jensen (the 
manager of Novavi Roskilde) have access. Afterwards, the baseline information and informed 
consent will be transferred safely to Medicinsk afdeling, Køge, where the baseline information will 
be entered into the REDCap (Reserch ELectronic Data Capture) to store the research data safely. 
The remaining documents in paper form - the informed consent and the trial master file including 
patient ID list - will always be locked safely in a room where only the researchers and Tine Lunding 
Bergenhagen (Køge) and Tina Skoubo Jensen (Roskilde) have access. 

 
Protokol_V2_05.01.2023 
 
 
 
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11 Economy 
We, the researchers, have initiated the research project, no companies or institutions have initiated 
the project and there are no financial or marketing interests associated with the project. 
Gro Askgaard, Sjællands Universitetshospital, received funding from ”Den fællesregionale pujle til 
forskning I forebyggelse (1.198.000 kr.), Fonden Novavi (900.000 kr.) and the Novo Nordisk 
Foundation (2.998.000 kr.). This funding will cover salary for researchers, project nurse, 
administrator and pay for analyses of blood samples. The funders have no role in research design or 
decision to publish. Moreover, the researchers in this project have no commitments to the funders. 
12 Economic compensation to participants 
Some participants in the study will have their documented transportation expenses covered for up 
to 200 Danish kr for their visit to Sjællands Universitetshospital Køge . The researchers will make a 
judgement according to the physical condition and economic situation of the study participant. This 
judgement will follow the principles of economic compensation given to hospital patients in routine 
hospital care – it can be given if patients are not able to transport themselves. This means that not 
all study participants will be offered economic compensation of transportation expenses. The 
requirements of Appendix 1 from VEK are fulfilled. 
13 Recruitment of participants and procedure for obtaining informed consent 
The recruitment and oral and written information will be conducted by the staff at the specialized 
alcohol treatment centers (Novavi Køge and Roskilde). All consecutive individuals attending 
treatment for alcohol use disorders will be screened for eligibility. Potential participants have the 
opportunity to contact the researchers for more information about the study, as written in the 

 
Protokol_V2_05.01.2023 
 
 
 
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recruitment material. We have made a written agreement (“samarbejdsaftale”) that both Novavi 
and Medicinsk Afdeling, SUH Køge have signed. The written agreement includes a statement of 
which persons at Novavi Køge and Roskilde that will give the oral and written information about the 
study, obtain the informed consent, and sign that information about the study was provided to the 
study participant. 
The Chief physician at the specialized alcohol treatment center organization (Novavi) is a member 
of the research team for this study and have agreed to ensure that study participants will receive 
the oral and written information about the study. Lone Galmstrup Madsen has the overall 
responsibility to ensure correct oral and written information of study participants at Novavi Køge 
and Roskilde. Alcohol therapists at Novavi Køge and Roskilde will screen possible participants 
among individuals attending treatment for alcohol use disorders at Novavi Køge and Roskilde and will 
do a screeningslog. Written information about the study will be found in Novavi Køge and Roskilde 
displayed so everyone can see it, and it can be sent by email after agreement with the individual in 
attending treatment for alcohol use disorders. Alcohol therapists and physicians at the alcohol 
treatment center will inform potential participants about the study. Physicians and alcohol 
therapists at the Novavi alcohol treatment center will obtain the oral and written informed consent 
for study participation. Participants will get oral information about the study in a quiet room. 
Participants will be invited to bring a relative with them when they receive the oral information 
about the study. When they are informed oral and written, they will sign an informed consent 
either immediately or after reflection time. The length of the reflection time is until the study stop 
for recruitment. The participant will sign an informed consent, where the participant agrees to 
participate in the study. 

 
Protokol_V2_05.01.2023 
 
 
 
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14 Publication of results 
Results will be published no matter positive, negative, or inconclusive via www.clinicaltrials.gov, 
and to the research community through one or more papers in peer-reviewed scientific journals, 
and at conferences. We will present and discuss our results with alcohol therapists and 
administrators by attending the National alcohol conference (Den Nationale Alkohol Konference). 
The organization of Alcohol and Society will help us communicate the results to individuals with 
alcohol problems, their relatives, alcohol workers, and politicians through their magazines, 
webpage, and “viden om alcohol”: https://alkohologsamfund.dk/viden-om-alkohol. 
15 Ethics 
The study does not involve more harm to participants than a routine outpatient hospital visit does. 
However, the liver stiffness measurement, like other screening examinations, potentially cause 
psychological distress for up to 4 weeks.33 Moreover, we don’t know yet if a liver stiffness 
measurement with a result indicating low risk of liver disease could motivate continuing alcohol 
consumption. For the individual participant there may be some benefits of participating such as 
diagnostic testing and patient empowerment, since many patients with alcohol use disorders feel 
neglected by the healthcare system.19 The increased awareness on alcohol may motivate alcohol 
abstinence. Participants of this research project will be covered by Patienterstatningen, since they 
will be followed by the department until the evaluation of liver disease has been performed. 
16 Participating institutions 
Novavi Køge: Place for screening, inclusion and randomization of participants. 
Novavi Roskilde: Place for screening, inclusion and randomization of participants. 

 
Protokol_V2_05.01.2023 
 
 
 
30
Medicinsk afdeling, Sjællands Universitetshospital Køge: Sponsor of the study together with Lever-
, Mave og Tarmsygdomme, Aarhus Universitets Hospital. Place for intervention and follow-up of 
participants. 
Lever-, Mave og Tarmsygdomme, Aarhus Universitetshospital: Expertise in clinical research, data 
management, and statistical analysis. 
Center for Klinisk forskning og forebyggelse: Expertise in randomized controlled studies. 
 
17 Collaborators 
Lone Galmstrup Madsen (overordnet forsøgsansvarlig): Work fulltime as a Clinical specialist of 
liver diseases and chief physician at the Medicinsk afdeling, Sjællands Universitets hospital Køge. 
Research experience within clinical research. Will contribute to research design, inclusion of 
patients, and manuscript writing. 
Gro Askgaard (primary investigator): Work part-time as researcher (post.doc) and part-time as a 
medical doctor. Has experience with research into alcohol and liver disease and the collection of 
clinical data. Contributed with systematic reviews and manuscript drafting for the national 
guideline on alcohol treatment. 
Role: Principal investigator of the project. Carry the overall responsibility for completing the 
studies, the data-analysis, and manuscript writing. 
Peter Jepsen: Work part-time as a senior researcher (professor) and part-time as a clinical specialist 
in hepatology. Research experience within epidemiology and clinical epidemiology. 
Role: Overall responsibility of the research design and methodology. Will supervise data-analysis 
and manuscript writing. 

 
Protokol_V2_05.01.2023 
 
 
 
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Signe Wegmann During: Chief Physician at Novavi, post.doc and experience with research into 
alcohol and psychiatric diseases. Role: supervise the planning and conduct of the study. 
Janne Petersen: Chief statistician at Center for Klinisk forksning og forebyggelse. Role: will 
supervise the statistical analysis of study data. 
 

 
Protokol_V2_05.01.2023 
 
 
 
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18 References 
1. 
Merrick EL, Hodgkin D, Garnick DW, et al. Unhealthy drinking patterns and receipt of preventive 
medical services by older adults. J Gen Intern Med. 2008;23(11):1741-1748. doi:10.1007/s11606-008-
0753-3 
2. 
Deutekom M, Vansenne F, McCaffery K, Essink-Bot ML, Stronks K, Bossuyt PMM. The effects of 
screening on health behaviour: A summary of the results of randomized controlled trials. J Public 
Health (Bangkok). 2011;33(1):71-79. doi:10.1093/pubmed/fdq050 
3. 
McBride CM, Emmons KM, Lipkus IM. Understanding the potential of teachable moments: The case 
of smoking cessation. Health Educ Res. 2003;18(2):156-170. doi:10.1093/her/18.2.156 
4. 
Sheron N, Moore M, O’Brien W, Harris S, Roderick P. Feasibility of detection and intervention for 
alcohol-related liver disease in the community: the Alcohol and Liver Disease Detection study 
(ALDDeS). Br J Gen Pract. 2013;63(615):e698-705. doi:10.3399/bjgp13X673711 
5. 
Thursz M, Gual A, Lackner C, et al. EASL Clinical Practice Guidelines: Management of alcohol-related 
liver disease. J Hepatol. 2018;69(1):154-181. doi:10.1016/j.jhep.2018.03.018 
6. 
Thiele M, Detlefsen S, Sevelsted Møller L, et al. Transient and 2-Dimensional Shear-Wave 
Elastography Provide Comparable Assessment of Alcoholic Liver Fibrosis and Cirrhosis. 
Gastroenterology. 2016;150(1):123-133. doi:10.1053/j.gastro.2015.09.040 
7. 
Larsen IK, Grotmol T, Almendingen K, Hoff G. Impact of Colorectal Cancer Screening on Future 
Lifestyle Choices: A Three-Year Randomized Controlled Trial. Clinical Gastroenterology and 
Hepatology. 2007;5(4):477-483. doi:10.1016/j.cgh.2006.12.011 
8. 
Deleuran T, Vilstrup H, Becker U, Jepsen P. Epidemiology of alcoholic liver disease in Denmark 2006-
2011: a population-based  study. Alcohol Alcohol. 2015;50(3):352-357. doi:10.1093/alcalc/agv003 
9. 
European Association for the Study of Alcoholic Liver Disease. EASL-ALEH Clinical Practice Guidelines: 
Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015;63:237-264. 
doi:10.1016/j.jhep.2015.04.006 
10. 
Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG Clinical Guideline: Alcoholic Liver Disease. Am J 
Gastroenterol. 2018;113(2):175-194. doi:10.1038/ajg.2017.469 
11. 
Gossop M, Neto D, Radovanovic M, et al. Physical health problems among patients seeking treatment 
for alcohol use disorders: A study in six European cities. Addiction Biology. 2007;12(2):190-196. 
doi:10.1111/j.1369-1600.2007.00066.x 
12. 
National Institute for Health and Care Excellence. Alcohol Dependence and Harmful Alcohol Use: Full 
Guideline.; 2011. 
13. 
Frederik J, Eivindson M, Jacobsen BA, et al. Dansk Selskab for Gastroenterologi Og Hepatologi. 
Udredning Og Behandling Af Uforklaret Anæmi Med Jernmangel Uden Synlig Blødning.; 2014. 
14. 
Sundhedsstyrelsen. National Klinisk Retningslinje: Behandling Af Alkoholafhængighed.; 2015. 
15. 
Joseph AM, Rothman AJ, Almirall D, et al. Lung Cancer Screening and Smoking Cessation Clinical Trials 
SCALE (Smoking Cessation within the Context of Lung Cancer Screening) Collaboration. Am J Respir 
Crit Care Med. 2018;197(2):172-182. doi:10.1164/rccm.201705-0909CI 

 
Protokol_V2_05.01.2023 
 
 
 
33
16. 
DiClemente CC, Doyle SR, Donovan D. Predicting treatment seekers’ readiness to change their 
drinking behavior in the COMBINE study. Alcohol Clin Exp Res. 2009;33(5):879-892. 
doi:10.1111/j.1530-0277.2009.00905.x 
17. 
Sarich P, Canfell K, Banks E, et al. A Prospective Study of Health Conditions Related to Alcohol 
Consumption Cessation Among 97,852 Drinkers Aged 45 and Over in Australia. Alcohol Clin Exp Res. 
2019;43(4):710-721. doi:10.1111/acer.13981 
18. 
Sobell LC, Sobell MB. Using motivational interviewing techniques to talk with clients about their 
alcohol use. Cogn Behav Pract. 2003;10(3):214-221. doi:10.1016/S1077-7229(03)80033-0 
19. 
Kelly JF, Wakeman SE, Saitz R. Stop talking “dirty”: clinicians, language, and quality of care for the 
leading cause of preventable death in the United States. Am J Med. 2015;128(1):8-9. 
doi:10.1016/j.amjmed.2014.07.043 
20. 
Deutekom M, Vansenne F, McCaffery K, Essink-Bot ML, Stronks K, Bossuyt PMM. The effects of 
screening on health behaviour: A summary of the results of randomized controlled trials. J Public 
Health (Bangkok). 2011;33(1):71-79. doi:10.1093/pubmed/fdq050 
21. 
Ginès P, Castera L, Lammert F, et al. Population screening for liver fibrosis: Toward early diagnosis 
and intervention for chronic liver diseases. Hepatology. 2022;75(1):219-228. doi:10.1002/hep.32163 
22. 
Berzigotti A, Tsochatzis E, Boursier J, et al. EASL Clinical Practice Guidelines on non-invasive tests for 
evaluation of liver disease severity and prognosis – 2021 update. J Hepatol. 2021;75(3):659-689. 
doi:10.1016/j.jhep.2021.05.025 
23. 
Bohn MJ, Babor TF, Kranzler HR. The Alcohol Use Disorders Identification Test (AUDIT): Validation of a 
screening instrument for use in medical settings. J Stud Alcohol. Published online 1995. 
doi:10.15288/jsa.1995.56.423 
24. 
Dansk Selskab for Almen Medicin. Spørg Til Alkoholvaner.; 2010. 
25. 
Ware J, Kosinski M, Keller S. A 12-Item Short-Form Health Survey: Construction of Scales a... : Medical 
Care. Med Care. Published online 1996. 
26. 
F. S, C. M, J. H, et al. The genetics of alcohol dependence and alcohol-related liver disease. J Hepatol. 
2017;66(1):195-211. doi:http://dx.doi.org/10.1016/j.jhep.2016.08.011 
27. 
Papatheodoridi M, Hiriart JB, Lupsor-Platon M, et al. Refining the Baveno VI elastography criteria for 
the definition of compensated advanced chronic liver disease. J Hepatol. 2021;74(5):1109-1116. 
doi:10.1016/j.jhep.2020.11.050 
28. 
Thiele M, Madsen BS, Hansen JF, Detlefsen S, Antonsen S, Krag A. Accuracy of the Enhanced Liver 
Fibrosis Test vs FibroTest, Elastography, and Indirect Markers in Detection of Advanced Fibrosis in 
Patients With Alcoholic Liver Disease. Gastroenterology. 2018;154(5):1369-1379. 
doi:10.1053/j.gastro.2018.01.005 
29. 
Sobell LC, Brown J, Leo GI, Sobell MB. The reliability of the Alcohol Timeline Followback when 
administered by telephone and by computer. Drug Alcohol Depend. Published online 1996. 
doi:10.1016/0376-8716(96)01263-X 
30. 
Hernán MA, Robins JM. Causal Inference: What If.; 2020. https://www.hsph.harvard.edu/miguel-
hernan/causal-inference-book/ 

 
Protokol_V2_05.01.2023 
 
 
 
34
31. 
Andersen K, Behrendt S, Bilberg R, et al. Evaluation of adding the community reinforcement approach 
to motivational enhancement therapy for adults aged 60 years and older with DSM-5 alcohol use 
disorder: a randomized controlled trial. Addiction. 2020;115(1):69-81. doi:10.1111/add.14795 
32. 
Thiele M, Detlefsen S, Sevelsted Moller L, et al. Transient and 2-Dimensional Shear-Wave 
Elastography Provide Comparable Assessment of Alcoholic Liver Fibrosis and Cirrhosis. 
Gastroenterology. 2016;150(1):123-133. doi:http://dx.doi.org/10.1053/j.gastro.2015.09.040 
33. 
Collins RE, Lopez LM, Marteau TM. Emotional impact of screening: A systematic review and meta-
analysis. BMC Public Health. 2011;11(1):603. doi:10.1186/1471-2458-11-603