case study of alcoholic liver cirrhosis

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• Volume 14, Issue 5
• How to manage alcohol-related liver disease: A case-based review
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• http://orcid.org/0000-0003-1530-5328 James B Maurice 1 ,
• http://orcid.org/0000-0001-5140-517X Samuel Tribich 2 ,
• Ava Zamani 3 ,
• Jennifer Ryan 4
• 1 Department of Gastroenterology and Hepatology, Southmead Hospital , North Bristol NHS Trust , Bristol , UK
• 2 Department of Hepatology, Royal London Hospital , Barts Health NHS Trust , London , UK
• 3 Hammersmith Hospital , Imperial College Healthcare NHS Trust , London , UK
• 4 Department of Hepatology and Liver Transplantation, Royal Free Hospital , Royal Free London NHS Foundation Trust , London , UK
• Correspondence to Dr James B Maurice, Department of Gastroenterology and Hepatology, Southmead Hospital, North Bristol NHS Trust, Bristol BS10 5NB, UK; james.maurice{at}nbt.nhs.uk

https://doi.org/10.1136/flgastro-2022-102270

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• alcoholic liver disease
• chronic liver disease

What is already known on this topic

Alcohol-related liver disease (ArLD) is a major cause of morbidity and mortality.

What this study adds

We present a typical case to illustrate current evidence-based investigation and management of a patient with ArLD.

This case-based review aims to concisely support the day-to-day decision making of clinicians looking after patients with ArLD, from risk stratification and fibrosis assessment in the community through to managing decompensated disease, escalation care to critical care and assessment for liver transplantation.

How this study might affect research, practice or policy

We summarise the evolving evidence for the benefit of liver transplantation in alcoholic hepatitis, and ongoing controversies shaping future research in this area.

ArLD is fundamentally a public health problem, and further efforts are required to implement effective policies to reduce consumption and prevent disease.

Introduction

Alcohol is the leading risk factor for premature death in young adults, of which alcohol-related liver disease (ArLD) is a major contributor. 1 The management of ArLD often requires complex decision-making, raising challenges for the clinician and wider multidisciplinary team. This case-based review follows the typical journey of a patient through the progressive stages of the disease process, from early diagnosis and risk stratification in the outpatient clinic through to alcoholic hepatitis and referral for liver transplantation. At each stage, we discuss a practical approach to clinical management and summarise the underlying evidence base.

Case part 1

A 47-year-old man is referred to the general hepatology clinic from his General Practitioner with abnormal liver function tests, ordered in the community following several episodes of non-specific abdominal pain which subsequently resolved. He is now asymptomatic. The referral states that he drinks one bottle of wine each weekday night and more at the weekends. He is on no regular medication, has no other significant medical history and works in construction. On clinical examination, there are a few spider naevi on the chest wall but no other stigmata of liver disease, and his body mass index is 26 kg/m 2 . The blood results show alanine aminotransferase (ALT) 65 IU/L, aspartate aminotransferase (AST) 92 IU/L, alkaline phosphatase (ALP) 100 IU/L, gamma-GT (GGT) 350 IU/L, bilirubin 15 µmol/L, albumin 45 g/L, platelets 256×10 9 /L, internation normalised ratio (INR) 1.0 and creatinine 50 µmol/L. Abdominal ultrasound reveals a mildly enlarged, hyperechoic liver but normal spleen and no ascites.

How can we risk-stratify patients with ArLD in the outpatient clinic?

Early diagnosis and risk stratification of patients enables appropriate selection of patients for follow-up in secondary care, while also providing an opportunity for preventative interventions in those with mild disease. Emergency admissions for hepatic decompensation, where up to 75% of patients present for the first time, represent a late stage of the disease process when 1-year mortality is very high. 2 It is therefore vital to make an early diagnosis of liver disease.

Hepatic fibrosis has been traditionally staged by liver biopsy; however, non-invasive methods of fibrosis staging have an emerging role in ArLD. Transient elastography (TE) has been validated against liver biopsy to accurately stage both advanced fibrosis and cirrhosis, 3–6 and current NICE guidance recommends TE for the diagnosis of cirrhosis in patients with ArLD.

Serological markers of fibrosis such as FIB-4 and AST-Platelet Ratio Index (APRI) have generally not performed well in ArLD, although the enhanced liver fibrosis (ELF) test, measuring direct markers of fibrosis in blood, has an Area Under the Receiver Operator Curve (AUROC) of 0.92 in diagnosing advanced fibrosis using a cut-off value of 10.5. 7

How can we screen for alcohol use disorder and ArLD?

The primary screening tools for alcohol use disorders are the Alcohol Use Disorders Identification Test (AUDIT) or abbreviated AUDIT-C questionnaires. 8 Although clear documentation of the amount of alcohol consumed is important, a diagnosis of alcohol use disorder is more nuanced than volume of alcohol alone, hence the improved sensitivity through use of validated questionnaires. Identifying increasing risk (AUDIT 8–15), higher risk (AUDIT 16–19) or possible dependence (AUDIT≥20) 8 provides an opportunity for targeted brief interventions in those who would most benefit and is a cost-effective method for reducing alcohol intake. 9 Typically only comprising a 5–20 min single interaction, brief interventions offer personalised advice using a motivational and empathetic style of interview ( Box 1 ). If delivered to all new patients registered in primary care, this could save 2500 alcohol-related deaths over 20 years. 10 Patients identified to have alcohol dependence through screening should be referred for specialist treatment.

Typical features of brief interventions

Feedback on the person’s alcohol use and any related harm.

Clarification as to what constitutes low-risk consumption.

Information on the harms associated with risky alcohol use.

Benefits of reducing intake.

Motivational enhancement to support change.

Analysis of high-risk situations for drinking.

Coping strategies and the development of a personal plan to reduce consumption.

Adapted from Public Health England Review: the public health burden of alcohol and the effectiveness and cost-effectiveness of alcohol control policies. An evidence review. 45

Although routine blood tests may be helpful in supporting a diagnosis of ArLD (eg, AST>ALT, increased GGT, macrocytosis), they are of limited value in determining the severity of liver disease before established cirrhosis has developed with impaired liver synthetic function (low albumin, high INR and bilirubin). Individuals drinking at harmful levels should be screened for liver fibrosis with TE. Hepatology referral should be considered in patients with TE 8–16 kPa, particularly in those who continue to drink at harmful levels. Patients with TE≥16 kPa are at high risk of developing complications of cirrhosis, therefore should be followed up in a specialist hepatology clinic and be screened for hepatocellular carcinoma and oesophageal varices. Screening endoscopy for varices should be offered when TE≥20 kPa or platelets≤150×10 9 /L. 11 In the primary care setting, fibrosis screening of individuals drinking at harmful levels may alternatively be done with the ELF test, although this is not uniformly available ( figure 1 ). 12

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Screening for cirrhosis in individuals drinking at hazardous and harmful levels. ARFI, Acoustic Radiation Force Impulse; AUDIT, Alcohol Use Disorder Identification Test; AUDIT-C, abbreviated Alcohol Use Disorder Identification Test; ELF, enhanced liver fibrosis; GGT, Gamma-GT; HCC, hepatocellular carcinoma; NICE, The National Institute of Health and Care Excellence. Reproduced with permission from Newsome et al . 46

A high-risk population that should be considered for ArLD screening are the patients admitted to hospital acutely with alcohol-related physical harm, such as acute alcohol withdrawal or alcohol-related trauma. These patients should all be referred to alcohol care teams, and in addition to their expertise in delivering brief interventions, tailored detoxification regimens and vital links to local alcohol support services in the community, some hospitals have trained to perform TE and screen for liver fibrosis. This has provided an opportunity to streamline at risk patients into the hepatology services.

Case part 2

The same patient presents on the acute medical take 1 year later with a 2-week history of jaundice and abdominal swelling. Unfortunately, he has continued drinking alcohol. On examination, he is jaundiced with moderate ascites, tender hepatomegaly and subtle asterixis. He is sarcopenic with arm muscle wasting. He has the following blood results: haemoglobin 100 g/L, mean cell volume 107 fL, white cell count 12×10 9 /L, platelets 135×10 9 /L, INR 2.3, sodium 132 mmol/L, potassium 3.0 mmol/L, creatinine 55 µmol/L, urea 2.0 µmol/L, bilirubin 250 µmol/L, ALT 25 IU/L, AST 60 IU/L, ALP 95 IU/L, GGT 200 IU/L, albumin 35 g/L, c-reative protein (CRP) 45 mg/L. A diagnostic paracentesis reveals an ascitic albumin 16 g/L, white cells 90/mm 3 (80% lymphocytes). An X-ray of the chest is normal. Ultrasound liver demonstrates hepatomegaly 17 cm, splenomegaly 15 cm, moderate ascites and a patent portal vein. A clinical diagnosis of alcoholic hepatitis (AH) is made.

What is the role of liver biopsy in the diagnosis of AH?

AH is a clinical syndrome characterised by jaundice and coagulopathy in the context of recent and prolonged heavy alcohol use. Rapid development of jaundice is accompanied by a systemic inflammatory response with constitutional symptoms and low-grade fever, with or without other features of decompensation.

The diagnosis of AH can be made using a standard consensus definition based on clinical and biochemical parameters ( table 1 ), originally established to allow inclusion in clinical trials without the need for a liver biopsy but now generalised to clinical practice. 13 Neither European Association for the Study of Liver Disease (EASL) nor American College of Gastroenterology (ACG) guidelines recommend liver biopsy in patients meeting the criteria for probable AH, 9 10 and these recommendations have been supported by more recent data, showing that liver biopsy rarely changes the diagnosis when clinical criteria are met for AH. 12 However, if diagnostic uncertainty remains, such as atypical biochemical markers, uncertain alcohol use or a suspected alternative cause of liver injury, a liver biopsy should be undertaken to confirm the diagnosis, particularly if planning to administer AH-directed medical therapies. 14

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Consensus definition for ‘probable’ alcohol hepatitis 13

In those patients in whom a biopsy is undertaken, specific histological features such as degree of neutrophil infiltration, fibrosis stage and presence of megamitochondria can be useful for prognostication using the Alcoholic Hepatitis Histologic Score, which is independently predictive of 90-day mortality. 15 However, the utility of this is significantly limited by interobserver variability between reporting pathologists. 16

Should this patient be treated with steroids?

Once a diagnosis of AH is established, patients should be risk stratified using a validated scoring system. The modified Maddrey’s discriminant function (mDF) is a commonly used score, which defines a cut-off of ≥32 as severe AH; however, this is very sensitive and risks over-treating patients with mild disease. 17 The Glasgow Alcoholic Hepatitis Score (GAHS) and Model for End-Stage Liver Disease (MELD) are better predictors of 28-day and 90-day mortality than mDF 18 19 and are also now included in EASL and ACG guidelines, with severe AH defined as GAHS≥9 or MELD≥21. 20 , 14

The STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH) study is the largest randomised controlled trial to investigate the efficacy of corticosteroids in the treatment of AH. It included 1103 participants with severe AH and the group that received prednisolone only had a small non-significant improvement in 28-day survival (OR 0.72, 95% CI 0.52 to 1.01, p=0.06), a benefit which was lost by 90 days and 1 year. In the multivariate analysis adjusting for baseline variables, prednisolone was associated with improved 28-day survival compared with placebo (OR 0.61, p=0.015), although not at 90 days or 1 year. 21 Further meta-analyses of pooled data have replicated these findings. 22

The EASL and ACG guidelines advise to take steroid treatment with prednisolone 40 mg per day in patients with severe AH, as defined by either the mDF, GAHS or MELD Score. Steroid responsiveness should be assessed using the Lille Score, typically on day 7, although there is data to support earlier application on day 4, 23 with steroids stopped in non-responders (Lille Score≥0.45); responders should complete a 28-day course. It may be possible to predict Lille response using a baseline neutrophil-to-lymphocyte ratio (NLR), with an NLR of 5–8 predictive of a significant reduction in 90-day mortality with corticosteroid treatment, compared with no reduction when NLR is less than 5 or more than 8. 24 Emerging data is further delineating which patients may derive the greatest benefit from corticosteroids 25 ; however, this remains an area of ongoing research.

Infection is a frequent complication of severe AH, contributing significantly to the high mortality rate and associated in particular with an increased 90-day mortality. 26 Corticosteroids are associated with an increased incidence of infection post-treatment compared with placebo (10% vs 6%), 21 and significantly worse 90-day mortality if patients develop infection within the first week of starting steroids. 26 Therefore, particular caution is required prior to starting prednisolone in patients with active sepsis, bearing in mind that patients with cirrhosis may not mount a classic immune response to infection. 26 Biomarkers to predict risk of incident infection on steroids are an area of research interest; baseline NLR of >8 is also associated with increased infection at day 7 of corticosteroid treatment (OR 2.60, p=0.006), but requires further validation. 24

In clinical practice, the commencement of steroids is delayed until infection is excluded, including negative cultures of blood, urine and ascitic fluid. This period also allows for the assessment of the bilirubin trend which, along with risk stratification scoring, helps to inform the decision to start corticosteroids. 27

What are the considerations in managing alcohol withdrawal in patients with advanced liver disease?

Alcohol withdrawal syndrome (AWS) should be assessed using the Clinical Institute Withdrawal Assessment for AlcoholScore, with a symptom-based regimen rather than fixed dosing in order to reduce drug accumulation. 28 Benzodiazepines reduce withdrawal symptoms and the risk of both seizures and delirium tremens and are considered the gold standard for treatment of AWS. Long-acting benzodiazepines such as chlordiazepoxide and diazepam should only be used with caution in patients with cirrhosis and impaired synthetic function due to their unpredictable half-life and significant accumulation in the presence of hepatic dysfunction, where the use of shorter-acting lorazepam or oxazepam may be preferable if available. In addition, benzodiazepines can both precipitate and worsen hepatic encephalopathy and so should be used with care.

Abstinence from alcohol remains the only independent predictor of long-term survival in patients presenting with severe AH 29 and early intervention from an alcohol liaison service during the hospital admission is of fundamental importance.

What is the role of nutrition in the management of AH?

Patients with both AH and cirrhosis are characterised by an almost universal state of malnutrition, sarcopenia and B vitamin deficiency, alongside increased resting energy expenditure and impaired metabolism of carbohydrates, lipids and proteins. 30 Early involvement of the dietetic team is vital to ensure patients with AH meet their nutritional requirements.

Increased caloric intake has been associated with a reduced incidence of infection, improved liver function and quicker resolution of hepatic encephalopathy in multiple randomised trials. 30 A recent large trial reported lower rates of infections and improved 1-month and 6-month mortality in patients with severe AH treated with corticosteroids who received a calorie intake of ≥21.5 kcal/kg/day compared with those who received<21.5 kcal/kg/day, regardless of Lille response or of the mode by which the calories were delivered. 31

EASL and European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend an aim of 35–45 kcal/kg/day and a daily protein intake of 1.2–1.5 g/kg/day, with the oral route as first line and nasogastric feeding advised if oral intake is inadequate. 30 Intravenous thiamine replacement should be given to all patients with a history of alcohol use to reduce the risk of Wernicke’s encephalopathy. Several clinical trials have failed to demonstrate evidence for the use of various specialised dietary formulas and ESPEN recommend using standard nutritional supplements or feed with a high energy density, with a late evening supplement to reduce overnight starvation duration. 30

Case part 3

A full septic screen including blood cultures did not reveal any evidence of sepsis. The patient is managed with nutritional supplements, lactulose 20 mL three times a day and prednisolone 40 mg once daily. At day 7, his blood results are bilirubin 355, INR 3.0, PT 27, Cr 90, albumin 29. Lille Score is 0.60 (>0.45) indicating a poor prognosis, so prednisolone is stopped. Overall 90-day mortality in patients with AH is approximately 30%, increasing to around 45% in patients with a Lille Score>0.45 after 7 days of corticosteroids. 19

Is liver transplantation an option in severe AH?

In Europe, ArLD is the leading indication for liver transplant (LT), but the timing and selection of patients for liver transplantation with ArLD is controversial. A period of abstinence is vital to understand the extent of hepatic recompensation that can occur without the need to undergo LT and to ensure the patient is engaged with the process. However, although pretransplant abstinence is one important predictor of post-LT sobriety, it is not the only factor, and there is data that the risk of relapse is no higher in carefully selected patients transplanted with severe alcoholic hepatitis (SAH) compared with those with alcohol-related cirrhosis under standard selection criteria. 32

Challenging the traditional exclusion of patients with SAH from consideration for LT, a multicentre cohort study in France offered LT to patients with SAH who met specific stringent selection criteria, including non-response to steroid therapy, a first presentation of liver decompensation and a robust social support network. 33 This study showed significantly improved survival in the group offered LT at 2 years (71% vs 23%), a benefit almost entirely gained in the first 6 months. Long-term follow-up data was recently presented, showing overall survival at 1, 5 and 10 years of 83%, 70% and 56%, respectively. Severe alcohol relapse was evident in 10%, similar to other cohorts transplanted for ArLD using standard selection criteria. 34

The largest study in the USA on LT in SAH is a retrospective review of United Network for Organ Sharing data. In 147 patients transplanted with SAH between 2006 and 2017, with no previous decompensation and abstinence of less than 6 months, 1-year and 3-year survival was 94% and 84%, while return to sustained drinking occurred in 10% at 1 year and 17% at 3 years. 35 Interestingly, in a smaller retrospective case-controlled study comparing patients transplanted with SAH with<6 months abstinence (n=46) with a group transplanted for standard ArLD criteria and>6 months abstinence (n=34), the two groups had comparable 1-year survival (97% vs 100%, p=1) and return to harmful drinking after median follow-up of 532 days (17% vs 12%, p=0.5). 32

The only prospective trial of early liver transplantation in SAH was a non-randomised, non-inferiority, controlled trial recently published by the group in France. Over 2 years of follow-up, patients with SAH offered early liver transplant (n=68) had a small but non-significant increased risk of alcohol relapse compared with those transplanted for alcohol-related cirrhosis after ≥6 months of abstinence (n=93, relative risk 1.45, 95% CI 0.82 to 2.60), but also a greater risk of high levels of alcohol intake (RR 4.10, 95% CI 1.56 to 10.75). The 2-year post-transplantation survival was similar between these groups (89.7% and 88.2% respectively, HR 0.87, 95% CI 0.33 to 2.26), whereas the overall 2-year survival of patients with SAH who were not transplanted (n=47) was significantly reduced compared with those who were (28.3% vs 70.6%, HR 0.27, 95% CI 0.16 to 0.47). 36

The landscape of public and medical opinion on offering transplantation for SAH is changing in light of this data. However, concerns remain that predictive models are suboptimal and over 50% of patients with an unfavourable prognosis based on the Lille Score will survive without LT. 37 As such, the UK pilot on LT in SAH failed to recruit any patients over a 3-year period and was closed. 38 The current UK position recommends that if liver insufficiency persists after 3 months of documented alcohol abstinence in individuals with an index presentation of severe AH, consideration should be given to referral for liver transplantation if their psychosocial risk profile is favourable. 37

Case part 4

The patient’s clinical condition deteriorates over the following week. He becomes febrile, an ascitic tap confirms spontaneous bacterial peritonitis (white cells 700 cells/mL, neutrophils>90%) and he develops an oliguric acute kidney injury with haemodynamic instability requiring regular fluid boluses. His liver function remains poor (UK Model for End Stage Liver Disease (UKELD) 68). You call the intensive care unit (ITU) to review the patient, but questions are raised about his suitability for level 3 care.

Should this patient be escalated to critical care?

This patient now requires organ support with inotropes and likely renal replacement therapy. Historically, patients with ArLD have experienced barriers to timely escalation to ITU due to a perceived poor prognosis. Data in the National Confidential Enquiry into Patient Outcome and Death report in 2013 confirmed this practice, showing that 31% of patients deemed to require and be appropriate for escalation of care on independent review of the case notes did not receive such treatment. 39

In the same report, a review by the treating clinicians identified only 7% of cases who were appropriate for escalation but did not receive it. Subjective judgements detrimentally influenced these decisions and led the report to conclude that failure to escalate was due to clinicians having a prior view that it was not appropriate to escalate care in patients with ArLD.’ 39

Over the last 20 years, there has been a significant improvement in survival of patients admitted to ITU with organ failure complicating decompensated chronic liver disease, with mortality falling from 41.0% to 32.5% over this period, despite comparable scores for severity of illness at presentation. Although ArLD was associated with worse survival, improvements were also reported in this group over the same period (50.9% mortality to 41.9%, mean (Acute Physiology and Chronic Health Evaluation (APACHE) II Score 20 vs 19), such that the majority admitted to ITU will survive. 40

However, mortality rates for patients with ArLD and acute-on-chronic liver failure admitted to the ITU remain high, and escalation decisions require careful discussion and shared decision-making between the medical and critical care teams, alongside patients and their families as required. One of the first questions posed by the ITU team may be whether they are a transplant candidate. This is not a straightforward question to answer and may not be the most pertinent issue at this point in the patient’s care: in his case, the immediate answer would be ‘no’ in the UK, for reasons discussed above. But if he survives this admission, maintains abstinence but continues to have a qualifying UKELD Score he may be considered for a transplant assessment in 3 months.

In this instance, the patient’s age and the fact this is a first presentation with hepatic decompensation strongly support escalation at this stage, but the CLIF-ACLF prognostic scoring system can be helpful to add objective data to discussions between the managing team and ICU. While not including some increasingly recognised prognostic factors such as the presence of sarcopenia, the European Foundation for the Study of Chronic Liver Failure Acute-on-chronic Liver Failure (CLIF-C ACLF) Score has nevertheless been validated in a large dataset of patients with decompensated chronic liver disease and organ failure. 41 Days 3–7 on the ITU may be the optimal time to calculate this score, when an accurate assessment on the trajectory and likely outcome can be made. 42 Applying it in this way can support decision-making between the patient’s primary team and the ITU and provide timescales and goals with which to assess the benefits of level 3 care when there is disagreement or uncertainty.

However, even in the setting of treatment escalation it is important to remember that his overall prognosis is poor at this stage and, therefore, early involvement of the palliative care (PC) team should be considered. This can be done in parallel with full active medical care; it is important to bear in mind that PC is not synonymous with ‘end-of-life care’ and they are excellently equipped to optimise symptom control and begin to address wider holistic issues in the care of a patient at high risk of death. As such, early involvement of PC has been shown to improve symptom control and quality of life. 43

Case part 5

After 2 weeks in the ITU and a prolonged inpatient stay, the patient makes sufficient recovery to be discharged home. He continues to have moderate ascites managed with spironolactone and significant liver synthetic dysfunction (UKELD 60). He begins to attend his local alcohol support group and his partner has removed all alcohol from the house to support his abstinence.

When should you refer for transplant assessment?

Although he has made significant progress, this patient remains very unwell and at high risk of further deterioration. His ‘window of opportunity’ for transplant assessment is small. There is no fixed rule on this, but recent guidelines suggest that referral should be considered after 3 months of abstinence, or even sooner if the patient is actively engaged in alcohol cessation support, if there are issues that may complicate the workup assessment, or if the risk of death within 3 months is high. 44 In parallel to referral, every effort should be made to optimise his physical fitness, including dietician input and a graded exercise plan.

The patient maintains abstinence, is referred and successfully receives a life-saving liver transplant. A multidisciplinary team approach is required for patients admitted with decompensated ArLD, in which a dedicated alcohol care team is vital, but preventative measures on a population (eg, minimum unit pricing) and individual (eg, brief interventions and fibrosis stratification) level early in the disease course will have the greatest impact.

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Twitter @jamesbmaurice

Contributors JBM conceptualised the original article and the case. JBM, ST and AZ drafted the initial version of the manuscript. JBM and ST contributed further editing of various sections. JR provided senior critical review and edited the manuscript. All authors agreed upon the final version.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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• Highlights from this issue UpFront R Mark Beattie Frontline Gastroenterology 2023; 14 357-358 Published Online First: 07 Aug 2023. doi: 10.1136/flgastro-2023-102519

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How does alcohol use impact morbidity and mortality of liver cirrhosis? A systematic review and dose–response meta-analysis

• Original Article
• Published: 08 September 2023
• Volume 18 , pages 216–224, ( 2024 )

Cite this article

• Laura Llamosas-Falcón   ORCID: orcid.org/0000-0003-4718-9376 1 ,
• Charlotte Probst 1 , 2 , 3 , 4 ,
• Charlotte Buckley 5 ,
• Huan Jiang 1 , 6 ,
• Aurélie M. Lasserre 1 , 7 ,
• Klajdi Puka 1 , 3 , 8 ,
• Alexander Tran 1 ,
• Yachen Zhu 9 &
• Jürgen Rehm 1 , 3 , 4 , 6 , 10 , 11 , 12  

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Alcohol consumption is the most important risk factor responsible for the disease burden of liver cirrhosis (LC). Estimates of risk relationships available usually neither distinguish between different causes such as alcohol-related LC or hepatitis-related LC, nor differentiate between morbidity and mortality as outcome. We aimed to address this research gap and identify dose–response relationships between alcohol consumption and LC, by cause and outcome.

A systematic review using PubMed/Medline and Embase was conducted, identifying studies that reported an association between level of alcohol use and LC. Meta-regression models were used to estimate the dose–response relationships and control for heterogeneity.

Totally, 44 studies, and 1 secondary data source, with a total of 5,122,534 participants and 15,150 cases were included. Non-linear dose–response relationships were identified, attenuated for higher levels of consumption. For morbidity, drinking 25 g/day was associated with a RR of 1.81 (95% CI 1.68–1.94) compared to lifetime abstention; 50 g/day and 100 g/day corresponded to 3.54 (95% CI 3.29–3.81) and 8.15 (95% CI 7.46–8.91), respectively. For mortality, for 25 g/day, a RR of 2.65 (95% CI 2.22–3.16); for 50 g/day, a RR of 6.83 (95% CI 5.84–7.97); for 100 g/day, a RR of 16.38 (95% CI 13.81–19.42) were identified. A higher risk for alcohol-related and all-cause LC as compared to hepatitis C-related LC was found.

Our results demonstrated higher acceleration for mortality compared to morbidity. The current findings will inform the way we quantify the burden due to LC attributable to alcohol use.

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Data availability

The original contribution presented in the study are included in the article and Supplementary Materials. Further inquiries can be directed to the corresponding author.

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Acknowledgements

We would like to thank Ms. Astrid Otto for referencing and copyediting the text and Mr. Omer S.M. Hasan for his work as an independent reviewer in the systematic review.

Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number R01AA028009. JR was additionally supported by NIAAA grant R01AA028224. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Conceptualization, CP and JR; methodology, LLF, JR, HJ, AT, KP, and YZ; data curation, LLF, JR, HJ, and AT; formal analysis, LLF, HJ, AT, and YZ; funding acquisition, CP; investigation, LLF, KP, AL, CB, and JR; project administration, CP; resources, CP and JR; software, LLF, JR, HJ,AT, KP, and YZ; supervision, CP and JR; validation, JR and HJ; visualization, LLF and AT; writing—original draft, LLF and JR and writing—review and editing, all authors. All authors have read and agreed to the published version of the manuscript.

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A.L. reported grants from Swiss National Science Foundation (SNSF) during the conduct of the study. Laura Llamosas-Falcón, Charlotte Probst, Charlotte Buckley, Huan Jiang, Aurélie M. Lasserre, Klajdi Puka, Alexander Tran, Yachen Zhu, Jürgen Rehm declare no competing interests.

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Llamosas-Falcón, L., Probst, C., Buckley, C. et al. How does alcohol use impact morbidity and mortality of liver cirrhosis? A systematic review and dose–response meta-analysis. Hepatol Int 18 , 216–224 (2024). https://doi.org/10.1007/s12072-023-10584-z

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• Liver cirrhosis
• Liver disease
• Systematic review
• Dose–response
• Meta-analysis
• Epidemiology
• Public health
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• Track your research

• Nutrition counsellor
• Food Allergy
• gastroenterology
• Heptologist In Delhi
• Liver transplant
• Alcoholic Liver Cirrhosis

Alcoholic liver cirrhosis is a late stage of fibrosis of the liver caused by many forms of liver diseases and conditions, such as chronic alcoholism. A person diagnosed with an alcoholic liver case may start from having fatty liver disease, then alcoholic hepatitis, and ultimately develop alcoholic cirrhosis. Hence, alcoholic liver cirrhosis stages in three levels. The diagnosed liver cirrhosis can be of two types :

• Compensated cirrhosis – when symptoms are not noticeable
• Uncompensated cirrhosis- when the symptoms can be noticed

The most common alcoholic liver causes are:

• Chronic alcohol consumption
• Chronic hepatitis
• Fatty liver disease
• Iron buildup in the body or hemochromatosis
• Copper accumulated in the liver (Wilson’s disease)
• Cystic fibrosis
• Biliary Atresia
• Inherited sugar metabolism or digestive disorders
• Infection like syphilis

Many other factors like the destruction of bile ducts(Primary Biliary Cirrhosis) or leaky gut also called, increased intestinal permeability are cofactors for the development of alcoholic liver cirrhosis.

Now, let us have a look at alcoholic liver cirrhosis symptoms:

• Food pipe problems
• Portal hypertension
• Swelling in legs (oedema) and abdomen (ascites)
• Bleeding in mouth
• Confusion, poor memory, loss of appetite
• Patchy red skin on palms (erythema)

Food pipe problem is also known as esophageal varices. Kidney failure and hypersplenism are other complications that happen due to this medical condition. If the symptoms are not taken seriously, then this deficient liver may arise a life-threatening situation. Hence, a person needs to keep a track of these indicators as if these signs are caught early and treated, it may slow down the progression of the disease.

How to treat alcoholic liver cirrhosis:

The first and foremost step in treatments is to help the patient to cease alcohol consumption. Medications like corticosteroids, calcium channel blockers, insulin can also be prescribed by the doctor as per the alcoholic liver care plan. Hepatologists may advise the patient to follow an alcoholic liver disease diet inclusive of fiber and protein. If the condition of the patient gets worsened, then the hepatologist may have to suggest a liver transplant surgery.

Dr. Nivedita Pandey is one of the best liver specialist doctors in Patna, Bihar. She is a well-renowned liver specialist doctor in Delhi, the best stomach doctor in Patna, the best gastroenterologist in Jammu, and a notable stomach doctor in Faridabad. Now, you can sway off all your gastroenterological worries online by booking an online gastroenterologist consultation with one of the best hepatologists in India. She is a liver specialist in Delhi NCR, one of the finest gastroenterologists in Jhansi and Jammu, and an acidity specialist doctor in Patna. Dr. Pandey’s gastroenterologist live chat has also helped people in several ways.

Case Review

This alcoholic liver case study presents a patient with liver cirrhosis. A 43-year-old man was brought into the hospital with a complaints of loss of appetite, abdominal distention, and arrhythmia. He also experienced itchy skin and blood in the stool. The patient’s family rushed him into the hospital, and he was in a half-conscious state. The patient was taken to the emergency room for evaluation. As told by the family, he had a past medical history and was a heavy alcohol consumer. This alcoholic liver case history consisted of various medical ailments like fatty liver, asthma, tuberculosis, malnutrition, hypertension, and hepatitis C. The patient had a heart attack three years back and stented for the same. Due to his health conditions, he was on several medications. In the emergency room, when the patient was under observation by a stomach specialist doctor in Patna and her team, they were able to diagnose from his symptoms that it was alcoholic liver cirrhosis. The patient went for a few scans including, a liver function test, liver ultrasound, and endoscopy along with CT, blood test, and urine tests.

Case Discussion

Though most of the liver cirrhosis causes remain unknown, with the help of her team, the best liver doctor and specialist in Patna was able to find out the reason for this one. The liver cirrhosis caused in this case was due to the medical history of the patient. His scans came out to be reasonably sound, and a liver biopsy was conducted to confirm the severity and type of liver disease. There were problems in his blood and urine culture, and they were taken care of by the team. His liver appeared swollen in the reports. There were certain other problems seen in his ultrasound and endoscopy. The crew decided to start with the treatment while keeping him under observation for the next 72 hours.

Clinical Symptoms

He was initially confused and was not able to respond or hear properly. According to the condition reported by his family i.e.- appetite loss, memory loss, and confusion were some other clinical symptoms of alcoholic liver cirrhosis. When the doctor talked to the family of the patient, she was able to get a clearer picture. The patient complained about acute abdominal pain. When Dr. Pandey, one of the best doctors in Patna for the stomach, observed the patient and talked to him, she noticed bleeding in his mouth. This further helped doctors to eliminate all doubts, and after looking at the lab results, they made out it was alcoholic liver cirrhosis.

The first and foremost management required when treating the alcoholic liver cirrhosis case is calming the patient down. The liver specialist with the help of her fellow doctors was able to counsel the patient and explain his medical condition to the family. After a complete diagnosis, the patient was taken to the ICU as he was under observation. The doctor prescribed him antioxidant drugs and insulin to control any future problems while treating the present one. The doctor is the best gastroenterologist in Faridabad, Delhi, and Patna, and she handled the situation well before any further complications. The patient got his discharge in due time and was sent back home in a healthy and sound condition.

1.   Which Group of People are More Likely to get diagnosed with alcoholic liver cirrhosis?

A person who has drunk heavily for a long time is more prone to acquire this disease. Women are also at risk for this medical disease due to the absence of many enzymes which break down alcohol particles.

Consider consulting the best gastroenterologist in India , Dr. Nivedita Pandey who is also well known for her nutritional counselling services and teleconsultation services. She is also famous for her care from afar service. You can also find her as the best liver specialist doctor in Patna, Bihar or hepatologist in Patna or the best doctor for hepatitis b in Patna , a gastroenterologist in Faridabad , the best gastro doctor in Delhi, NCR , a gastroenterologist In Uttarakhand , a liver specialist in Jhansi , best gastroenterologist in Jammu take advantage of the online gastroenterology consultation to gastroenterologist live chat and receive the best treatment that your body deserves!

2.   Is liver cirrhosis cancer?

No, liver cirrhosis is not a type of cancer. If a person has alcoholic liver cirrhosis, he/she has an increased risk of liver cancer.

3.   Is liver cirrhosis a hereditary disease?

Negative, alcoholic liver cirrhosis is not a hereditary disease, rather it is a type of an acquired disease.

Privacy Preference Center

Privacy preferences, nutrition counselling.

Nutrition counseling is the assessment of an individual’s dietary intake after which, they are helped set achievable goals and taught various ways of maintaining these goals. The nutrition counselor provides information, educational materials, support and follow-up care to help an individual make and maintain the needed dietary changes for problems like obesity.

Obesity/ Food allergy

I assist people dealing with weight-related health problems by evaluating the health risks and help in obesity management. I also help patients manage various food allergies.

As a hepatologist, I specialize in the treatment of liver disorders, pancreas, gallbladder, hepatitis C, jaundice and the biliary tree. I also see patients suffering from pancreatitis, liver cancers alcoholic cirrhosis and drug induced liver disease(DILI), which has affected the liver.

Gastroenterology

As a gastroenterologist, my primary focus is the overall health of the digestive system. I treat everything from acid reflux to ulcers, IBS, IBD: Crohns disease and ulcerative colitis, and colon cancer.

Endoscopy is a nonsurgical procedure to examine a person’s digestive tract. It is carried out with an endoscope, a flexible tube with a light and camera attached to it so that the doctor can see pictures of the digestive tract on a color TV monitor.

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Gastroenterology is a specialty that evaluates the entire alimentary tract from the mouth to anus and involves studying the diseases of the pancreas.

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A liver transplant is a surgical procedure that removes a patient’s non-functioning liver and replaces it with a healthy liver from a deceased donor or a portion of healthy liver from a living donor. It is reserved as a treatment option for people who have significant complications due to end-stage chronic liver disease or in case of sudden failure of a previously healthy liver.

• Open access
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Global prevalence, incidence, and outcomes of alcohol related liver diseases: a systematic review and meta-analysis

• Xuanxuan Niu 1 ,
• Lin Zhu 1 ,
• Yifan Xu 1 ,
• Menghan Zhang 1 ,
• Yanxu Hao 1 ,
• Yan Li 1 &
• Huichun Xing   ORCID: orcid.org/0000-0002-9111-9669 1 , 2  

BMC Public Health volume  23 , Article number:  859 ( 2023 ) Cite this article

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A Correction to this article was published on 18 July 2023

This article has been updated

Alcohol related liver disease (ARLD) is one of the major chronic liver diseases worldwide. This review aimed to describe the global prevalence, incidence, and outcomes of ARLD.

Medline, Embase, The Cochrane Library, and China National Knowledge Infrastructure (CNKI) were searched from inception to May 31, 2022. The language was restricted to English or Chinese. According to the criteria, articles describing the basic characteristics of the population were selected. Two reviewers extracted the data independently.

A total of 372 studies were identified: 353 were used for prevalence analysis, 7 were used for incidence analysis, and 114 were used to for outcome analysis. The prevalence of ARLD worldwide was 4.8%. The prevalence in males was 2.9%, which was higher than female (0.5%). Among the ethnic groups, the percentage was highest in Caucasians (68.9%). Alcoholic liver cirrhosis comprised the highest proportion in the disease spectrum of ARLD at 32.9%. The prevalence of ascites in ARLD population was highest (25.1%). The ARLD population who drinking for > 20 years accounted for 54.8%, and the average daily alcohol intake was 146.6 g/d. About 59.5% of ARLD patients were current or former smokers, and 18.7% were complicated with hepatitis virus infection. The incidence was 0.208/1000 person-years. The overall mortality was 23.9%, and the liver-related mortality was 21.6%.

The global prevalence of ARLD was 4.8% and was affected by sex, region, drinking years, and other factors. Therefore, removing the factors causing a high disease prevalence is an urgent requisite.

Trial registration

PROSPERO Nr: CRD42021286192

Peer Review reports

According to Global Status Report on Alcohol and Health 2018 [ 1 ], about 2.3 billion people are drinking alcohol worldwide currently, and more than half of the population in the USA, Europe, and the Western Pacific consumes alcohol. Chronic heavy drinking is the etiology or risk factor for many diseases, such as alcohol related liver diseases (ARLD) , acute pancreatitis, and alcohol-related cardiomyopathy [ 2 ]. A study showed a 2.1-fold increase in deaths from alcohol poisoning between 2000 and 2019 in USA [ 3 ]. According to the WHO data, the global number of deaths caused by alcohol was about 3 million in 2016. Among them, the deaths caused by alcohol-related digestive diseases accounted for 21.3% of all diseases with highest proportion [ 1 ]. The total number of deaths was 637,000, including 607,000 cases of ARLD [ 1 ]. Therefore, ARLD has become one of the major causes of alcohol-related death.

Due to the popularity of hepatitis B vaccine and the effective application of antiviral therapy worldwide, the status of the HBV as the main cause of the chronic liver disease is declining gradually [ 4 ], while alcohol has gained increasing attention. A study [ 5 ] showed that the global prevalence of chronic liver diseases due to alcohol use increased by 3.73% between 2005 and 2015. The prevalence of alcoholic liver cirrhosis in cirrhosis population was increased by 43% in 7 years in the USA [ 6 ]. The number of deaths from ARLD in South Korea increased from 1403 to 3588 between 2000 and 2009 [ 7 ]. These studies suggested that the burden of ARLD is increasing gradually. Therefore, understanding the epidemiology of ARLD is essential to formulate the relevant prevention and control policies.

However, the current epidemiological data on ARLD were obtained from small-scale research. There is no global consensus. In addition to alcohol consumption as a direct factor of liver injury [ 8 , 9 ], region, gender [ 10 ], race, smoking, and other factors have an impact on the prevalence of ARLD. Thus, this meta-analysis described the characteristics of ARLD population in epidemiology, which could help improve the healthcare strategies and reduce the global prevalence of the disease.

This meta-analysis of observational studies was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and registered in PROSPERO.

Search strategy and selection criteria

Pubmed, Embase, The Cochrane Library, and CNKI, were searched using the keywords “Liver Diseases, Alcoholic”, “Alcoholic Liver Diseases”, “Alcoholic Liver Disease”, and “Liver Disease, Alcoholic”. The details are described in the Supplementary Table 1 . Studies published from the respective inception dates of the databases to May 31, 2022 were eligible for inclusion in this meta-analysis. The language of the literature was limited to English or Chinese.

Data extraction and quality assessment

Two reviewers searched the studies and extracted the data independently. Any disagreements on the eligible studies and data extraction were resolved by consensus and/or discussion with a third author. The included literature is listed in the Supplementary Tables 2 , 3 , 4 and 5 . Newcastle–Ottawa scale was used to evaluate the quality of the studies, ranging from 0–9: 7–9 represented a high-quality score, 4–6 represented a medium score, and 1–3 represented a low score. Studies with scores < 4 were excluded.

Study definitions

ARLD is a series of liver injuries caused by long-term high-alcohol intake, including mild alcoholic liver disease, alcoholic fatty liver disease, alcoholic hepatitis, alcoholic cirrhosis, and related complications [ 11 ]. ARLD was diagnosed according to long-term drinking history or short-term heavy drinking history, without autoimmune hepatitis, drug-induced liver diseases, or other genetic disorder related liver diseases. It should be evaluated though blood biochemical testing, ultrasound, transient elasticity, CT, MRI, and biopsy [ 12 , 13 ]. The concrete situation was determined based on the latest diagnostic criteria of the corresponding year. The general population without defined diseases was referred to the physical examination at the health care center and participated in the epidemiological survey. Original research articles that defined their population as ARLD and/or general population were included. Including studies should also provide the data on the prevalence, incidence and outcomes of ARLD. Study designs with unrestricted types were eligible for inclusion. In case of duplicate data, the largest and latest datasets were selected. Articles were excluded if the diagnosis of ARLD were unclear; the number of participations were < 50 in the baseline; age < 18-years-old; the study population was limited to either one gender; specific groups with other chronic diseases, such as non-alcoholic liver disease, drug-induced liver disease, and acquired immune deficiency syndrome.

Data analysis

The incidence of ARLD was studied in the general population at baseline without the disease. To estimate the incidence, we used the number of new cases and the follow-up time (person-years). The baseline characteristics of ARLD population, including prevalence, mortality, and cause of death, were described. In order to study the influencing factors of prevalence, we analyzed region, sex, race, disease severity, complications, drinking years, smoking, virus infection, and other factors. Moreover, the global prevalence was compared between 2000–2010 and 2011–2021.

Statistical analysis

Cochran Q and I 2 statistics were used to assess the heterogeneity. p -value < 0.05 in Q-statistic and I 2  ≥ 50% were considered moderate or severe heterogeneity. Due to the heterogeneity of global data, random-effects model was applied to analyze each study dataset. Funnel plot and Egger’s test (the figures of main result are listed in Supplementary Figs.  1 –  5 ) were used to evaluate the publication bias. All statistical analyses were conducted using Meta package in Stata statistical software.

Study selection and characteristics

According to the above-defined search terms in methods, 64,321 studies were retrieved, and 368 studies were included according to the inclusion criteria. While searching for relevant articles, four additional studies were added. Finally, 372 articles were included: 353 studies for prevalence analysis, 7 for incidence analysis, and 114 for outcome analysis (some studies provided data on prevalence, incidence and/or outcomes at the same time; hence, the total number was different from the sum of subgroups) (Fig.  1 ).

Study selection. The entire screening process were described, including the selected the reasons for the exclusion of articles and the number of including and excluding artcles. ARLD: alcohol-associated liver disease. HBV: hepatitis B virus. HCV: hepatitis C virus. HIV: human immunodeficiency virus. DILI: drug-induced liver injury.* Some articles were used for more than one of the analyses of prevalence, incidence, and outcomes. # When searching for relevant articles found 4 additional articles that met the inclusion criteria

Prevalence of ARLD

The overall prevalence of ARLD in general population was 4.8% [95% confidence interval (CI): 4.1–5.6] (99 studies, 198,423,289 participations) (Table 1 ). The prevalence fluctuated from 1.0 to 16.1% and higher in male compared to female (2.9% vs . 0.5%, p  < 0.001).

By geographic region and province

The information on the prevalence of ARLD in different countries and regions is summarized in Table 1 and Figs.  2 and 3 . The study encompassed 14 countries, including Portugal [ 14 ], Canada [ 15 ], Iceland [ 16 ], France [ 17 , 18 ], China (see the following paragraph), USA [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], Denmark [ 36 , 37 , 38 ], South Korea [ 39 , 40 ], Uganda [ 41 ], India [ 42 , 43 ], UK [ 10 , 44 , 45 , 46 , 47 ], Sweden [ 48 ], Japan [ 49 , 50 , 51 , 52 , 53 , 54 ], and Italy [ 55 , 56 , 57 ](Fig.  2 and Table 1 ). The global prevalence of ARLD in general population was 4.8% (95% CI: 4.1–5.6) (Fig.  2 ), which we got from 99 datasets. As the region with the highest alcohol consumption in the world [ 12 ], Europe had the highest prevalence (5.4%, 95% CI: 3.9–7.1). According to the analysis results in Table 1 and the color depth distribution in Fig.  2 , the prevalence of ARLD was higher in most European countries. Italy had the highest prevalence rate of 16.1% (95% CI: 1.2–43.3), followed by Sweden (14.0%, 95% CI: 13.0–15.0) and the UK (7.2%, 95% CI: 3.0–13.0), while France, Denmark, Iceland and Portugal had the lowest prevalence rates: 1.4% (95% CI: 1.3–1.4), 1.2%(95% CI: 0.1–3.4), 1.0% (95% CI: 0.8–1.2) and 1.0% (95% CI: 0.9–1.1), respectively (Table 1 , Fig.  2 ). Although alcohol consumption in Asia was less than that in Europe, the prevalence in India (11.8%, 95% CI: 10.7–12.9) and Japan (10.4%, 95% CI: 3.2–20.9) was high (Table 1 ). Uganda in Africa has the high prevalence of 11.0% (95% CI: 7.7–10.2). Surprisingly, the United States, with the largest number of studies (17 studies) and participants (137,929,285 persons), had the lower prevalence (5.0%, 95% CI: 2.9–7.6) (Table 1 ).

The global prevalence of ARLD. The prevalence in 14 countries was indicated by depth of red. The 14 countries included Portugal, Canada, Iceland, France, China, USA, Denmark, South Korea, Uganda, India, UK, Sweden, Japan, and Italy

The prevalence of ARLD in China by provinces. The prevalence in 21 provinces of China was indicated by depth of red. The prevalence in China was obtained from the analysis of 21 cities or provinces including Sichuan, Beijing, Guangdong, Jiangsu, Shanghai, Gansu, Shaanxi, Guizhou, Zhejiang, Henan, Hunan, Jilin, Heilongjiang, Taiwan, Tibet, Liaoning, Yunnan, Anhui, Shandong, Hebei, and Xinjiang provinces

Since the pathogenesis of ARLD in Western countries, which has been well-documented, differed from that in China [ 9 ], the prevalence in China’s provinces was analyzed separately. The prevalence of ARLD was 3.9% (95% CI: 2.9–5.1) (Table 1 ) in Chinese people, which was lower than the global prevalence. Data from 21 cities or provinces, including Sichuan [ 58 , 59 , 60 , 61 , 62 ], Beijing [ 63 , 64 , 65 , 66 ], Guangdong [ 67 , 68 , 69 , 70 , 71 ], Jiangsu [ 72 , 73 ], Shanghai [ 74 , 75 ], Gansu [ 76 , 77 ], Shaanxi [ 78 , 79 , 80 ], Guizhou [ 81 , 82 ], Zhejiang [ 83 , 84 , 85 , 86 , 87 , 88 , 89 ], Henan [ 90 , 91 ], Hunan [ 92 , 93 ], Jilin [ 94 , 95 , 96 , 97 ], Heilongjiang [ 98 ], Taiwan [ 99 ], Tibet [ 100 ], Liaoning [ 101 ], Yunnan [ 102 , 103 ], Anhui [ 104 , 105 ], Shandong [ 106 , 107 ], Hebei [ 108 ], and Xinjiang [ 109 ] provinces, were collected (Fig.  3 and Table 1 ). The prevalence in Xinjiang was 10.7% (95% CI: 9.5–11.9), which was much higher than the overall prevalence in China. It was the province with the highest prevalence, followed by Hebei (9.8%, 95% CI: 7.9–12.0) and Shandong provinces (8.1%, 95% CI 7.5–8.7), which were famous for strong drinking. Surprisingly, Shaanxi and Gansu provinces, famous for binge drinking, had the lower prevalence. Further analysis of Northeast China [ 95 , 96 , 97 , 98 , 101 ] (including Heilong, Jilin, and Liaoning provinces) and Northwest China [ 76 , 77 , 78 , 79 , 80 , 109 , 110 , 111 ] (including Xinjiang, Shaanxi, and Gansu provinces) showed that the prevalence was 4.8% (95% CI: 3.7–6.0) and 5.9% (95% CI: 4.2–7.9), which were much higher than the national prevalence. The prevalence rates were relatively low in Sichuan (1.8%, 95% CI: 1.1–2.6), Beijing (1.9%, 95% CI: 0.1–5.5), Guangdong (1.9%, 95% CI: 0.7–3.6), Jiangsu (2.2%, 95% CI: 1.9–2.5), and Shanghai (2.9%, 95% CI: 2.5–3.3), all which were relatively economically developed regions (Table 1 ).

Herein, 58 studies [ 14 , 15 , 16 , 18 , 19 , 20 , 22 , 23 , 24 , 25 , 29 , 30 , 31 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 44 , 45 , 46 , 50 , 53 , 55 , 56 , 58 , 59 , 60 , 63 , 64 , 65 , 66 , 67 , 71 , 77 , 78 , 80 , 81 , 84 , 85 , 86 , 92 , 93 , 96 , 97 , 99 , 100 , 101 , 104 , 105 , 106 , 107 , 111 ] were included to analyze the influence of sex on the prevalence of ARLD. The prevalence of male was 2.9% (95% CI: 2.4–3.5), which was much higher than that of women (0.5%, 95% CI: 0.4–0.7) (Table 1 ).

By study period

In order to further analyze the changes in the global ARLD prevalence in different periods, seventy three articles indicating the study years were included. From these, 48 articles [ 10 , 20 , 25 , 26 , 30 , 34 , 35 , 37 , 40 , 42 , 43 , 44 , 48 , 50 , 53 , 59 , 60 , 61 , 62 , 63 , 67 , 68 , 69 , 71 , 72 , 73 , 74 , 76 , 80 , 81 , 83 , 85 , 87 , 88 , 89 , 90 , 91 , 93 , 94 , 95 , 96 , 97 , 99 , 100 , 101 , 102 , 109 , 111 ] were used for subgroup analysis of the prevalence from 2000 to 2010: 4.6% (95% CI: 4.2–5.1) (Table 1 ). A total of 18 articles [ 10 , 17 , 19 , 22 , 26 , 41 , 43 , 49 , 51 , 52 , 65 , 70 , 75 , 78 , 79 , 82 , 104 , 106 ] were used to analyze the prevalence in 2011–2021, and the result was 5.6% (95% CI: 2.4–10.1), which was significantly higher in this period than in 2000–2010 (Table 1 ).

The characteristic of ARLD

The characteristics of ARLD patients in nationality, race, disease severity, complication, drinking years, smoking/smoked, and hepatitis virus infection are different. This part was described by comparing the percentage of each part of ARLD population.

By race and nationality

For race, categories included Caucasians, Africans, Hispanic and Asians, and these are the relatively lager amount of data that we can gather from the studies. According to the 46 articles [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 29 , 30 , 31 , 33 , 35 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 ] collected, the proportion of Caucasians was the highest (68.9%, 95% CI: 67.6–70.2) in ARLD, which was much higher than Africans (8.9%, 95% CI: 8.5–9.4) and Hispanic (8.6%, 95% CI: 7.9–9.4) (Table 2 ). The Asians was the lowest (0.3%, 95 CI: 0.1–0.6), with wide variation between races.

China has multiple ethnic groups. The data [ 103 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 ] collected in this study divided Chinese people with ARLD into Han nationality and other minorities, which including Mongol, Chosen, Li, Hmong, Kazak, Uyghurs, Xibe, Hani, Yi and Dai (Table 2 ). The minority group accounted for 61.6% (95% CI: 52.8–70.0), which was much higher than in the Han group (38.4%, 95% CI: 30.0–47.2).

By duration of alcohol intake and the daily dose of pure alcohol consumption

Alcohol as a pathogenic factor, drinking years and average daily drinking consumption affected the natural course of ARLD. According to the data of ARLD population, they were divided into three subgroups with drinking years of 5–9, 10–19, > 20. The ARLD with drinking duration > 20 years accounted for 54.8% (95% CI: 46.9–62.6) (Table 2 ). The analysis of the 19 studies [ 78 , 80 , 81 , 84 , 92 , 95 , 146 , 148 , 149 , 151 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 ] describing the correlation between drinking years and ARLD revealed that the longer the drinking years, the more patients with ARLD. The average daily alcohol consumption of 4184 ARLD patients [ 98 , 133 , 140 , 153 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 ] included in the study was up to 146.6 g/d (95% CI: 123.8–169.4) (Table 2 ), which was much higher than the excessive drinking defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA): > 4 cups/day for men and > 3 cups/day for women (1 standard cup = 14 g alcohol) [ 180 ].

By smoking and hepatitis viral infectious

As a risk factor of many diseases, tobacco has been proven to increase the risk of liver fibrosis [ 181 ]. Among 27 articles [ 19 , 23 , 24 , 33 , 37 , 40 , 49 , 163 , 171 , 172 , 173 , 179 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 ], 106,599 people were diagnosed with ARLD, of which 53,661 were former or current smokers, accounting for 59.5% (95% CI: 55.9–63.1) (Table 2 ). Three articles [ 37 , 186 , 188 ] described that smoking promoted disease progression, and two studies [ 23 , 33 ] showed that smoking increased the mortality and hospitalization rates. In addition to advising the patients to quit alcohol, education on smoking cessation was also conducive to improving the progress of ARLD.

Hepatitis virus infection and alcohol are the major causes of chronic liver disease. Among the 67 articles [ 19 , 21 , 25 , 26 , 30 , 40 , 53 , 87 , 99 , 114 , 115 , 120 , 121 , 123 , 125 , 126 , 156 , 158 , 161 , 167 , 168 , 171 , 172 , 176 , 192 , 194 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 ] included, 92,548/1473951 patients with ARLD were complicated with a hepatitis viral infection, with the prevalence of 18.7% (95% CI: 16.0–21.5), and the infection rate of HCV (5.6%, 95% CI: 4.1–7.4) was higher than that of HBV (3.6%, 95% CI: 3.0–4.3) (Table 2 ). Three of the 67 articles [ 210 , 235 , 236 ] described that the liver damage caused by concurrent hepatitis virus infection and alcohol was severe. One article [ 194 ] suggested that the presence of both causes an increased possibility of 30-day readmission. The data of 4 studies [ 30 , 126 , 201 , 204 ] showed that the mortality of ARLD with virus infection was higher than that of ARLD only. Therefore, antiviral drugs are essential for ARLD with hepatitis viral infection while abstaining from alcohol.

By the stage of disease and complications

ARLD caused by long-term heavy drinking included the whole disease spectrum from liver steatosis to liver cirrhosis and even liver cancer [ 237 ]. The constituent ratio of alcoholic cirrhosis in ARLD population was the highest, up to 32.9% (95% CI: 27.3–38.7) (Table 2 ) got from 147 articles [ 16 , 19 , 25 , 26 , 27 , 31 , 36 , 46 , 64 , 66 , 80 , 81 , 84 , 86 , 91 , 92 , 98 , 100 , 101 , 102 , 111 , 113 , 117 , 119 , 121 , 122 , 123 , 124 , 145 , 148 , 149 , 152 , 153 , 157 , 159 , 160 , 161 , 162 , 165 , 170 , 173 , 174 , 175 , 176 , 187 , 193 , 194 , 197 , 199 , 208 , 219 , 221 , 222 , 223 , 225 , 227 , 229 , 230 , 231 , 232 , 233 , 234 , 236 , 238 , 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 , 300 , 301 , 302 , 303 , 304 , 305 , 306 , 307 , 308 , 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 , 317 , 318 , 319 , 320 , 321 ]. A total of 119 datasets [ 25 , 26 , 30 , 43 , 47 , 113 , 115 , 116 , 122 , 125 , 126 , 128 , 129 , 131 , 132 , 136 , 137 , 142 , 153 , 156 , 157 , 161 , 162 , 168 , 171 , 172 , 173 , 176 , 178 , 186 , 190 , 193 , 194 , 195 , 196 , 197 , 204 , 207 , 208 , 213 , 215 , 221 , 225 , 226 , 227 , 228 , 229 , 230 , 241 , 242 , 243 , 245 , 250 , 251 , 252 , 255 , 262 , 267 , 272 , 275 , 276 , 294 , 297 , 299 , 306 , 311 , 318 , 321 , 322 , 323 , 324 , 325 , 326 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 , 335 , 336 , 337 , 338 , 339 , 340 , 341 , 342 , 343 , 344 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , 352 , 353 , 354 , 355 , 356 , 357 , 358 , 359 , 360 , 361 , 362 , 363 , 364 , 365 , 366 , 367 , 368 , 369 , 370 , 371 , 372 ] were used to analyze the prevalence of ascites, gastrointestinal bleeding, hepatic encephalopathy, spontaneous peritonitis (SBP), hepatorenal syndrome, and bacterial infection in ARLD. Ascites were the most common complication, with a prevalence of 25.1% (95% CI: 20.5–30.0), three times that of gastrointestinal bleeding (Table 2 ).

SBP is the most common and life-threatening bacterial infection in cirrhotic patients with ascites. The prevalence of SBP in ARLD population was not high (0.2%, 95% CI: 0–0.5) (Table 2 ). However, the prevalence of SBP in alcoholic cirrhosis [ 25 , 122 , 132 , 194 , 204 , 208 , 356 , 362 , 368 , 373 ] with ascites was 12.5% (95% CI: 10.7–14.4). Since the clinical symptoms of SBP were often occult and only limited research data were available, the prevalence may be underestimated. The occurrence of the above complications often indicated decompensated alcoholic cirrhosis, which was the predictor of mortality. Diabetes is also one of the critical factors affecting prognosis. A total of 40 studies [ 26 , 33 , 77 , 131 , 145 , 156 , 159 , 171 , 172 , 176 , 178 , 183 , 207 , 215 , 220 , 221 , 223 , 226 , 228 , 260 , 270 , 294 , 295 , 297 , 306 , 307 , 348 , 360 , 368 , 372 , 374 , 375 , 376 , 377 , 378 , 379 , 380 , 381 , 382 , 383 ] showed that 15.6% (95% CI: 12.8–18.7) ARLD were complicated by diabetes.

Incidence of ARLD

To estimate the incidence of ARLD, data from 7 eligible cohort studies [ 16 , 39 , 47 , 384 , 385 , 386 , 387 ] were selected, with a cumulative follow-up of 368,565,116.7 person-years. The number of newly defined ARLD cases was 62,819, and the incidence was 0.208 (95% CI: 0.125–0.305) per 1000 person-years (Table 3 ). The incidence in males was about four times as high as that in females (0.163 vs . 0.035 per 1000 person-years, p  < 0.05) (Table 3 ), suggesting a significant gender difference in the incidence.

Mortality and cause of ARLD death

A total of 114 datasets [ 17 , 23 , 25 , 26 , 30 , 33 , 36 , 39 , 43 , 46 , 64 , 115 , 126 , 128 , 130 , 136 , 140 , 142 , 156 , 162 , 168 , 169 , 173 , 176 , 186 , 189 , 190 , 192 , 196 , 197 , 204 , 208 , 213 , 216 , 220 , 223 , 225 , 228 , 231 , 236 , 242 , 243 , 244 , 245 , 249 , 258 , 265 , 267 , 273 , 276 , 280 , 283 , 294 , 307 , 309 , 311 , 320 , 321 , 322 , 324 , 325 , 326 , 327 , 328 , 329 , 332 , 333 , 334 , 335 , 336 , 338 , 339 , 340 , 341 , 342 , 343 , 344 , 345 , 347 , 348 , 353 , 355 , 356 , 359 , 364 , 366 , 367 , 368 , 369 , 370 , 371 , 372 , 373 , 374 , 375 , 380 , 382 , 385 , 386 , 388 , 389 , 390 , 391 , 392 , 393 , 394 , 395 , 396 , 397 , 398 , 399 , 400 , 401 , 402 ] were used to analyze the mortality, including 786,199 ARLD patients, while 183,929 people died during the study (Table 4 ). The mortality was 23.9% (95% CI: 18.9–29.2). Since not all studies provided the analysis of the causes of death, 22 articles [ 33 , 46 , 47 , 162 , 168 , 189 , 243 , 245 , 249 , 265 , 273 , 326 , 338 , 340 , 344 , 345 , 356 , 364 , 378 , 390 , 396 , 401 ] were selected for subsequent analysis, with the mortality of 37.1% (95% CI: 27.7–47.1). According to the funnel plot and Egger’s test, p  = 0.612 indicated that the funnel plot was symmetrical, i.e., no publication bias in the 22 datasets. A total of 15,965 individuals suffered from ARLD, of which 4746 died of liver disease and related complications. The mortality related to liver diseases was 21.6% (95% CI: 15.8–28.1), about twice that of non-liver diseases (10.4%, 95%CI: 6.3–15.3) (Table 4 ).

ARLD is a common chronic liver disease caused by long-term heavy drinking. Alcoholic fatty liver could develop into alcoholic hepatitis characterized by inflammation, which further progresses to alcoholic liver fibrosis, alcoholic cirrhosis, and even cancer in some cases. The whole process is affected by the interaction of many risk factors involved in this article, such as sex, race, hepatitis virus infection and smoking. Genetic and other potential etiology of liver diseases which identified in this article could also affect the natural course of the disease. The co-existence of multiple risk factors could largely promote the progression of ARLD through complex molecular mechanisms. Several studies have shown that alcohol abuse is accompanied by metabolic syndrome [ 252 , 403 ] or hepatitis virus infection [ 404 , 405 ], would accelerate the speed of liver fibrosis. Another study demonstrated that 70% of HCV-infected patients in Europe and North America are heavy drinkers [ 406 ], which is in agreement with the high prevalence shown in the present study.

According to the 2018 National Survey on Drug Use and Health , 14.4 million adults ≥ 18-years-old suffered from alcohol use disorders in the United States, including 9.2 million men and 5.3 million women [ 407 ]. Since 2000, men have been drinking about three times as much as women, according to the latest WHO data [ 408 ]. The current data also showed that the prevalence of ARLD in male was 2.9% which was nearly six times that in female, which could be related to the socioeconomic status and alcohol consumption level of men and women. Although the prevalence of different sexes varied greatly, women’s susceptibility to alcohol cannot be ignored. According to the WHO statistics, the global alcohol consumption is increasing [ 1 ], with the average level of alcohol consumption in 2005 was 5.5 L of pure alcohol per capita, and in 2016 was 6.1L [ 1 , 408 ]. The current findings showed that the prevalence during 2011–2021 was higher than that during 2000–2010, which was consistent with the epidemiological characteristics of alcohol.

Significant differences in alcohol consumption patterns, metabolism, genetics, and socio-economic factors among different subgroups affected the prevalence of ARLD. A direct correlation was established between alcohol and liver disease. The longer the drinking years and/or the higher the average daily drinking amount, the higher the risk of ARLD. Therefore, the distribution of high prevalence rates was consistent with regions where drinking culture was in vogue. Although Europe is still the region with the highest prevalence in the world, Portugal and France are the lowest which have a long history of wine. Thus, it could be deduced that the type of alcohol may also have an impact on the prevalence. Askgaard et al. demonstrated that red wine had a lower risk than other types of alcoholic beverages when drinking the same amount of alcohol [ 384 ]. In Uganda, the prevalence of homemade alcoholic beverages is high [ 409 ]. Similar issues may be seen in some provinces in China, such as Xinjiang, Hunan and Henan provinces [ 410 ]. This phenomenon may be also related to the cultural customs of different ethnic groups. Many minorities had the tradition of homemade alcoholic beverages. For example, Duihua wine, the special homemade wine unique to the Dai nationality, has a high alcohol content of over 60%. Its health risk may also be attributed to its toxic impurities, such as heavy metals and acetaldehyde [ 411 ]. The prevalence in USA which is lower than our expectations may be attributed to the government restriction on alcohol consumption. The United States established NIAAA in 1971 [ 412 ], and has a stable government funding program. For example, the raised alcohol taxes and the restriction of the time and place of alcohol sales have significantly reduced the incidence of ARLD. The comparison of prevalence in different countries reflected the advantages, which could be used as a reference for countries with a high prevalence. With the improvement of the economic level of developing countries, the prevalence in Asia is raising, which should be paid more attention. Base on the WHO data, the total per capita alcohol consumption in India increased from 2.4L in 2005 to 5.7L in 2016, while the per capita alcohol consumption in China increased from 4.1L in 2005 to 7.2L in 2016 [ 1 ]. Although the alcohol consumption in India was lower than that in China, the prevalence in India was significantly higher than that in China, which was related to socio-economic factors.

Smoking is an independent risk factor for liver fibrosis that could accelerate the natural course of ARLD [ 181 ]. Whether a dose-related correlation was established between tobacco and the disease and whether the progression of ARLD was related to smoking years needs to be confirmed further by a large number of studies. Based on the current results, > 50% of ARLD had former or current smoking. The harmful effect of smoking on liver-related diseases should be under intensive focus. Hepatitis virus infection and alcohol are the main pathogenic factors of chronic liver injury; their co-existence could aggravate liver damage through virus replication and immune suppression [ 406 , 413 ]. Therefore, treating the co-existent viral hepatitis with antiviral drugs is imperative.

Some studies proposed that moderate drinking was beneficial to health [ 414 , 415 , 416 ], but the defined alcohol intake and types of alcohol have not reached a consensus. American Association for the Study of Liver Diseases has set a safe threshold of alcohol consumption for men (no more than 2standard drinks per 24 h) and women (no more than 1standard drinks per 24 h) [ 417 ]. Meanwhile, the research results have shown that the longer the drinking years, the more patients suffer from ARLD. Early abstinence from alcohol is crucial to reducing the risk of ARLD.

While analyzing the influence of race on ARLD, we found that the proportion varies greatly among different subgroups, especially Caucasians and Asians. Notably, the percentage of the minority group with ARLD was much higher than the Han group. This phenomenon could be attributed to the difference in the constitution and the cultural customs; whether we could improve the early detection rate by setting different safety thresholds for different ethnicities needs to be investigated further.

The advantages of this study were to provide as complete as possible the epidemiological characteristics of ARLD. Presently, the epidemiological investigations of ARLD are mainly regional studies. This study provided the necessary data for countries to study ARLD and provided the trend of the disease to help the government in formulating alcohol management policies and conducting public education. Nevertheless, the present study had some limitations: the high heterogeneity between each study, which is common in such meta-analysis; only 1 or 2 datasets were included in subgroups resulting in the limitations of the results.

The eight studies to calculate the incidence are mainly concentrated in Europe, where the alcoholic population is concentrated, so the results are relatively high. Large cohort study, which cost a lot of manpower and material resources, is very important to explore the global incidence. Based on the premise of large population base and long follow-up time, the results of this review can reflect the global incidence to a certain extent. The phenomenon—mortality deduced from the 22 datasets was used to analyze the cause of death, which was much higher than that of 114 studies used for the analysis of mortality. This phenomenon could be attributed to the following reasons: the populations in the articles providing the cause of death were serious; the sample size was small; the study population was concentrated in European countries. Therefore, 23.9% was similar to the level of global mortality.

Taken together, these results showed that ARLD is one of the most common chronic liver diseases in the world, with a prevalence of 4.8%. With an improved economy, the per capita alcohol consumption is increasing rapidly, and the increasing risk of ARLD in developing countries is gaining much attraction. In addition to strengthening the management of abstinence from alcohol, we should investigate the metabolism, histology, and clinical characteristics of ARLD. Also, we should get rid of the dependence on asking the patients about their drinking history for diagnosis. Thus, non-invasive examinations and specific biomarkers are essential for early recognition. In addition to banning alcohol intake, developing safe and effective intervention measures, such as using the gut-liver axis with probiotics and prebiotics to improve the gut microbiota. Nonetheless, there are still many issues with respect to the prevention, development, and prognosis of ARLD that need to be investigated to improve the epidemiology of ARLD.

Conclusions

Overall, the global prevalence of ARLD is 4.8%, and the prevalence varies greatly among different regions, which may be influenced by various factors such as gender, race/ethnicity, drinking years, comorbidities and so on. With the improvement of economic level, the prevalence of ARLD is on the rise. By increasing alcoholic taxes and controlling the quantity and timing of alcohol sales, the harm caused by alcohol can be reduced to some extent. Large—scale cross-sectional and cohort studies are helpful to understand the epidemiological characteristics of ARLD.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author.

Change history

18 july 2023.

A Correction to this paper has been published: https://doi.org/10.1186/s12889-023-15986-0

Abbreviations

Alcohol related liver disease

China National Knowledge Infrastructure

National Institute on Alcohol Abuse and Alcoholism

Spontaneous peritonitis

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This study was supported by National Key R&D Program of China (2021YFC2301801); Capital’s Funds for Health Improvement and Research of China (CFH 2020–2171); The Digestive Medical Coordinated Development Center of Beijing Hospitals Authority under Grant No.XXT26.

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XHC designed the study, conducted and oversaw data extraction, statistical analysis, data interpretation, article preparation, article review, and correspondence. NXX, ZL contributed to the design and data interpretation, article preparation, and article review. XYF, ZMH, HYX, ML, LY contributed to the data checking, data analysis, article review, article preparation, and article review. All authors contributed to the final article and approved the final version.

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Additional file 1:.

Supplementary methods. Supplementary Table 1. Search strategy. Supplementary Table 2. Characteristics of included studies for analysis of overall ARLD prevalence. Supplementary Table 3. Summary of articles used to analyze the characteristics of ARLD. Supplementary Table 4. Characteristics of included studies for analysis of overall ARLD incidence. Supplementary Table 5. Characteristics of included studies for analysis of overall ARLD Mortality. Supplementary Figure 1. The forest plots of global prevalence. Supplementary Figure 2. The forest plots of China prevalence. Supplementary Figure 3. The forest plots of men prevalence. Supplementary Figure 4. The forest plots of female prevalence. Supplementary Figure 5. Funnel plot of studies included for analysis of overall ARLD prevalence.

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Niu, X., Zhu, L., Xu, Y. et al. Global prevalence, incidence, and outcomes of alcohol related liver diseases: a systematic review and meta-analysis. BMC Public Health 23 , 859 (2023). https://doi.org/10.1186/s12889-023-15749-x

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Al Pate is a 52-year-old Caucasian male who is employed in a sales department of a major software company. He first presented to you 10 days ago at the urging of his wife, who said that he often is confused and that she thinks that his eyes look yellow.  She also noted that he “has terrible breath”.  Al admits that he drinks often, because “I have to show my clients a good time at lunch, dinner, and golfing”.  He states that he thinks he “should be okay” because he never feels heartburn nor gets a hangover from his drinking, he brags that he is his company’s top salesman every year.

His wife complains that he “actually drinks every single day.” Upon questioning he admits to drinking in the morning on occasion, “just to help me get going”.  He has also complained about fatigue and a couple of weeks of watery diarrhea. He feels tired and weak.  His wife says that he has gained some weight and that he has no interest in his children or her. “He barely touches me doctor” and she starts crying in your office while pointing at Al, “Doctor, I cannot live with him anymore.”  Upon questioning further, you decide to consult a social worker and refer him to a local support group.  You order some blood tests and decide to follow up in a couple of weeks.

Laboratory Studies:

ABDOMINAL ULTRASOUND: shows a diffusely enlarged fatty liver with a nodular contour, splenomegaly and moderate ascites. The portal vessels are prominent.

Surgical History: Inguinal hernia repair at 43 years old.

Medical History: History of diabetes mellitus and alcohol abuse.

Social History: Married to wife for almost 15 years.  Has 5 kids.  Ages 14, 12, 8, 6, and 2 months.   He has been working at the same company for almost 4 years. Wife does not work, stays at home with the kids.

Family History: His father died when he was 3 years old and says his mother never indicated why his father died.

Allergies: Penicillin

Medications: None

Review of Systems: Positive for diarrhea, weakness and impotence.

His vital signs are: Height 5’7’’ft (175cm), Weight 233 lbs (106kg), Temp; 97.5 F, Pulse: 110 bpm; RR: 22, BP 120/80, O2 95%.

HEENT: PEERL, EOMI, yellow discoloration of sclera, acanthosis nigricans on neck.

EARS: Normal TM and light reflex.

MOUTH: Strong alcohol odor, caries, otherwise mouth and pharynx normal.

NECK: No carotid bruits or jugular venous distention while sitting upright.  No cervical adenopathy noted.  Thyroid not palpated.

CHEST: Lungs with fine crackles on both bases, good air movement, no wheezing on inspiration/expiration.  Heart regular rate and rhythm, no murmurs heard.  Gynecomastia present bilaterally.

ABDOMEN: Obese and enlarged abdomen, reduced hair growth, varicocele umbilical vein present, telangiectasias, positive for shifting dullness, unable to palpate any visceromegaly’s due to distention.

GENITAL: Uncircumcised male, both testes descended bilaterally atrophy noticed.

EXTREMITIES: Thin appearance, poor muscle tone.  Lower extremity 2+ edema to the knees bilaterally; Strength 5/5, pulses present bilaterally, no other abnormalities.  Palmar erythema noted.

NEURO: Slurred speech, cranial nerves 2-12 normal; asterixis present.

Ten Days Later :

Today is the follow up visit.  Upon entering the room, you notice alcoholic odor and a large hematoma on his left arm which he indicates is the blood draw location from a couple of weeks ago.  He remarks that “sometimes I feel confused doc”, and says, “my energy is low, you gotta fix me.”  He mentions “my wife left with the kids to her mom’s house” and later, “I lost this year’s sales bonus at my company and I have started drinking more than usual.”

You decide to ask Al more details about his drinking.  He admits that he has gotten several DUIs over the past year.  Sometimes he forgets where he is at and when he tries to stop drinking, he feels bad, one time he had a seizure.  He has not tried to stop drinking because of that.

You ask Albert the following CAGE questions:

• Have you ever felt you should C ut down on your drinking?
• Have people A nnoyed you by criticizing your drinking?
• Have you ever felt bad or G uilty about your drinking?
• Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover ( E ye opener)?

Al answers in the affirmative for each of the CAGE questions and on examination, you notice that he has yellow discoloration of the sclera, some parts of his skin have bruises especially on his back and trunk.  You observe cherry red papules, lacy-looking patches and fragile skin.  Al complains about generalized itching “Doc I cannot sleep with this”. Upon examination of his abdomen, you realize that now he has markedly dilated abdominal wall veins, something that he did not have previously.  Diligently, you decide to auscultate the abdomen to evaluate his peristalsis.  To your surprise, you do not hear bowel sounds. You decide to do percussion and roll Al to his sides.  You can demonstrate “shifting dullness” and you are unable to palpate the liver or any other organ due to distension.  His extremities are thin and Al just tells you that he feels so tired and weak that, “I want to die doctor…”

Compassionately, you decide to take your time and listen to Al’s story.  Finalizing, you explain to him in plain terms that his liver is not functioning as it needs to.  Al asks, “What is wrong with it?”  You explain that the liver controls coagulation, protein synthesis to mention some.  Al remembers to tell you that his diarrhea has a “black color doc” and points out that this has been going on for the last couple of months.

With this information you decide to send Al to the hospital for inpatient admission for further management of his condition.  Your nurse just left since it is past 5pm and you had spent more than the allocated time with Al.  You decide to start the referral process and call the local ED yourself to present your patient. When asking Al about his preferred hospital, he tells you that he forgot to pay his insurance premium almost 2 months ago and now he is uninsured.  You send Al to the county hospital and you wonder if something else can be done.

“Bad Breath”: An integrated case study of alcoholic liver disease for first year medical students. Copyright © 2020 by Omar Matuk-Villazon, MD, MBA and Kevin Rowland, PhD is licensed under a Creative Commons Attribution 4.0 International License , except where otherwise noted.

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Liver disease case studies: Case study level 1 – Alcoholic cirrhosis; alcohol withdrawal

In this chapter Case studies levels 1–3 explore the management of a patient with alcoholic liver disease. The patient has alcoholic liver cirrhosis and first presents with alcohol withdrawal (Case study level 1), then the patient’s risk of bleeding and treatment for the maintenance of alcohol abstinence are considered (Case study level 2). The patient then goes on to develop encephalopathy (Case study level 3). Case studies levels Ma and Mb consider two patients: one presents with TB and the other liver failure.

Case study level 1 – Alcoholic cirrhosis; alcohol withdrawal

Learning outcomes Level 1 case study: You will be able to:

• describe the risk factors
• describe the disease
• describe the pharmacology of the drug
• outline the formulation, including drug molecule, excipients, etc. for the medicines
• summarise basic social pharmacy issues (e.g. opening containers, large labels).

Mrs MW, 59 years old, is divorced and unemployed. She was admitted to an acute medical ward at the hospital presenting with general malaise, a grossly distended abdomen, swollen ankles, and jaundice. It was also noted that she smelt of alcohol and was showing signs of alcohol withdrawal.

1. What is cirrhosis of the liver?

2. List possible causes of cirrhosis.

3. What other clinical signs and symptoms may Mrs MW present with?

4. What drug treatment, including dose, would you recommend for Mrs MW’s alcohol withdrawal? What recommendations would you make if the patient was unable to take the medication orally?

1       What is cirrhosis of the liver?

Cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury. It is an advanced stage of liver fibrosis that is accompanied by distortion of the hepatic vasculature.

2        What are the risk factors for developing primary dysmenorrhoea?

Causes of cirrhosis can usually be identified by the patient’s history combined with serological and histological investigation. Alcoholic liver disease and hepatitis C and B are the most common causes of cirrhosis.

The association of excessive alcohol consumption with liver disease has been recognized for centuries. After the identification of the hepatitis C virus and of non-alcoholic steatohepatitis in obese patients with diabetes, the diagnosis of cirrhosis without an apparent cause (cryptogenic cirrhosis) is rarely made. Genetic causes of cirrhosis include hemochromatosis and Wilson’s disease.

Epidemiological studies have identified a number of factors that contribute to the risk of developing cirrhosis. Regular (moderate) alcohol consumption, age older than 50 years, and male gender are examples that increase cirrhosis risk in chronic hepatitis C infection, and older age, obesity, insulin resistance or type 2 diabetes, hypertension and hyperlipidemia in non-alcoholic steatohepatitis.

3        What other clinical signs and symptoms may Mrs MW present with?

Cirrhosis is often asymptomatic until complications of liver disease are present. Mrs MW may present with itching, jaundice, dark urine, pale fatty stools, abdominal pain, nausea, fatigue, bleeding – such as nosebleeds, hepatic encephalopathy, hepatomegaly, ascites, distended abdominal veins, spider angiomata, palmar erythema and asterixis. She may also present with the signs and symptoms of alcohol withdrawal, which include irritability, anxiety, tachycardia, tremor, sweating, confusion, and hallucinations.

4        What drug treatment, including dose, would you recommend for Mrs MW’s alcohol withdrawal? What recommendations would you make if the patient was unable to take the medication orally?

Long-acting benzodiazepines (e.g. diazepam and chlordiazepoxide) are used to attenuate alcohol withdrawal symptoms but they also have a dependence potential. To minimize the risk of dependence, administration should be for a limited period only (e.g. chlordiazepoxide 20 mg 4 times daily, gradually reducing to zero over 7–14 days). Mild alcohol withdrawal symptoms may be treated with a lower starting dose, such as 15 mg four times a day. In all cases, the patient should be counseled about the proposed length of the treatment course . Benzodiazepines should not be prescribed if the patient is likely to continue drinking alcohol.

In patients unable to take medication by the oral route, diazepam may be administered by intramuscular or slow intravenous injection (into a large vein, at a rate of not more than 5 mg/min), at a dose of 10 mg, repeated if necessary after not less than 4 hours. Alternatively, diazepam may be administered via the rectal route as a rectal solution or suppository. The intramuscular route should only be used when both the oral and intravenous routes are not possible.

General references

• Schuppan D and Afdhal NH (2008) Liver cirrhosis. Lancet 371: 838–851.
• Heidelbaugh JJ and Sherbondy M (2006) Cirrhosis and chronic liver failure: Part II. Complications and treatment. American Family Physician 74: 767–776.
• Joint Formulary Committee (2008) British National Formulary 55. London: British Medical Association and Royal Pharmaceutical Society of Great Britain, March.
• Vincent WR, Smith KM, Winstead PS and Lewis DA (2007) Review of alcohol withdrawal in the hospitalized patient: management . Orthopedics 30: 446–449.

Author: Caron Weeks [BPharm (Hons), MRPharmS, DipPharmPrac. Lead pharmacist – Medicine, Southampton University Hospitals NHS Trust] and Mark Tomlin [BPharm, MSc, MRPharmS (IPresc) Consultant Pharmacist, Critical Care, Southampton General Hospital]

• Alcohol withdrawal
• Case study for pharmacist
• liver cirrhosis
• liver disease
• Pharmacy case study

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Cardiovascular Case Studies: Case study level Mb – Myocardial infarction

Noakhali Science and Technology University (NSTU)

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FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease

FDA News Release

Today, the U.S. Food and Drug Administration approved Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise. 

“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, M.D., acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.” 

NASH is a result of the progression of nonalcoholic fatty liver disease where liver inflammation, over time, can lead to liver scarring and liver dysfunction. NASH is often associated with other health problems such as high blood pressure and type 2 diabetes. By at least one estimate, approximately 6-8 million people in the U.S. have NASH with moderate to advanced liver scarring, with that number expected to increase. Rezdiffra is a partial activator of a thyroid hormone receptor; activation of this receptor by Rezdiffra in the liver reduces liver fat accumulation. 

The safety and efficacy of Rezdiffra was evaluated based on an analysis of a surrogate endpoint at month 12 in a 54-month, randomized, double-blind placebo-controlled trial. The surrogate endpoint measured the extent of liver inflammation and scarring. The sponsor is required to conduct a postapproval study to verify and describe Rezdiffra’s clinical benefit, which will be done through completing the same 54-month study, which is still ongoing. To enroll in the trial, patients needed to have a liver biopsy showing inflammation due to NASH with moderate or advanced liver scarring. In the trial, 888 subjects were randomly assigned to receive one of the following: placebo (294 subjects); 80 milligrams of Rezdiffra (298 subjects); or 100 milligrams of Rezdiffra (296 subjects); once daily, in addition to standard care for NASH, which includes counseling for healthy diet and exercise. 

At 12 months, liver biopsies showed that a greater proportion of subjects who were treated with Rezdiffra achieved NASH resolution or an improvement in liver scarring as compared with those who received the placebo. A total of 26% to 27% of subjects who received 80 milligrams of Rezdiffra and 24% to 36% of subjects who received 100 milligrams of Rezdiffra experienced NASH resolution and no worsening of liver scarring, compared to 9% to 13% of those who received placebo and counseling on diet and exercise. The range of responses reflects different pathologists’ readings. In addition, a total of 23% of subjects who received 80 milligrams of Rezdiffra and 24% to 28% of subjects who received 100 milligrams of Rezdiffra experienced an improvement in liver scarring and no worsening of NASH, compared to 13% to 15% of those who received placebo, depending on each pathologist’s readings. Demonstration of these changes in a proportion of patients after just one year of treatment is notable, as the disease typically progresses slowly with a majority of patients taking years or even decades to show progression.

The most common side effects of Rezdiffra included diarrhea and nausea. Rezdiffra comes with certain warnings and precautions, such as drug-induced liver toxicity and gallbladder-related side effects. 

Use of Rezdiffra should be avoided in patients with decompensated cirrhosis. Patients should stop using Rezdiffra if they develop signs or symptoms of worsening liver function while on Rezdiffra treatment. 

Using Rezdiffra at the same time as certain other drugs, in particular statins for lowering cholesterol, may result in potentially significant drug interactions. Health care providers should refer to the full prescribing information  for additional information on these potentially significant drug interactions with Rezdiffra, recommended dosage and administration modifications. 

The FDA approved Rezdiffra under the accelerated approval pathway, which allows for earlier approval of drugs that treat serious conditions and address an unmet medical need, based on a surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit. The required aforementioned 54-month study, which is ongoing, will assess clinical benefit after 54 months of Rezdiffra treatment. 

Rezdiffra received Breakthrough Therapy, Fast Track and Priority Review designations for this indication. 

The FDA granted the approval of Rezdiffra to Madrigal Pharmaceuticals.

Related Information

• NIH: Nonalcoholic Fatty Liver Disease (NAFLD) & NASH

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, radiation-emitting electronic products, and for regulating tobacco products.

• Open access
• Published: 26 March 2024

Liver stiffness and associated risk factors among people with a history of injecting drugs: a prospective cohort study

• Karl Trygve Druckrey-Fiskaaen 1 , 2 ,
• Jørn Henrik Vold 1 , 2 , 3 ,
• Tesfaye Madebo 1 , 4 , 5 ,
• Håvard Midgard 6 ,
• Olav Dalgard 7 ,
• Rafael Alexander Leiva 8 &
• Lars T. Fadnes 1 , 2

for the INTRO-HCV Study Group

Substance Abuse Treatment, Prevention, and Policy volume  19 , Article number:  21 ( 2024 ) Cite this article

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Persons with opioid use disorders (OUD) and persons with substance use disorders (SUD) who inject substances have a reduced life expectancy of up to 25 years compared with the general population. Chronic liver diseases are a substantial cause of this. Screening strategies based on liver stiffness measurements (LSM) may facilitate early detection, timely intervention, and treatment of liver disease. This study aims to investigate the extent of chronic liver disease measured with transient elastography and the association between LSM and various risk factors, including substance use patterns, hepatitis C virus (HCV) infection, alcohol use, body mass index, age, type 2 diabetes mellitus, and high-density lipoprotein (HDL) cholesterol among people with OUD or with SUD who inject substances.

Data was collected from May 2017 to March 2022 in a cohort of 676 persons from Western Norway. The cohort was recruited from two populations: Persons receiving opioid agonist therapy (OAT) (81% of the sample) or persons with SUD injecting substances but not receiving OAT. All participants were assessed at least once with transient elastography. A linear mixed model was performed to assess the impact of risk factors such as HCV infection, alcohol use, lifestyle-associated factors, and substance use on liver stiffness at baseline and over time. Baseline was defined as the time of the first liver stiffness measurement. The results are presented as coefficients (in kilopascal (kPa)) with 95% confidence intervals (CI).

At baseline, 12% ( n  = 83) of the study sample had LSM suggestive of advanced chronic liver disease (LSM ≥ 10 kPa). Advanced age (1.0 kPa per 10 years increments, 95% CI: 0.68;1.3), at least weekly alcohol use (1.3, 0.47;2.1), HCV infection (1.2, 0.55;1.9), low HDL cholesterol level (1.4, 0.64;2.2), and higher body mass index (0.25 per increasing unit, 0.17;0.32) were all significantly associated with higher LSM at baseline. Compared with persistent chronic HCV infection, a resolved HCV infection predicted a yearly reduction of LSM (-0.73, -1.3;-0.21) from baseline to the following liver stiffness measurement.

Conclusions

More than one-tenth of the participants in this study had LSM suggestive of advanced chronic liver disease. It underscores the need for addressing HCV infection and reducing lifestyle-related liver risk factors, such as metabolic health factors and alcohol consumption, to prevent the advancement of liver fibrosis or cirrhosis in this particular population.

Introduction

Persons with substance use disorders (SUD) such as opioid use disorder (OUD) and persons who inject substances have a substantially shorter life expectancy than the general population [ 1 , 2 , 3 ]. This is attributable to a high burden of diseases, including infectious diseases, chronic liver disease, cancer, cardiovascular diseases, and substance-related deaths [ 4 , 5 , 6 , 7 ]. For persons with OUD, opioid agonist therapy (OAT) is an essential treatment approach, which almost halves mortality in this population, yet the mortality remains high within this group [ 8 , 9 ]. Diseases of the digestive system, such as chronic liver disease, significantly contribute to the morbidity and mortality of persons with OUD or injecting substance use [ 10 , 11 ]. In a systematic review, the standard mortality rate related to diseases of the digestive system was estimated to be 3.4 for males and 7.9 for females [ 10 ]. In an autopsy study from Norway of 122 patients who died during OAT treatment, at least one liver disease was identified in 84% of the decedents [ 11 ]. Amidst a growing global prevalence of liver cirrhosis, there is a need to improve the understanding of the risk factors for liver disease and their progression among persons with OUD or injecting substance use [ 12 , 13 ] to achieve timely detection and prevent disease progression [ 14 ].

Viral hepatitis, high alcohol consumption, and metabolic dysfunction such as obesity, low high-density lipoprotein (HDL) cholesterol and type 2 diabetes mellitus are acknowledged as frequent causes of chronic liver disease worldwide [ 15 , 16 , 17 ]. Among persons with SUD, polysubstance use, including alcohol [ 8 , 18 ] and intravenous substance use, have been associated with liver diseases [ 19 ]. Polysubstance use is common among persons with SUD and predicts more severe comorbidities such as suicidal attempts, liver diseases or overdose deaths than among those with mono-substance use [ 20 , 21 , 22 ]. Multiple risk factors for chronic liver disease significantly increase the likelihood of compensated advanced chronic liver disease (cALCD), leading to liver cirrhosis and hepatocellular carcinoma [ 23 , 24 ]. However, there is less knowledge on the prevalence and magnitude of the association of various risk factors with the risk of chronic liver disease among persons with SUD.

Persons with SUD have a higher barrier to seeking primary healthcare compared to the general population, leading to delayed initiation of diagnostics and treatments in a primary care setting [ 25 ]. To ensure early detection and prevent liver disease from progressing among persons at risk, case-finding procedures and risk assessment strategies may help identify persons needing assessment for treatment and follow-up [ 14 ]. Non-invasive methods such as liver elastography have largely replaced liver biopsy for staging liver diseases such as liver fibrosis or cirrhosis [ 26 , 27 ]. Liver stiffness measurements (LSM) can identify persons at risk of developing cALCD, and repeated measurements have a prognostic value for determining the risk of disease progression [ 16 , 28 ]. LSM correlates with the histological stage of liver disease, portal hypertension, and the risk of liver decompensation events and death [ 26 , 29 , 30 ]. Thus, elastography is an essential tool to identify patients at risk and to determine the stage of liver disease and prognosis.

This study aims to investigate the prevalence of cALCD as assessed by transient elastography and to estimate how potential risk factors such as HCV infection, substance use patterns, and metabolic risk factors impact the LSM among persons receiving OAT or persons with SUD injecting substances but not receiving OAT. We hypothesise that metabolic risk factors and polysubstance use, in addition to HCV infection and alcohol use, will predict increased LSM. We further hypothesise that the participants in our study face several simultaneous risk factors for increased LSM.

Material & method

Study setting and sample.

We used data from a prospective cohort nested in the INTRO-HCV study in Bergen and Stavanger, Norway [ 31 ]. Data were collected from May 2017 to March 2022 as a part of annual health assessments, and participants were recruited from eight OAT outpatient clinics in Bergen and Stavanger and two municipal outpatient SUD treatment centres in the Bergen Municipality. The cohort has also been described previously [ 32 ]. The target populations were persons receiving OAT or persons with SUD injecting substances but not receiving OAT. Participants recruited from the OAT clinics were all diagnosed with opioid dependency (F10.2) according to World Health Organization International Classification of Diseases version 10 [ 33 ] and received OAT at OAT clinics in Bergen or Stavanger. Participants recruited from the municipal SUD treatment centres had SUDs and injected substances but did not receive OAT. Persons receiving OAT accounted for 81% of the study sample. Supplementary Table 1, Additional File 1 shows the baseline characteristics for the participants recruited from OAT clinics and municipal SUD clinics separately. Persons were recruited by the staff at the participating clinics; see Fig.  1 for an overview of recruitment and inclusion. Persons in the target population were offered an initial health assessment, informed about the study, and asked to consent to participation. Participants were eligible for our study if they had completed at least one elastography measurement at a participating OAT clinic or municipal SUD treatment centre, one annual health assessment and consented to participate. We included 676 persons who completed at least one annual health assessment. All participants completed at least one liver stiffness measurement, and 274 persons had completed two or more measurements, rendering 345 repeated liver stiffness measurements (Fig.  1 ). The median time interval between the first and last liver stiffness measurements was 14 months (interquartile range (IQR): 11–19).

Overview of the recruitment and inclusion of participants in the study. The figure indicates which treatment facilities the participants were recuited from and the number of persons in the target population. The figure further indicates the number of participants with one or more elastographies

Data collections

All participants included in the study underwent an annual health assessment, encompassing the gathering of blood samples, liver elastography, assessment of substance use for the past twelve months, and sociodemographic and clinical data collection. Blood samples were systematically annually screened for hepatitis B and C viruses as well as human immunodeficiency virus (HIV). In addition, a thrombocyte count and analysis of liver transaminases and cholesterol including high- and low-density lipoproteins, glycated haemoglobin, and creatinine were performed. We analysed for triglycerides if the participants were fasting. Educational attainment and other demographic information were collected at the first health assessment. The data were collected using electronic data collection software (CheckWare, Checkware AS, Norway) under the supervision of research nurses and stored in a health register. Baseline was defined as the time of the first liver stiffness measurement. Blood samples were analysed at the Department of Laboratory Medicine, Haukeland University Hospital, Bergen, Norway, and the Department of Medical Biochemistry and Microbiology, Stavanger University Hospital, Stavanger, Norway (both accredited by ISO standard 15189).

Measuring liver stiffness

Trained research nurses performed transient elastography according to the European Association for the Study of the Liver Guidelines [ 34 ] using a Fibroscan® mini 430 with a medium probe to measure the participants’ liver stiffness. Before the examination, the participant had been instructed to fast for at least 2 h. The liver stiffness estimate is reported in kPa as a median score of at least ten elastography measurements with an interquartile range/ median of < 30%. LSM values < 10 kPa in the absence of other known clinical/imaging signs rule out cACLD; values between 10 and 15 kPa are suggestive of cACLD; values > 15 kPa are highly suggestive of cACLD [ 27 ].

Definition of study variables

The study sample was categorized into the following age groups: below 30 years of age, 30–39 years, 40–49 years, 50–59 years, and 60 years and older. Body mass index (BMI) was defined as body weight in kilograms divided by height in meters squared. The housing situation in the 30 days prior to the assessment was defined as “stable” if living in an owned or rented home or being incarcerated. An “unstable” housing situation was defined as living in a homeless shelter with family or friends or on the street. The OAT medication (if any) was defined as the type of medication used at baseline.

We estimated the self-reported substance use during the past 12 months prior to the health assessment using a Likert scale for each substance class, including alcohol, non-prescribed benzodiazepines, tobacco, non-prescribed opioids, cannabis, and stimulants including amphetamines or cocaine. The scale ranges from zero to five points, where zero represents never using, one represents less than monthly, two represents one to three days per month, three represents one to three days per week, four represents more than three days per week, and five represents daily use of a substance. Regular use was defined as weekly use (≥ 3 points). To investigate the impact of the intensity of polysubstance use on LSM, we built an illegal substance use severity index (iSUSI) based on the sum score responses for non-prescribed benzodiazepines, cannabis, illicit opioids, and stimulants (cocaine and amphetamines). The sum score was divided by 20 to generate a continuous range from 0 to 1, where zero indicates no use and one indicates daily use of all substance classes. The data collection software only allowed valid responses to each substance and prompted empty questions before submission to minimize missing data.

We systematically screened participants for chronic infectious blood-borne virus diseases in the blood samples including HCV (using HCV ribonucleic acid by polymerase chain reaction), hepatitis B virus infection (hepatitis B virus surface antigens), and HIV (HIV antigen/antibodies). We defined that an HCV infection was cured if HCV RNA was negative once following successful HCV treatment or by spontaneous HCV clearance.

Based on the available data from the cohort we included the following cardio-metabolic risk factors in the analysis [ 17 ]: Blood sugar levels were defined as “elevated” if glycated haemoglobin (HbA1c) was ≥ 48 mmol/mol [ 35 ]. HDL cholesterol < 1.3 mmol/L for women and < 1.0 mmol/L for men were defined as “low” [ 36 , 37 ]. Obesity was defined as BMI ≥ 30 kg/m2 [ 38 ].

Statistical analysis

We used Stata/SE17 (StataCorp, TX, USA) and IBM SPSS version 26 (International Business Machines, Chicago, USA) for descriptive statistics including means and standard deviation (SD), and for linear mixed model analyses. The threshold for statistical significance was set to p  < 0.05 unless otherwise stated.

Any missing values in the exposure variables, including HCV RNA, BMI, alcohol, benzodiazepine, cannabis, tobacco, opioid and stimulant use, HbA1c, injecting behaviour, and HDL cholesterol, were considered “missing at random” when performing the expectation–maximization algorithm. Missing values were identified in 8.0% of the exposure variables, and all were replaced with estimated values using the expectation–maximization algorithm [ 39 ]. A total of 17% of the HCV RNA results and 14% of the HDL cholesterol results were replaced with estimated values. The distribution of missing values among participants are shown in Supplementary Table 2, Additional File 1 .

We performed a linear mixed model analysis to assess the association of age, alcohol consumption, use of illegal substances, BMI, HCV, low HDL cholesterol, and elevated HbA1c (exposure variables) on liver stiffness measurements (continuous outcome variable) at baseline and to what extent they were associated with changes in liver stiffness over time. This is presented with 95% confidence interval (CI). We did not adjust HDL cholesterol or HbA1c values for the use of lipid-lowering drugs or antidiabetic drugs, as this information was not provided by the participants. Except for HCV infection status, due to relatively stable exposure variable values over time [ 40 ], all these variables including age group were kept constant at the baseline level in predicting the level and changes in the outcome variable. Interactions between these variables and time were added to the model to investigate whether exposure variables predicted changes in outcome. All available liver stiffness measurements were included. The model used a random intercept and fixed slope with the estimator set to restricted maximum likelihood. Time was defined as years from baseline.

Using the exposure variables as in the linear mixed model, we performed a sensitivity analysis with a dichotomous outcome variable of liver stiffness based on the threshold of 10 kPa (Supplementary Table 3, Additional File 1 ). The threshold of ≥ 10 kPa indicates that patients with liver stiffness measurements equal to or above this cut-off have an increased risk of liver disease, according to Baveno VII criteria [ 27 ]. Liver stiffness measurements using a medium probe in persons with obesity may produce unreliable results overestimating the liver stiffness [ 34 , 41 ]. Thus, we ran a sensitivity analysis which only included persons with BMI < 30 kg/m 2 (Supplementary Table 4, Additional File 1 ). We further performed sensitivity analyses by adding sex as an exposure variable (Supplementary Table 5, Additional File 1 ).

Participants’ characteristics at baseline

At baseline, a total of 185 (27%) of the participants were females, and the mean age was 43 years (SD: 11 years); 542 patients (81%) received OAT (Table  1 ). Most participants smoked tobacco at least once a week ( n  = 587, 93%), and 163 (26%) reported drinking alcohol one or more days a week. The mean of the iSUSI was 0.36 (SD 0.23). A total of 344 persons (55%) had injected substances during the twelve months leading up to baseline, 310 participants (46%) were HCV RNA positive, less than five (0.7%) were infected with hepatitis B virus, and less than five (0.7%) had a HIV infection (all persons with hepatitis B virus and HIV were co-infected with HCV).

Liver stiffness measurements at baseline and over time

The mean liver stiffness at baseline was 6.8 kPa (SD 5.1), and 12% had liver stiffness values ≥ 10 kPa. Figure  2 shows the distribution of liver stiffness (≥ 10 kPa) according to age groups, HCV status, and sex. For the 274 persons who completed more than one liver stiffness measurement, the mean liver stiffness at the time of the last measurement was 6.2 kPa (SD 3.8), and 9% ( n  = 25) of participants had liver stiffness measurement ≥ 10 kPa (Fig.  3 ).

Distribution of liver stiffness according to age, HCV status, and sex. The figure indicates how the increased risk of liver disease, indicated by liver stiffness ≥ 10 kPa, is distributed between age groups, HCV infection status, and sex. The Pearson χ 2 test indicates that there were significant differences between age groups (χ 2  = 33.8, p  < 0.001) and by HCV infection status (χ 2  = 9.4, p  < 0.002), but not between females and males (χ 2  = 3.1, p  < 0.078)

Distribution of liver stiffness measurements and its changes among the 676 patients included in the study. The red line indicates the baseline measurements sorted in incremental order. Spikes away from the red line indicate the change in liver stiffness from the first to the last measurement measured with elastography (in kPa). The black dashed line at 10.0 kPa indicates liver stiffness suggestive of compensated advanced chronic liver disease, whereas the black dashed line at 15.0 kPa indicates the threshold for liver stiffness highly suggestive of compensated advanced chronic liver disease such as liver fibrosis or cirrhosis [ 27 ]

Liver stiffness and associated factors at baseline and over time

The liver stiffness was 1.0 kPa (CI 0.68; 1.3) higher for each ten-year increase of age at baseline (Table  2 ). At baseline, having a chronic HCV infection was associated with a 1.2 kPa (CI 0.55;1.9) higher liver stiffness level compared to persons with negative HCV PCR, whereas lower levels of HDL cholesterol and higher BMI were associated with a 1.4 kPa (CI 0.64;2.2) and an 0.25 (CI 0.17;0.32) higher level of liver stiffness, respectively. Regular use compared to no or non-regular use of alcohol was associated with a 1.3 kPa (CI 0.47;2.1) higher liver stiffness. The overall time trend for LSM among persons in the sample, with two or more measurements, was an increase of 2.8 kPa (CI 0.57; 5.1) per year. Achieving sustained virological response of HCV infection was associated with a decreasing liver stiffness over time by -0.73 kPa per year (CI -1.3; -0.21).

Comparable results were seen in the sensitivity analysis with a dichotomised outcome variable (Supplementary Table 3, Additional File 1 ). The sensitivity analysis of the mixed model, only including participants with BMI < 30 kg/m 2 indicated comparable results except for regular alcohol use, which was not associated with LSM (Supplementary Table 4, Additional File 1 ). There were no significant effects of adding sex as an exposure variable in the linear mixed model (Supplementary Table 5, Additional File 1 ). No substantial changes in the results were seen when all persons with a missing variable were excluded from the analysis (Supplementary Tables 6 and 7, Additional File 1 ). Regular tobacco use (at least once a week) did not significantly predict changes in LSM (Supplementary Table 8, Additional File 1 ).

Among the 676 persons receiving OAT or reporting injection of substances in this study, 12% had a likely cALCD. The most prevalent risk factors for chronic liver disease were HCV infection (46%), low HDL cholesterol (26%), alcohol consumption at least once a week (26%) and obesity (15%). At baseline, HCV infection, regular alcohol use, higher age, low HDL cholesterol levels, and higher BMI were associated with higher liver stiffness. The time trend analyses showed that sustained virologic response from HCV infection was associated with a significant decrease in liver stiffness. In contrast persistently elevated HbA1c levels were associated with a significant increase in liver stiffness.

In our sample, almost half the participants had a current HCV infection (HCV RNA positive) at baseline. In total, 83% were HCV antibody positive. In a global review from 2017, about one-half of persons who inject substances in Western Europe were HCV antibody positive [ 42 ]. In contrast, another study from 2018 found HCV-antibody positive rates of up to 90 percent in similar populations in high-income countries [ 10 ]. The treatment of HCV has received considerable international attention, particularly after the introduction of direct-acting antiviral medication [ 43 ]. As indicated by our study, HCV infection was associated with increased liver stiffness whereas treatment for HCV infection was associated with decreased liver stiffness. The magnitude of the associations was in line with observations in other studies [ 44 ]. However, there are few longitudinal studies on the impact of HCV treatment on LSM among persons with SUD who have a history of injecting substances [ 45 ]. Our study provides additional knowledge on the impact of HCV treatment on the risk of liver disease among persons with SUD. Integrated models of care have been shown to increase the uptake of HCV treatment among persons with SUD and injective behaviour [ 46 ]. Flexible, tailored and culturally informed interventions targeted at specific populations with HCV may facilitate HCV screening and treatment [ 47 ].

Our study indicates that elevated BMI and low HDL are relevant risk factors for increased LSM: One in six participants were obese, one in four had low HDL and higher BMI and low HDL were significantly associated with higher LSM at baseline. This indicates a need for lifestyle interventions to reduce metabolic risk. A systematic review of physical activity among persons receiving OAT concluded that regular physical activity improved physical fitness, mental health, and substance use [ 48 ]. Robust studies on the efficacy of dietary interventions for persons with SUD are lacking, but a review of five studies indicates that interventions may improve dietary outcomes [ 49 ]. Most included studies reported low adherence, often due to health-related issues, homelessness, lack of transportation and lack of follow-up [ 48 , 49 ]. The frequency of obesity is lower in our sample compared to a cohort recruited from the Norwegian general population in which one-quarter of the participants were obese [ 50 ]. Compared to the findings of a systematic review on the prevalence of metabolic syndrome among persons with alcohol use disorder, which estimated a 38% prevalence of obesity and an 8% prevalence of low HDL, our sample had fewer participants with obesity. However, the prevalence of low HDL was higher [ 51 ]. In comparison, in a sample of 122 patients on methadone maintenance therapy recruited from an outpatient clinic in Barcelona, Spain, the prevalence of low HDL was 52%, and obesity was 27% [ 52 ]. A possible explanation for the lower prevalence of obesity in our population is the weight-lowering effect of stimulants among the one-third of the participants who reported regular use of stimulants [ 53 ]. Methadone as an agonist treatment to recover from opioid use disorder has been associated with mild to moderate weight gain [ 54 ]. As one-third of our sample received methadone the weight-gaining effect of methadone in our sample probably is lower than in a sample of persons solely receiving methadone.

The frequency of alcohol consumption within the study sample was not particularly high; 26% reported using alcohol at least once a week. In comparison, in the yearly report on all patients receiving OAT in Norway, 9,1% of the sample reported drinking amounts of alcohol during the last four weeks that resulted in a feeling of intoxication [ 55 ].

Low heterogeneity impeded the analysis of the effects of HbA1c and tobacco use on LSM. In our study sample, two percent had elevated HbA1c levels, and 93% smoked tobacco at least once a week. Tobacco use was not included in the main analysis to avoid introducing and adjusting for several variables with low heterogeneity, increasing random variation and the risk of residual confounding. A supplementary analysis indicated a non-significant association of at least weekly tobacco use with lower LSM. This is contradicted by findings from the general population, indicating growing evidence that tobacco smoking is associated with the development and progression of liver disease [ 56 ]. Among persons aged 55 and younger with alcohol-related cirrhosis, smokers had a 5-year survival rate of 42% compared to a 73% survival rate in non-smokers [ 57 ]. An estimated 85% of persons with SUD are smoking tobacco [ 58 ] Thus, tobacco smoking may be an important risk factor for liver disease in the SUD population that warrants further investigation.

The existence of multiple risk factors for liver disease in this cohort complicates causal inferences. In addition to injection-related diseases such as HCV infection, participants often used alcohol, smoked tobacco, and were obese. Nonetheless, the results of this study highlight the importance of continuous monitoring and regular assessments to identify possible liver disease development and progression [ 14 , 59 ]. Integration of HCV treatment at OAT clinics and community care clinics has demonstrated an increased uptake of HCV treatment [ 46 ]. Integrating lifestyle interventions at OAT clinics and community care clinics could possibly improve adherence to and feasibility of such interventions.

The Baveno criteria define LSM cut-offs of 10 and 15 kPa and the rule-of-five to determine the risk of liver disease [ 13 , 27 ]. From a clinical point of view, it may make the most sense to see this from a categorical perspective and assess LSM in relation to a certain cut-off; it has been demonstrated that persons with liver stiffness > 9.5 kPa have a significantly lower five-year survival rate [ 60 ]. However, this requires a longer observation period. On the other hand, one could assume that such differences would progress over time and that shorter observation time could provide estimates on the trend of LSM development, and that LSM later could progress past different cut-offs. A continuous analysis of factors affecting LSM could capture future relevant differences.

The strength of our study is the inclusion of all persons willing to participate at opioid agonist therapy clinics and municipal low-threshold centres. Persons with SUD are considered a hard-to-reach population with standard care and are often excluded from liver stiffness studies. However, integrated care and treatment have been shown to counteract low participation within this group [ 46 ]. The population of our study is comparable to the Norwegian population of persons who receive OAT, with about one-third females. However the mean age of our population was 43 years versus 47 years among persons receiving OAT [ 61 ]. A limitation is that we had two or more measurements for less than half of the population, limiting the possibility of concluding from the longitudinal results on change over time. Transient electrography was only performed using the medium probe. Liver stiffness measurements using a medium probe in persons with obesity may produce unreliable results overestimating the liver stiffness [ 34 , 41 ]. The use of illegal substances was reflected in the aggregated iSUSI index. By using this index as a predictor in the regression analysis, we could not determine the associations between LSM and specific substances. Since there was no observed association across all substances combined and considering that substances were not measured using biological markers, we did not assess the associations with liver stiffness measurement (LSM) for individual substances except alcohol. As tobacco smoking was nearly universal within this cohort with a low degree of heterogeneity, assessing the association to liver stiffness was unfortunately not possible. Our model indicated that HbA1c was a strong predictor of higher liver stiffness. The generalizability of this finding is limited as the result is based on fourteen persons in our sample. Due to factors inherent in the way of life of persons with SUDs, measurements and tests were not all performed on the same day and at the same time intervals.

Our study showed that 12% of the study sample had liver stiffness values indicating an increased likelihood of chronic liver disease at baseline. Achieving sustained virologic response from HCV was associated with decreased liver stiffness over time. Higher liver stiffness at baseline was observed among people with low levels of HDL cholesterol, higher age, regular alcohol use and being overweight. These results highlight the importance of HCV treatment, regular health assessments, including monitoring of liver disease and specific lifestyle interventions to reduce liver disease-associated risk for this high-risk population. This approach may identify people with advancing chronic liver disease and improve their long-term health outcomes.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

• Substance use disorder

Opioid use disorder

Opioid agonist therapy

Hepatitis C virus

Human immunodeficiency virus

Compensated advanced chronic liver disease

Body mass index

Illegal Substance use severity index

Ribonucleic acid

Glycated haemoglobin

High-density lipoprotein

Standard deviation

Confidence interval

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Acknowledgements

We thank the devoted clinical staff for their enthusiasm during the study’s planning and the involved participants. We also thank all participating investigators in the INTRO-HCV Study Group: Bergen: Vibeke Bråthen Buljovcic, Jan Tore Daltveit, Karl Trygve Druckrey-Fiskaaen, Lars T. Fadnes (principal investigator), Trude Fondenes, Per Gundersen, Beate Haga Trettenes, Siv-Elin Leirvåg Carlsen, Mette Hegland Nordbotn, Maria Olsvold, Marianne Cook Pierron, Christine Sundal, Jørn Henrik Vold. Stavanger: Maren Borsheim Bergsaker, Eivin Dahl, Tone Lise Eielsen, Torhild Fiskå, Marianne Larssen, Torgeir Gilje Lid, Eirik Holder, Tesfaye Madebo, Ewa Joanna Wilk. Mari Thoresen Soot.

INTRO-HCV Study Group members:

Vibeke Bråthen Buljovcic 1 , Jan Tore Daltveit 1 , Karl Trygve Druckrey-Fiskaaen 1, 2 , Lars T. Fadnes 1,2 (principal investigator), Trude Fondenes 1 , Per Gundersen 1 , Beate Haga Trettenes 1 , Siv-Elin Leirvåg Carlsen 1 , Mette Hegland Nordbotn 1 , Maria Olsvold 1 , Marianne Cook Pierron 1 , Christine Sundal 1 , Jørn Henrik Vold 1,3 . Maren Borsheim Bergsaker 1,8 , Eivin Dahl 1,8 , Tone Lise Eielsen 1,8 , Torhild Fiskå 1,8 , Marianne Larssen 1,8 , Torgeir Gilje Lid 1,9 , Eirik Holder 1,8 , Tesfaye Madebo 1,4 , Ewa Joanna Wilk 1,8 , Mari Thoresen Soot 1,8 .

8 Clinic for psychiatric health, children, adolescents and addiction treatment, Stavanger University hospital, Stavanger, Norway

9 Centre for Alcohol and Drug Research, Stavanger University Hospital, Stavanger, Norway

Open access funding provided by University of Bergen. The Regional Health authorities of Western Norway funded this study.

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Bergen Addiction Research, Department of Addiction Medicine, Haukeland University Hospital, Bergen, Norway

Karl Trygve Druckrey-Fiskaaen, Jørn Henrik Vold, Tesfaye Madebo & Lars T. Fadnes

Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway

Karl Trygve Druckrey-Fiskaaen, Jørn Henrik Vold & Lars T. Fadnes

Division of Psychiatry, Haukeland University Hospital, Bergen, Norway

Jørn Henrik Vold

Department of Respiratory Medicine, Stavanger University Hospital, Stavanger, Norway

Tesfaye Madebo

Department of Clinical Science, University of Bergen, Bergen, Norway

Department of Gastroenterology, Oslo University Hospital, Oslo, Norway

Håvard Midgard

Department of Infectious Diseases, Akershus University Hospital, Lørenskog, Norway

Olav Dalgard

Department of Infectious Diseases, Haukeland University Hospital, Bergen, Norway

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• Vibeke Bråthen Buljovcic
• , Jan Tore Daltveit
• , Karl Trygve Druckrey-Fiskaaen
• , Lars T. Fadnes
• , Trude Fondenes
• , Per Gundersen
• , Beate Haga Trettenes
• , Siv-Elin Leirvåg Carlsen
• , Mette Hegland Nordbotn
• , Maria Olsvold
• , Marianne Cook Pierron
• , Christine Sundal
• , Jørn Henrik Vold
• , Maren Borsheim Bergsaker
• , Eivin Dahl
• , Tone Lise Eielsen
• , Torhild Fiskå
• , Marianne Larssen
• , Torgeir Gilje Lid
• , Eirik Holder
• , Tesfaye Madebo
• , Ewa Joanna Wilk
•  & Mari Thoresen Soot

Contributions

All authors (KTDF, JHV, TM, HM, OD, RAML, and LTF) were involved in the study’s design and data analysis and contributed to the manuscript. KTDF wrote the first draft and led the writing process. All authors read and approved the final manuscript.

Authors’ information

KTDF is a consultant in addiction medicine at the Haukeland University Hospital in Bergen, Norway, and a Ph.D. fellow at the University of Bergen, Norway.

Corresponding author

Correspondence to Karl Trygve Druckrey-Fiskaaen .

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The study was reviewed and approved by the Regional Ethical Committee for Health Research West, Norway (REK Vest 2017/51). Each participant provided written informed consent prior to enrolling in the study.

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Druckrey-Fiskaaen, K.T., Vold, J.H., Madebo, T. et al. Liver stiffness and associated risk factors among people with a history of injecting drugs: a prospective cohort study. Subst Abuse Treat Prev Policy 19 , 21 (2024). https://doi.org/10.1186/s13011-024-00603-z

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The effects of alcohol on the liver and how to prevent damage

Posted: 24 September 2023 | Last updated: 31 October 2023

The liver is an essential organ and the largest solid organ in the body. It does many things, including filtering all the blood in our bodies and breaking down unwanted substances like alcohol and drugs. Consuming alcohol, especially in excessive amounts, can cause damage to the liver and lead to a multitude of problems ranging from fatty liver to cirrhosis . Thankfully there are ways to protect the liver and even reverse damage .

Please consult a health professional if you have any health-related concerns, as we’re not doctors.

Fatty liver

When you consume too much alcohol, your liver begins to build up fat inside of the liver cells. According to a 2017 study published by the NIH , fatty liver (or steatosis) is the earliest response to heavy drinking, which is characterized by four to five drinks per day over decades. But it can also develop after a few days of binge drinking, which is four to five drinks in two hours or less. Fatty liver often shows no symptoms , but can cause belly discomfort, weight loss, and tiredness.

Alcoholic hepatitis

A severe syndrome related to alcoholic liver disease (ALD), alcoholic hepatitis is inflammation of the liver that’s directly caused by drinking, usually in the case of heavy drinkers over many years of consumption. The excessive alcohol causes the liver to be overloaded with toxins that it can’t process and remove. When the liver can’t keep up, it then becomes injured, which can lead to permanent damage and even death.

Liver cancer

According to the American Cancer Society , long-term alcohol use has been linked to an increased risk of liver cancer. Liver cancer is one of the fastest-growing cancer types in the United States, with such causes as alcohol overuse, chronic hepatitis B or C virus infection, morbid obesity with diabetes, and metabolic disease. One surgical oncologist explains there aren’t a lot of early signs of liver cancer, but some people might have abdominal pain, weight loss, and yellowing of the skin or eyes.

Ascites occurs when too much fluid builds up in your abdomen and is often caused by people who have scarring (cirrhosis) of the liver, which can be a result of a long-term overconsumption of alcohol. A thin membrane called the peritoneum covers your abdominal organs, including the liver. The peritoneum has two layers, and when fluid builds up between them it’s called ascites, explains the Cleveland Clinic . The main symptoms of ascites are a large belly and rapid weight gain.

Cirrhosis of the liver is a condition characterized by permanent scarring of the liver, and can be caused by chronic alcohol use. The damage happens gradually over time, when scar tissue replaces healthy tissue and stops the liver from functioning as it should. Considered the last stage of chronic liver disease , cirrhosis exhibits early symptoms including fatigue, loss of energy, nausea or belly pain, and weight loss.

Chronic alcohol consumption can create severe changes to a person’s appearance, including jaundice, which is when the skin or the whites of the eyes look yellow. When a person has jaundice from drinking, it’s called alcoholic jaundice and is often a sign of advanced alcohol use disorder (also known as alcoholism). Jaundice is a sign that the liver isn’t functioning properly and is severely inflamed.

Liver abscess

A liver abscess is a pocket of infected fluid that forms in the liver and contains blood, dead cells and germs. It’s typically caused by an infection that can be bacterial, fungal or parasitic. One study found that alcoholism plays a major role in the formation of liver abscesses because of the damage alcohol does to the liver.

Portal hypertension

Portal hypertension refers to an increase in pressure in the portal venous system. This system includes the portal vein, which is a major vein that leads to the liver. According to Johns Hopkins Medicine , the most common cause of portal hypertension is scarring of the liver (cirrhosis). The liver scarring slows down blood flow and puts added pressure on the portal vein . The biggest concern with the added pressure is that a blood vessel could burst and be fatal.

Liver fibrosis

When there is an excessive amount of scar tissue on the liver, fibrosis occurs. According to the American Liver Foundation , if fibrosis isn’t treated it can lead to cirrhosis and liver cancer. Fibrosis develops when the liver has persistent inflammation or damage and can’t repair itself. When fibrosis progresses, the scars will build and replace healthy tissue, which then restricts blood flow. Because alcohol causes inflammation to the liver, chronic alcohol use can lead to fibrosis.

Hepatic encephalopathy

Found in people with advanced liver dysfunction, hepatic encephalopathy is caused when toxins that are normally cleared by the liver accumulate in the blood and travel to the brain. Considered a rare and complex brain disorder , it’s a subtle condition that often doesn’t have any outward signs or symptoms. Hepatic encephalopathy is a serious complication of alcoholic liver disease and is caused when the damaged liver can’t remove toxins from the blood.

Prevention: Limit alcohol consumption

The best way to protect your liver is to reduce or eliminate alcohol consumption. The 2023 guidelines from the Canadian Centre on Substance Abuse and Addiction recommends not drinking more than two drinks a week and not exceeding more than two drinks on any day, stating that no amount of alcohol is safe , with even small amounts having serious health consequences. More than 90% of alcohol is eliminated by the liver ; however, long-term alcohol consumption overwhelms this critical organ.

Prevention: Maintain a healthy diet

The liver does a lot for the body , including removing toxins, processing nutrients from food, and helping to regulate the body’s metabolism, to name just a few of its vital functions. Maintaining a healthy diet can not only prevent liver damage from starting, but reverse liver disease in its early stages. For liver health, a registered dietitian and nutritionist at the University of Chicago Medicine's Metabolic and Fatty Liver Disease Clinic recommends healthy fats, plant-based foods, and up to three cups of coffee per day.

Prevention: Avoid mixing alcohol with medications

In 2021, Statistics Canada released a study that found 55% of adults aged 18 to 79 used at least one prescription medication in the past month, while 36% used two or more. Mixing alcohol with medications can be dangerous for many reasons, including making the medication toxic to your body, increasing the side effects of the medication, or heightening the effects of alcohol. The over-the-counter pain reliever acetaminophen has been shown to cause liver damage when used in combination with alcohol, even within a few hours of drinking.

Prevention: Get vaccinated against Hepatitis A and B

Hepatitis A is a highly contagious liver infection and is spread by contaminated food and water or direct contact with an infected person, while Hepatitis B is another serious liver infection that is spread through bodily fluids. Vaccines for these infections are available and getting immunized against both can help prevent infection and potential liver damage.

Prevention: Exercise regularly

Physical activity isn’t just good for your heart and waistline, but your liver, too. A physician at Penn State Cancer Institute explains some of the benefits exercise has on the liver, including improved blood flow, decreased inflammation, and reduced fat in the liver, with studies showing that physical activity is even beneficial for people who have cirrhosis. Currently the U.S. Department of Health and Human Services recommends adults get at least 150 to 300 minutes of moderate to intense physical activity every week.

Prevention: Stay hydrated

Proper hydration is critical for maintaining healthy liver function. According to the Mayo Clinic , water lessens the burden on both your kidneys and liver, by helping to flush our waste and toxins. Every day your body loses eight to 12 cups of water, although how much water you need to drink differs from person to person based on a variety of factors including activity level, climate, age, diet and medications.

Prevention: Maintain a healthy weight

There is a direct connection between having a healthy weight and liver function, which is why it’s important to keep your weight within a healthy range. The liver is considered the centre of metabolism, so when the liver is overwhelmed, “metabolic activities get deranged,” a doctor told The Economic Times . Excess weight can trigger chronic liver inflammation and lead to fibrosis, with one landmark study showing that losing 10% of your body weight can reduce liver fat, resolve inflammation, and even improve scarring.

Prevention: Cut down on salt

It’s well known that too much salt can lead to issues like high blood pressure and heart disease, but one recent study found that a high-salt diet might contribute to liver damage, adding to the list of issues that result from excessive sodium consumption. The American Heart Association recommends people consume less than 2,300 mg of sodium daily, and yet the average person typically consumes 50% more. The liver plays a role in balancing water and sodium in the body, which is why excess salt can be especially problematic for those already suffering with liver issues.

Prevention: Avoid the use of illicit drugs

The use of illicit drugs has a multitude of negative impacts ranging from overdose to addiction, and can harm many internal organs, including the liver. According to the National Institute on Drug Abuse, certain drugs can lead to significant damage to the liver , and the damage is exacerbated when combined with alcohol or other drugs. Aside from being illegal and potentially addictive, illicit drugs should be avoided to prevent any possible harm to your liver.

Prevention: Seek professional help

Drinking in moderation , meaning no more than two drinks per day if you’re a man, and one drink or less if you’re a woman, is usually harmless. However, if drinking interferes with your day-to-day life and relationships, or if you’re unable to stop drinking once you start, you might be dealing with alcohol abuse or alcoholism and should seek professional help.

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Pathophysiology and Management of Alcoholic Liver Disease: Update 2016

Felix stickel.

1 Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland

Christian Datz

2 Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria

Jochen Hampe

3 Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany

Ramon Bataller

4 Division of Gastroenterology and Hepatology, Department of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Alcoholic liver disease (ALD) is a leading cause of cirrhosis, liver cancer, and acute and chronic liver failure and as such causes significant morbidity and mortality. While alcohol consumption is slightly decreasing in several European countries, it is rising in others and remains high in many countries around the world. The pathophysiology of ALD is still incompletely understood but relates largely to the direct toxic effects of alcohol and its main intermediate, acetaldehyde. Recently, novel putative mechanisms have been identified in systematic scans covering the entire human genome and raise new hypotheses on previously unknown pathways. The latter also identify host genetic risk factors for significant liver injury, which may help design prognostic risk scores. The diagnosis of ALD is relatively easy with a panel of well-evaluated tests and only rarely requires a liver biopsy. Treatment of ALD is difficult and grounded in abstinence as the pivotal therapeutic goal; once cirrhosis is established, treatment largely resembles that of other etiologies of advanced liver damage. Liver transplantation is a sound option for carefully selected patients with cirrhosis and alcoholic hepatitis because relapse rates are low and prognosis is comparable to other etiologies. Still, many countries are restrictive in allocating donor livers for ALD patients. Overall, few therapeutic options exist for severe ALD. However, there is good evidence of benefit for only corticosteroids in severe alcoholic hepatitis, while most other efforts are of limited efficacy. Considering the immense burden of ALD worldwide, efforts of medical professionals and industry partners to develop targeted therapies in ALF has been disappointingly low.

INTRODUCTION

Alcohol consumption accounts for approximately 3.8% of all global deaths and 4.6% of global disability-adjusted life-years. 1 In Europe, this problem seems to be particularly relevant, with 6.5% of all deaths attributable to alcohol, 2 and recent estimates indicate that harmful drinking, particularly when associated with alcohol dependence, is responsible for one in seven deaths in men and one in 13 deaths in women aged 15 to 64 years. 3 Alcohol use disorders (AUD) are the most frequent cause of liver cirrhosis in Europe, and alcoholic liver disease (ALD) the most important cause of death due to alcohol in adults. 4 Liver cirrhosis mortality over the past 30 years declined in most Western European countries, while it increased in several Eastern European countries, as well as in the United Kingdom, Ireland, and Finland. 5 Of note, the all-cause mortality of middle-aged white non-Hispanic men and women in the United States between 1999 and 2013 increased significantly, largely to increasing death rates from drug and alcohol poisonings, chronic liver diseases and cirrhosis. 6 A strong determinant for alcohol-related organ damage in many–but not all–patients is the alcohol dependence syndrome, a common behavioral disorder characterized by tolerance to the psychotropic effects of alcohol consumption, a preoccupation with alcohol and persistent drinking despite its harmful consequences. Chronic and episodes of binge alcohol abuse also contribute to the development of various somatic and psychiatric disorders and injuries, as well as to several diseases which are predominantly or entirely attributable to alcohol, such as alcohol-induced pancreatitis 7 and the fetal alcohol syndrome. 8 Furthermore, alcohol is also a contributory factor to other, diseases and injuries. Among the most important disease conditions affected by alcohol consumption are cancers of the oropharynx, esophagus, liver, colon, rectum and the female breast; 9 cardiovascular diseases; 10 neuropsychiatric disorders (epilepsy, depressive disorders); 11 a (not necessarily complete) summary of physical and mental diseases related to alcohol consumption is given in Table 1 .

Alcohol-Associated Somatic and Mental Diseases

EPIDEMIOLOGY AND BURDEN OF DISEASE

AUD contributes to a large proportion of deaths from liver diseases, either by causing genuine ALD or as a cofactor in patients with non-ALDs such as chronic viral hepatitis, hemochromatosis and fatty liver due to nonalcoholic causes. The Global Burden of Disease Study reported a steadily increasing mortality due to liver diseases with approximately 1 million deaths in 2010, which is roughly 2% of the global total mortality. 12 With this, liver-related years of liver lost (YYL) outscore that of YYL due to cancers of the respiratory tract, esophagus, stomach, colorectum and pancreas together. 13 To what proportion alcohol consumption contributes to this burden, is not entirely clear since the underlying etiologies of liver disease are not gaplessly recorded in most countries, with great variation across Europe. The most precise figures can be obtained from Finland where 87% of death cases due to liver disease seem to be alcohol-related. Taking into account the variability across Europe and figures extracted from the World Health Organization (WHO) mortality database, 14 one can estimate for the European Union that 60% to 80% of liver-related mortality is due to excessive drinking. 15 According to WHO, morbidity attributable to alcohol in developed countries accounts for 10.3% of disability adjusted life years and comes second only to that of tobacco (11.7%). Within this figure, liver cirrhosis is responsible for 70% to 80% of the directly recorded mortality from alcohol. In 2010, alcoholic liver cirrhosis was responsible for 493,300 deaths (47.9% of all liver cirrhosis deaths), representing 0.9% of all deaths regardless the cause (0.7% of all deaths of women and 1.2% of all deaths of men), and 80,600 deaths (14,800 deaths of women and 65,900 deaths of men) were attributable to alcohol-related liver cancer. 4 Apart from mere mortality figures, harmful alcohol consumption is the second most common indication for liver transplantation, accounting for approximately 40% of all primary liver transplants in Europe and about 25% in the United States. 16 Besides its remarkable health impact, this huge disease burden has an economic impact of about 125 billion Euros annually in Europe, accounting for 1.3% of the gross domestic product. 17

SPECTRUM AND PATHOPHYSIOLOGY OF ALD

Above a certain quantity, alcoholic consumption can elicit a spectrum of liver lesions among which steatosis is present in nearly all drinkers who consume in excess of 40 g/day regularly. Beyond fatty liver, ALD comprises a continuum of partly overlapping liver abnormalities with variable degrees of inflammation and progressive fibrosis in 10% to 35% of alcoholics, and liver cirrhosis in approximately 10% to 15% of heavy drinkers ( Fig. 1 ). 18 A great concern is the rising incidence of hepatocellular carcinoma (HCC) which evolves in approximately 1% to 2% of alcoholic cirrhotics per year. 19 While steatosis and inflammation are reversible upon abstinence, and probably also fibrosis below the level of cirrhotic transformation, severe alcoholic steatohepatitis (ASH), decompensating cirrhosis and HCC have a grave prognosis.

The progression for alcoholic liver injury to steatosis with scarring, inflammation and architectural distortion leading to cirrhosis. As a complication of cirrhosis, hepatocellular carcinoma may occur. However, only a minority of patients with alcoholic steatosis progress to severe liver injury.

The cellular and molecular mechanisms of ALD pathogenesis are still incompletely understood but seem to be related to a complex interaction between behavioral, environmental and genetic factors. The histological hallmarks of ALD, steatosis, inflammation and fibrosis are the result of interrelated and consecutive pathophysiological events in the context of continuous alcohol exposure. A pivotal component in the evolution of ALD is the direct toxicity of the first metabolite of alcohol degradation, acetaldehyde (AA). 20 Two major enzyme systems can metabolize alcohol to AA via oxidative degradation, of which alcohol-dehydrogenase is the system primarily responsible for the processing of lower amounts of alcohol. It is located in the cytosol and cannot be upregulated upon demand. In contrast, cytochrome P450 2E1 (CYP2E1) located in microsomes is inducible and can be upregulated 10- to 20-fold in heavy drinkers. 21 Both enzyme systems generate AA, a highly reactive toxic and mutagenic metabolite, by which they not only degrade ethanol (and other organic substances), but also contribute to alcohol-related toxicity ( Fig. 2 ). Apart from generating AA, CYP2E1 also contributes of oxidative damage by the formation of reactive oxygen species (ROS) such as superoxide anion and hydrogen peroxide. Hepatic CYP2E1 activity in humans may already increase following the ingestion of only 40 g of ethanol/day for 1 week. 22 In rodents, the induction of CYP2E1 correlated with NAD phosphate oxidase activity, the generation of hydroxyethyl radicals, lipid peroxidation and the severity of hepatic damage, all of which could be prevented by the CYP2E1 inhibitor clome-thiazole. 23 , 24 Importantly, AA is also a powerful carcinogen in experimental animals and in humans, and considered an important reason for the association of certain cancers with alcohol consumption. 25

Hepatic metabolism of ethanol by enzymes ADH, CYP2E1 and catalase. Each enzyme generates acetaldehyde, a toxic and mutagenic metabolite of ethanol. While ADH is metabolically stable regardless of the alcohol challenge and catalase is irrelevant with respect to its role in hepatic alcohol degradation, CYP2E1 is inducible and contributes most to acetaldehyde production during heavy alcohol consumption.

The initial liver lesion in alcoholics is steatosis which occurs in literally all heavy drinkers as a result of disrupted lipid turnover. 26 Above all, decreased fatty acid oxidation, increased fatty acid and triglyceride synthesis, increased fat entry into the liver by fatty acid mobilisation from peripheral fat stores and via chylomicrons from the intestine are instrumental. Furthermore, increased lipogenesis by dysregulation of steatogenic enzymes and transcription factors including sterol regulatory-binding protein 1c, peroxisome proliferator-activated receptor α, and microsomal triglyceride transport protein are involved. A more recent revelation is the potential role of protein enzymes involved in lipid processing such as PNPLA3 and TM6SF2 for which genetic variants of the coding genes were found associated with ALD (see below). Whether and how alcohol consumption affects the function of these enzymes, however, is still unclear.

Similar to non-ASH, inflammation can occur as an important feature in alcoholic steatosis resulting in ASH, and evolve as a major driving force for fibrogenesis leading to fibrosis, cirrhosis and most likely, hepatocarcinogenesis. Histologically, ASH is characterized by variable degrees of steatosis, a typical inflammatory infiltrate consisting of predominantly polymorphonuclear (PMN) cells, centrilobular hepatocyte ballooning, Mallory-Denk inclusion bodies, and a “chicken wire”-like fibrosis network. 27 A key pathogenic pathway in this stage is the gut-liver axis. Thus, alcohol ingestion increases gut permeability and promotes the translocation of endotoxins from Gram negative bacteria such as lipopolysaccharides (LPS) into the portal bloodstream to reach Kupffer cells which, upon binding of LPS to the endotoxin receptor CD14 activate the MyD88-independent signaling pathway through TLR4, with consecutive production of proinflammatory cytokines such as tumor necrosis factor α that contribute to hepatocellular damage. 28 – 30 Additional cytokines and chemokines involved in the activation/recruitment of inflammatory and mesenchymal cells contributing to inflammation and fibrotic repair processes in ALD are interleukin (IL)-1, IL-8, and IL-17, osteopontin, chemokine (CXCL)1, CXCL4, CXCL5, and CXCL6. 30 – 32 These proinflammatory sequelae are particular prominent in patients with ASH.

The key lesion in chronic liver disease is fibrosis that, in essence, resembles the process of excessive wound healing as a result of increased fibrogenesis and decreased fibrolysis. In progressive fibrosis, liver parenchyma is replaced by excess extra-cellular matrix produced by activated hepatic stellate cells (HSC) and myofibroblasts (MFB), resulting in a distorted liver architecture and progressive functional impairment. 33 Various triggers can activate liver macrophages (Kupffer cells) and other inflammatory cells which leads to the production of the profibrogenic cytokines platelet-derived growth factor and transforming growth factor-β1 which can stimulate HSC/MFB to produce collagens, noncollagenous glycoproteins, proteoglycans, and glycosaminoglycans up to 10-fold compared to normal liver tissue. Here, the fibril forming collagens type I and III make up for >80% of total liver collagen. In turn, matrix-degrading enzymes termed matrix-metalloproteinases are downregulated by their corresponding tissue inhibitors. 33 In ALD, HSCs/MFBs can be stimulated by AA, 34 ROS, 35 leptin, 36 endocannabinoids 37 and lipid peroxides. 38

The most worrisome complication of ALD is HCC, and the vast majority of HCCs develops on the background of alcoholic cirrhosis. 39 Besides cirrhotic transformation as a precancerous condition, a number of pathophysiological aspects are specific to alcohol-associated HCC. An important trigger of tumor development is AA, which is not only a toxin, but also a highly reactive mutagen that forms stable DNA adducts, causes point mutation, sister chromatid exchanges, inhibits DNA repair, and via induced CYP2E1, activates pro-carcinogens to carcinogens. 9 Other molecular mechanisms include epigenetic modifications from alcohol by altering DNA methylation. Indeed, epigenetic silencing of hypermethylated tumor suppressor genes and activation of oncogenes via hypomethylation correlate with survival in human HCC including patients with alcoholic cirrhosis. 40

Recent studies have shed some light on the pathogenesis of ASH. Here, failure of the liver to regenerate the hepatocellular mass seems to play a major role. Explants from ASH patients that underwent liver transplantation revealed that nonresponders to medical therapy had reduced hepatic expression of liver regeneration-related cytokines and the lack of proliferative hepatocytes. 41 This observation was further confirmed by others, which showed that presence of proliferating hepatocytes in alcoholic hepatitis (AH) is associated with a better prognosis. 42 In addition, a massive expansion of liver progenitor cells (LPCs) called “ductular reaction” is often observed in AH patients, but these LPCs fail to differentiate into mature hepatocytes and correlate positively with severity of liver disease and short-term mortality in these patients. 43

Experimental ALD

Studying ALD experimentally has been extremely difficult since no animal model exists that closely mirrors all relevant features of severe ALD in humans or only pivotal elements of it. 44 Rodents are notoriously resistant to the hepatotoxic effects of alcohol due to species-related differences in alcohol metabolism, and rats or mice only develop significant chronic liver injury when exposed to alcohol in combination with a second toxin (e.g., carbon tetrachloride and thioacetamide) or major dietary manipulations (e.g., choline/methionine deficiency) that still do not produce a histological picture that fully models that of human ALD. 45 The experimental setup that produces liver lesions most similar to those in humans is the intragastric feeding model, or Tsukamoto-French model in which continuous infusion of alcohol-containing food via a surgically-implanted gastric tube results in typical alcohol-induced liver injury including steatohepatitis, fibrosis and microscopic lesions such as ballooning, Mallory-Denk bodies and neutrophilic inflammatory infiltration. 46 The lack of a suitable animal model has been a significant impediment to more deeply study ALD experimentally, and is one of the reasons for the suboptimal research on novel biomarkers retrieved from human omics studies (vide infra). Recent advances, such as the National Institute on Alcohol Abuse and Alcoholism model of ALD, that combine binge drinking patterns with chronic alcohol exposure may pave the way for more suitable models. 47 This can be promising when combined with novel technologies to design genetically modified rodents such as with the CRISPR/Cas9 technique to overcome species-related differences in alcohol susceptibility. 48

FACTORS MODULATING PROGRESSION OF ALD

Significant ALD with progressive fibrosis and cirrhosis develops only in a minority of heavy drinkers suggesting that apart from alcohol itself, modifying variables exist that modulate the individual susceptibility to the toxic effects of alcohol. ALD is considered a complex disease in which numerous factors interact to allow for liver disease to occur. These factors are referred to as environmental (exogenous) or host (inherent) disease modifiers which partly explain the large inter-individual variability in the likelihood to develop ALD. Much progress has been made in our understanding of how these factors are entangled as outlined below.

1. Environmental factors

The development of ALD requires heavy alcohol drinking, and consensus exists that there is a clear dose-relationship between the amount of alcohol and the likelihood of its development. 49 , 50 According to the Dionysos Study from Italy the risk of developing alcoholic cirrhosis is highest in those with a daily consumption of above 120 g of pure alcohol per day. 51 Drinking patterns were suggested as modifier of ALD, such as drinking with meals appeared to confer less risk than consuming alcohol outside separately. Regarding the type of alcoholic beverage it was suggested that wine drinking is associated with a lower risk of ALD; 52 however, scientific persuasion prevails that it is rather the amount of alcohol contained in certain alcoholic beverages than the nonalcoholic contents, and that the effect of different beverages on ALD risk are rather related to lifestyle and dietary factors. 53 Coffee drinking appears to protect alcohol-related liver injury with people drinking four or more cups a day having one-fifth of the risk of developing cirrhosis as non-coffee drinkers. 54 In turn, cigarette smoking increases the risk of alcoholic cirrhosis with smokers of ≥1 pack daily showing a 3-fold higher risk than nonsmokers. 55

Coinfection with viral hepatitis B and C is also recognized as an important promoter of ALD, although the clear distinction between viral hepatitis worsened by alcohol, or vice versa, is often difficult to make and relies mainly on the predominant histology lesion prevalent in a patient with both conditions. The most abundant data exist for the interaction between alcohol and chronic hepatitis C for which numerous population-based, cross-sectional and cohort studies have demonstrated a higher prevalence of alcohol abuse among hepatitis C virus (HCV)-infected subjects, and a higher prevalence of HCV antibodies among drinkers. 56 In a large study including 800 patients with chronic HCV infection, Monto et al . 57 showed that those who drink alcohol in excess of 50 g/day have a significantly higher risk of advanced fibrosis than those who drink less or not at all. Mechanistically, published data suggest that alcohol accelerates the progression of hepatitis C-related liver disease via increased oxidative stress, cytotoxicity, immune dysfunction and reduction of response to antiviral treatment. Similar mechanisms are believed to be in place regarding hepatitis B virus-infected subjects, although the data regarding the latter is less abundant. 58

Overweight has been consistently associated with an increased risk of developing alcohol-related fibrosis and cirrhosis potentially reflecting a synergistic interaction between alcohol and lipotoxicity from steatosis as a consequence of obesity. 59 – 61

2. Host genetic factors

Several observations indicate an at least partial genetic background of ALD and its progression. Persuasive evidence for a genetic background of ALD stems from a twin study undertaken in a population of 15,924 male twin pairs in which the concordance for alcohol-related cirrhosis was found three times higher in monozygotic twins than in dizygotic twins. 62 Another strong genetic modifier is gender: women carry a greater risk of developing alcohol-related cirrhosis, likely attributable to hormonal effects on oxidative stress and inflammation, 63 differences in expression patterns of alcohol-metabolizing enzymes, 64 and a smaller distribution volume of alcohol in women and, thus, higher tissue levels of alcohol exposure. 65

In the United State white Hispanic men and women reveal a higher risk for alcoholic cirrhosis compared with black and Caucasian white men and women, 66 and present with alcohol-related cirrhosis up to 10 years earlier than their Caucasian counterparts. 67 However, besides constitutional differences in alcohol metabolism these differences could very well be related to cultural differences, amounts and types of alcohol consumed, dietary intake, socioeconomic status, and access to health care.

After an avalanche of relatively small candidate gene studies investigating hypothesis-based single nucleotide polymorphisms within genes considered relevant for ALD phenotypes generated data which could not be replicated, recent candidate gene studies and genome-wide scans have identified genetic risk factors which robustly associate with ALD and its complications. These data shed new light on yet unknown pathophysiological aspects of ALD, and potentially open the field for better prevention, screening and the development of novel therapies. The first and most robustly confirmed risk locus for ALD is a sequence variation within the gene coding for patatin-like phospholipase encoding 3 ( PNPLA3 , rs738409C>G, I148M) which was found to modulate the evolution of steatosis, necroinflammation, fibrosis and HCC in alcoholics. 68 , 69 The genetic risk of ALD has also been studied on a genome-wide level by two recent studies in alcoholic cirrhosis 70 and alcoholic hepatitis. 71 Both studies confirmed PNPLA3 rs738409 as a strong genetic risk locus for both alcoholic cirrhosis and AH with genome-wide significance, and for cirrhosis, two additional, hitherto unknown loci were identified: membrane bound O-acyltransferase domain containing 7 ( MBOAT7 ) (P=9.25×10 −10 ) and transmembrane 6 superfamily member 2 ( TM6SF2 ). Both PNPLA3 and TM6SF2 are implicated in hepatic lipid trapping, while MBOAT7 mediates the transfer of fatty acid between phospholipids and lysophospholipids, a potent driver of hepatic inflammation. 69 However, the functional implication of the mutant PNPLA3 variant is not yet fully understood, partly due to a lack of experimental translation in animals, but a homology model of the patatin domain derived from a plant protein structure suggests that the isoleucine to methionine substitution at position 148 in rs738409 is stereotypically close to the catalytic dyad of the protein ( Fig. 3 ). 72 This substitution likely results in impaired accessibility of PNPLA3 substrates, i.e., triglycerides, to the catalytic serine moiety, a theory supported by subsequent molecular dynamic simulations. 73 This would result in a reduction in hydrolytic function, “lipid trapping” and the accumulation of fat.

Structural modifications at the PNPLA3 rs738409 locus (I148) affect the substrate binding groove rather than the catalytic center of the protein. Substituting methionine (Met) for isoleucine (Ile) at position 148 of the PNPLA3 protein reduces accessibility for substrates (e.g., triglycerides) and thus results in a loss of function.

CLINICAL MANAGEMENT OF ALD

1. diagnostic evaluation.

In most cases, ALD is a clinically silent disease with little or no symptoms in patients with early ALD and in patients with compensated cirrhosis. Thus, diagnosis depends highly on clinical suspicion, various laboratory tests and invasive or noninvasive techniques. 74 In some patients with early ALD stigmata of alcohol abuse such as bilateral parotid gland hypertrophy, muscle wasting, malnutrition, Dupuytren’s sign, and signs of peripheral neuropathy may be present, but more often patients are entirely asymptomatic and reluctant to openly admit that their drinking behavior may be the reason of their liver abnormalities. On physical examination of cirrhotic patients, liver-typical skin signs include gynecomastia, spider angiomata, palmar erythema, and smooth tongue. Moreover, jaundice, hepatic encephalopathy, ascites and pedal edema may also be visible at first glance in patients with end-stage liver disease. The diagnosis of ALD is frequently suspected upon documentation of excess alcohol consumption (>40–50 g/day) and the presence of clinical and/or biological abnormalities suggestive of liver injury. However, on taking the medical history one needs to be aware that self-reported alcohol consumption is often under-reported and that quantification of alcohol consumption is at best semi-quantitative. 75 Past complications of liver cirrhosis such as gastrointestinal bleeding, ascites, jaundice episodes, or accidents due to encephalopathy or drunkenness reported by the patient or an accompanying person are important diagnostic information.

Laboratory tests such as mean corpuscular volume of red blood cells, γ-glutamyltransferase (GGT) and aspartate amino-transferase (AST), IgA, can indicate early ALD while a decrease of albumin, increased international normalized ratio (INR), elevated bilirubin level and/or a low platelet count are signs of advanced ALD. Many heavy drinkers also reveal elevated levels of triglycerides and uric acid, the latter often associated with gout attacks. 76 Alcohol-specific markers include carbohydrate deficient transferrin and ethyl-glucuronide, 77 however, sensitivity of the former is limited as many drinkers remain undetected due to normal levels. 78 Clinically, GGT is the most frequently used marker to detect previous alcohol consumption, however, it lacks specificity and can also rise due to other etiologies. 79 In patients with ALD, the AST/alanine aminotransferase (ALT) ratio typically is >1, and may be >2 in patients with AH. However, it can also be found in patients with advanced cirrhosis regardless of the etiology.

Liver biopsy is not routinely advised in patients with early or cirrhotic stages of ALD if clinical, analytical and imaging data are undisputed. 74 , 80 However, a liver biopsy may be useful to rule out nonalcoholic etiologies or when noninvasive tools fail to obtain a clear result. Biopsies are mostly performed percutaneously, but may require a transjugular route in patients with impaired coagulation due to a low platelet count and/or a prolonged prothrombin time, or when portal pressure shall be measured in addition. Sometimes, a liver biopsy can help to convince a patient of the cause of their liver abnormalities, and to persuade patients to change their drinking behavior, although this line of reasoning is not entirely scientific. 81 A clear indication exists in patients with aggressive forms of ALD such as ASH requiring specific therapies (e.g., corticosteroids and/or pentoxifylline) and in patients with other cofactors suspected of contributing to liver disease, e.g., coexisiting viral hepatitis or iron overload. 74 The typical findings in patients with ALD include steatosis, hepatocellular damage (ballooning and/or Mallory-Denk bodies), inflammatory infiltrates composed of PMN cells predominating in the lobules, and a variable degree of fibrosis and lobular distortion that may progress to cirrhosis ( Fig. 4 ). 82

Typical appearance of alcoholic cirrhosis showing three prominent features of alcoholic liver disease, i.e., fibrosis (blue arrow), steatosis (red arrow) and ballooning (yellow arrow). Significant inflammation is often not seen but consists of neutrophilic and lymphocytic infiltrates when visible (chromotrope anilin-blue stain; magnification × 100).

For the assessment of liver fibrosis in patients with ALD, there are noninvasive methods including serum markers and liver stiffness measurement, however, none has been sufficiently validated in ALD. Simple tests that rely on AST levels, such as AST to platelet ratio index and AST/ALT ratio, are not particularly useful in ALD due to the higher AST values in such patients that do not necessarily correlate with severe fibrosis. 83 Single variables such as hyaluronic acid are useful to confirm advanced fibrosis or cirrhosis, but are neither specific nor helpful in early diagnosis of ALD. Branded panels such as FibroTest, FibroMeter and Enhanced Liver Fibrosis score have not been sufficiently validated for ALD. Common to all these tests is that they are useful to distinguish between mild and severe fibrosis, but have limited value in intermediate stages of fibrosis. 83

Transient elastography (Fibroscan ® ) is widely established to assess fibrosis in patients with chronic liver disease and has recently been approved by the Food and Drug Adminstration (FDA). In patients with ALD, liver stiffness correlates with the stage of fibrosis, 84 but elevated values need to be interpreted with caution in patients with ALD and AST serum levels >100 U/L due to the possibility of falsely elevated liver stiffness as a result of inflammation-related liver congestion. Moreover, recent alcohol consumption can also increase liver stiffness, perhaps related to the vasodilatory effects of alcohol. 85 Imaging techniques can also be used to assess the severity of ALD. Ultrasonography, magnetic resonance imaging (MRI), and computed tomography are useful to detect steatosis, advanced fibrosis/cirrhosis as well as signs of portal hypertension. 86 Moreover, they are useful for the screening and assessment of complications such as ascites and portal vein thrombosis. Among those methods, ultrasound is the most widely used due to its low cost. MRI and MR spectroscopy are reliable tools for quantifying steatosis but their use is limited by high cost. 87 Transient elastography (Fibroscan ® ) offers a software update to quantify liver fat termed Controlled Attenuation Parameter (CAP function) as a significantly cheaper alternative; 88 however, comparative studies are lacking.

A distinct entity represents severe ASH as a relatively rare but serious complication of ALD characterized by new onset jaundice and/or ascites in heavy drinkers with or without underlying advanced ALD. Population based studies estimate approximately 4.5 hospitalizations for AH per 100,000 persons each year, with a slight male predominance, and wide variation across countries. 89 Prospective studies assessing the incidence, risk factors and clinical features of AH are clearly needed as it is assumed that a large proportion of ASH cases remain unrecognized and therefore not appropriately treated.

Patients with ASH typically present with rapidly progressive jaundice, often accompanied by fever, abdominal discomfort, anorexia, and weight loss. In severe cases, patients present with ascites, encephalopathy, hepatorenal failure and/or variceal bleeding. Patients with severe AH frequently present with the clinical picture of a so-called systemic inflammatory syndrome characterized by tachycardia, leucocytosis, and elevated C-reactive protein and procalcitonin probably due to sterile inflammation and/or or concomitant infections. 90 In some patients, ASH is the first manifestation of a previously unnoticed ALD, in others it can be a complication of cirrhosis.

Serum liver enzyme levels are often elevated 2- to 6-fold, and lower that in acute viral hepatitis, characteristically with AST elevation exceeding that of ALT related to an alcohol-induced deficiency of pyridoxal 5′-phosphate (vitamin B 6 ). 91 Most patients with AH have some degree of coagulopathy with an increased INR impaired liver function, and/or low platelet numbers due to splenomegaly from portal hypertension or direct alcohol toxicity on platelets. Particularly severe is the development of kidney failure due to hepatorenal syndrome or acute tubular necrosis which identifies the subgroup with the worst prognosis. 92

Of note, patients with ALD can also show an episode of jaundice and liver decompensation due to other reasons than AH such as in sepsis, biliary obstruction, diffuse HCC, drug-induced liver injury or gastrointestinal bleeding. Infections, particularly spontaneous bacterial peritonitis, must be ruled out as they can present with similar clinical findings (abdominal pain, fever, leukocytosis), and because they are a contraindication to specific therapy with corticosteroids. This is why a correct diagnosis and detailed work-up is so important and advocates a liver biopsy as set forth in recent clinical practice guidelines. 74 , 80 , 93 Due to frequent coexisting ascites and/or coagulopathy a transjugular route is often preferred which also allows for the measurement of hepatovenous pressure gradient as a surrogate marker of portal pressure. Serologic evaluation for viral hepatitis and imaging with Doppler ultrasound to exclude biliary or vascular disorders and HCC are recommended.

Several models have been developed to help predict outcomes of patients with AH and to guide therapy ( Table 2 ). The most widely used is the Maddrey et al .’s 94 discriminant function (DF) introduced already in 1978, which is calculated as 4.6×(pro-thrombin time/patient–prothrombin time/control)+serum bilirubin. A DF value ≥32 is indicative of a high risk of short-term mortality (35% at 1 month) and selects patients for corticosteroid therapy. Additional predictive models include the Model for End-Stage Liver Disease (MELD), the Glasgow alcoholic hepatitis (GAH) score, the Age, Bilirubin, INR, Creatinine (ABIC) score. 95 – 97 The MELD is a statistical model that is calculated using serum bilirubin, creatinine, and INR, which is able to predict 30- and 90-day mortality in patients with AH with accuracy similar to the DF. 95 , 97 The GAH score incorporates age, serum bilirubin, blood urea nitrogen, prothrombin time, and peripheral white blood cell count, and accurately predicts short- (28 days) and midterm- (84 days) mortality. The ABIC uses age, bilirubin, INR, and creatinine to estimate a 90-day risk of mortality, and can categorize patients into low (0%), intermediate (30%), and high (75%) risk of death. The MELD has been evaluated in the U.S. cohorts, the GAH in populations from the United Kingdom, and the ABIC in Spain. 98 – 100 An important innovation was the creation of the Lille model which assesses the patients’ prognosis as per response to corticosteroid therapy. The Lille model measures the change in serum bilirubin after one week of corticosteroid incorporating age, albumin, creatinine, and prothrombin time. 101 In those not responding to corticosteroids within 7 days of treatment clinical practice guidelines recommend cessation of corticosteroids since the risks, i.e., severe infections, with continued therapy outweigh the benefits. A large multicentric study recently developed a histological scoring system, Alcoholic Hepatitis Histological score (AHHS), capable of predicting short-term survival in AH patients. AHHS computes fibrosis stage, PMN infiltration, type of bilirubinostasis and presence of megamitochondria which are independently associated with patients’ survival in a semiquantitative manner and allows for stratification of patients into low, intermediate, or high risk for death within 90 days. 102

Scores for Assessing AH Severity

AH, alcoholic hepatitis; DF, discriminant function; PT, prothrombin time; MELD, Model for End-Stage Liver Disease; INR, international normalized ratio; ABIC, Age, Bilirubin, INR, Creatinine; GAH, Glasgow alcoholic hepatitis.

THERAPY OF PATIENTS WITH ALD

1. achieving abstinence.

The backbone of the treatment of patients with ALD is the achievement and maintenance of alcohol abstinence since the efficacy of medical treatments for ALD is limited in those who continue to drink. As many patients with ALD display clinical criteria of AUD, a generic term covering a wide variety of drinking behaviours and their consequences often labeled as “heavy drinking,” “harmful drinking,” “alcohol misuse/abuse,” “problem drinking” and “alcohol dependence” defined by the fourth edition of the DSM criteria (DSM-IV) 103 and the 10th edition of the ICD criteria (ICD-10). 104 Both systems describe drinking behavior leading to physical, psychosocial and mental disadvantages requiring therapeutic intervention. Clinical research efforts have focused on treating AUD in ALD patients and current consensus is that a combination of psychosocial interventions, pharmacological therapy and medical management seems to be the most effective management strategy for AUD patients with ALD. 105 Pharmaceutical approaches to treat AUD are available, however, their safe use in patients with ALD has only been tested for a few drugs. So far, only baclofen has a published track record that confirms both efficacy and safety in several open label trials 106 , 107 and one randomized controlled trial, 108 while the FDA-approved AUD drugs disulfiram and naltrexone are contraindicated in ALD patients due to possible hepatotoxicity. Nalmefene, a μ- and δ-opioid receptor antagonist and κ-opioid receptor partial-agonist, was recently approved for the treatment of AUD by the FDA, but safety data in patients with ALD is limited since patients with advanced ALD were excluded from the registrations trial. 109

Assigning the appropriate treatment for each AUD category in ALD patients requires careful assessment of patients in the context of integrated concepts in which physicians, addiction specialists and psychosocial support providers jointly treat ALD patients to achieve abstinence, or at least substantial risk reduction.

2. Nutritional support

While patients with early ALD usually are adequately nourished, those with advanced ALD, and AH in particular, reveal significant clinical signs of malnutrition. Up to 60% of alcoholics with cirrhosis and literally all hospitalized alcoholic cirrhotics reveal some degree of malnutrition which aggravates along with the severity of ALD. 110 And although alcohol provides 7.1 kcal/g of energy which is more than that of carbohydrates (4.1 kcal/g), patients with ALD often present with severe primary and secondary malnutrition, and particularly, protein energy malnutrition. 110 Therefore, adequate nutritional support is recommended in recent guidelines. 74 , 80 , 111 The causes of primary malnutrition in ALD include: (1) low dietary intake due to imbalanced diet composition or replacement of food calories by those derived from alcohol; (2) lack of appetite related to dysgeusia, esophagitis, gastritis, poor dental status; (3) lack of palatability of diets low in sodium; (4) malabsorbtion because of diarrhea, exogenous pancreatic insufficiency; and (5) complications of liver disease, e.g., ascites, hepatic encephalopathy. Besides inadequate dietary intake, heavy alcohol consumption can also lead to profound interactions with the metabolism of numerous micronutrients. Uptake and bioavailability of a wide array of water- and fat-soluble vitamins as well as trace elements are influenced by concomitant heavy alcohol and can cause clinical syndromes unrelated to ALD per se , but which should be remembered when treating patients ( Table 3 ).

Micronutrients Affected by Heavy Alcohol Consumption and Corresponding Clinical Syndromes

While clinical trials failed to demonstrate a benefit from parenteral nutritional therapy in ALD, numerous studies provided robust evidence for a benefit from enteral nutritional support on several surrogate markers of nutritional status such as nitrogen balance, anthropometric variables and survival. 110 Several studies suggested a benefit from supplementing diets with the branched-chain amino acids valine, leucine and isoleucine to maintain adequate protein intake without worsening of hepatic encephalopathy in protein-intolerant cirrhotic patients, 112 , 113 but a recent Cochrane analysis of 37 clinical trials not restricted to ALD found only weak evidence supporting the routine use of parenteral nutrition, enteral nutrition, or oral nutritional supplements in patients with liver disease. Benefits of nutritional therapy were limited to weak endpoints such as improved bilirubin levels and a better nitrogen balance in patients actively treated with nutrition, but not on prolongation of survival. 114

From a practical point of view, current guidelines recommend a dietary intake of 1.2 to 1.5 g of protein/kg and 35 to 30 kcal/kg body weight, frequent meals including a nighttime snack. 74 , 80 , 111 Considering the numerous micronutrient deficiencies in advanced ALD, adequate supplementation thereof is also advised.

In patients with severe AH the prevalence of malnutrition reaches 100% and a significant correlation of malnutrition with short- and long-term survival has been demonstrated. 115 While earlier randomized trials in relatively small patient numbers reported a possible benefit of vigorous nutritional support in patients with alcoholic cirrhosis and AH, including on improved survival, 116 only one recent randomized controlled trial in 136 patients with biopsy-proven AH studied a combination of intensive enteral nutrition via feeding tube plus methylprednisolone against conventional nutrition plus methylprednisolone (controls). 117 The primary endpoint was 6-month survival, and secondary end points comprised mortality at 1 month, rates of infection, and occurrence of hepatorenal failure at 6 months. Survival in both groups was similar (44.4% vs 52.1% in controls, p=0.406), and the feeding tube was poorly tolerated. However, patients with a calorie intake of less than 21.5 kcal/kg/day were more likely to die emphasizing the need for adequate nutrition.

3. Pharmaceutical therapy

Despite the prominent burden of ALD on liver-related morbidity and mortality, therapies that specifically target established ALD and/or fibrosis/cirrhosis are not available and very little progress has been made in this regard over the last decades in comparison to the tremendous advances in other liver diseases. For many, the therapeutic watchword has been “just stop drinking” and interest of pharmaceutical companies and clinicians in developing and testing novel drugs to treat ALD has been low. So, numerous preparations are distributed which are at best harmless, but far from truly effective.

Longest known and widely used is an extract of Silybum marianum (milk thistle) which contains silibinin as the biologically most active compound. The premier indication for silymarin treatment is Amanita phalloides (death cup fungus) intoxication in which silymarin acts as a life-saving hepatoprotectant. 118 The popularity of silymarin products among patients with chronic liver disease was promoted by a clinical trial in 170 patients with cirrhosis of various etiologies which demonstrated a significant survival benefit in those treated with silymarin. 119 Another multicenter trial in 200 patients with alcoholic cirrhosis treated with 450 mg silymarin daily did not confirm a benefit, 120 and a Cochrane systematic review of 13 randomized controlled trials found not benefit from silymarin treatment. 121

The same fate is shared by data on propylthiouracil, 122 col-chicine, 123 S-Adenosyl-L-methionine (SAMe), 124 and polyenyl-phosphatidylcholine 125 which all proved no more effective than placebo in the treatment of ALD.

1) Alcoholic steatohepatitis

A somewhat different situation is that of severe ASH in which therapeutic challenges reside in the restoration of liver synthetic function as well as reducing hepatic and systemic inflammation. The linchpin of AH treatment are abstinence, corticosteroids and intensive care addressing the complications of ASH such as renal failure and sepsis.

Corticosteroids have been used in the treatment of ASH for more than 40 years. 126 A meta-analysis from individual data from studies considered of high quality showed improved survival in patients with a high DF when treated with corticoste-roids. 127 The most studied formulation is prednisolone 40 mg daily for 4 weeks, with or without a taper after that period. The response to prednisolone can be assessed based on the change in bilirubin after one week of therapy and quantified using the Lille score, as outlined above. 101 For those with a poor response as indicated by a Lille score ≥0.45, stopping therapy can be considered, as these patients are not likely to benefit from continued corticosteroids and rather incur side-effects. Based on these data, expert practice guidelines recommend the use of corticosteroids in AH patients with a DF >32, and the European guideline advises cessation thereof should response after 7 days of treatment should be insufficient according to the Lille model. 74 , 80

Numerous reports suggested a benefit of pentoxifylline (PTX), an orally absorbed nonselective phosphodiesterase inhibitor approved for the treatment of intermittent claudication, in reducing the development of the hepatorenal syndrome in patients with ASH. 128 However, recent data from the Steroid or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial, a large randomized-controlled trial of treatment of patients with severe AH with prednisolone or PTX, or their combination has raised doubts over the benefit of PTX in AH patients. 129 Prednisolone alone reduced the risk of 28-day mortality, but no additional benefit derived from PTX. But the trial was underpowered to analyze the subgroup of patients with hepatorenal failure which may have resulted in a failure to detect a benefit in a specific group where PTX could have been of value. Similar results came from a similar trial, which however was again underpowered for the subgroup of patients with hepatorenal syndrome. 130

N-acetylcysteine (NAC) is well-established in the treatment of fulminant hepatic failure due to paracetamol overdose, 131 and improves transplant-free survival in early stage nonparacetamol acute liver failure. 132 A recent randomized trial showed that the combination of NAC with prednisolone reduced 1-month mortality (8% vs 24%) and the incidence of hepatorenal syndrome and infection. 133 The favorable safety profile of NAC makes it a potential option, in combination with corticosteroids, for patients with severe disease.

4. Liver transplantation

ALD is among the most frequent indications for orthotopic liver transplantation (OLT) worldwide. 16 In general, mortality and morbidity after LT in ALD patients is similar to patients with other etiologies, but the causes of death after transplantation for ALD differ from those in non-ALD recipients. 134 In particular, cardiovascular causes and de novo malignancies are more frequent in the patients transplanted for ALD both of which are associated with decreased survival. 16 , 135 The combination of cardiovascular deaths and of new onset cancers of the aerodigestive tract in patients after OLT for ALD strongly suggest a causal linkage with cigarette smoking, which is common among ALD transplanted patients. These data highlight a serious health risk for ALD patients after OLT and demonstrate the need for stringent clinical monitoring and intervention for tobacco use in the pre- and post-transplant periods.

OLT listing should be considered for patients who develop liver dysfunction corresponding to a Child-Pugh score ≥7 or MELD score ≥10, or clinical decompensation (ascites, variceal bleeding, or hepatic encephalopathy). 93

Most transplant programs require a 6-month period of abstinence before consideration for LT, mainly for two reasons: (1) to allow for recovery of liver function which may improve to the point that OLT is no longer necessary and (2) to reduce the risk of posttransplant recidivism, although its value for predicting abstinence after OLT is poor. 136 , 137 According the “6-month rule,” patients with AH are ineligible for OLT and die if they do not respond to corticosteroids. However, posttransplant outcomes including that of abstinence seem to be good for highly selected patients with severe AH unresponsive to medical therapy, as demonstrated by a recent French multicenter study in nonresponders to prior corticosteroid therapy. 138 Mathurin et al . 138 selected 26 patients with severe AH with a median Lille score of 0.88 indicating a high risk of short-term death for OLT after careful pretransplant assessment. The cumulative 6-month survival rate was 77%, a figure comparable to those for other indications. Recurrence to harmful drinking was extremely rare, likely due to the stringent selection criteria (first AH episode, support from family background, exclusion of psychiatric illnesses, other substance abuse, consensus among OLT team members, absence of violence). This indication of liver transplantation is increasingly accepted in many transplant centers including in the United State. 139

After OLT, ALD patients require lifelong follow-up for prevention and management of complications, just as all other OLT patients, too. As mentioned above, cardiovascular disease, chronic kidney disease, and cancer must be kept in mind. Calcineurin inhibitor-based immunosuppression (particularly cyclosporine A) increase the risk of metabolic complications such as hypertension, diabetes, and dyslipidemia, which may contribute to the high incidence of cardiovascular disease and kidney disease in ALD patients. However, ALD is a good indication of OLT as demonstrated by data from the European Liver Transplant Registry, showing survival at 84%, 78%, 73%, and 58% after 1, 3, 5, and 10 years, respectively, which is better than that with viral hepatitis and cryptogenic cirrhosis. 16

Patients transplanted due to ALD often present with multisystemic effects of long-term ethanol abuse. 140 These comorbidities include malnutrition, muscle wasting due to alcoholic myopathy, vitamin deficiencies, peripheral and central neural system abnormalities, and others. Therefore, the care of patients transplanted for ALD ideally calls for a multidisciplinary approach.

CONCLUSIONS

Although much insight has been gained in the epidemiology, pathophysiology and clinical diagnosis of ALD, the armoury of therapies is still disappointing. This lack of therapeutic options to treat AUD, ALD and related complications will only improve if more scientific, medical and societal attention is paid to this prevalent and deadly disease. A coalition among political, scientific, and industry-based stakeholders is required to make a step forward. So far, these peers devoted the topic “ALD” only the role of a fringe group when drafting their health policies, research efforts and conference programs. In essence, this attitude is a good example of a prepossession that made ALD an orphan disease in its own right. But ALD is a fully preventable disease, and more efforts should be made to use this fact as an advantage.

ACKNOWLEDGEMENTS

The present work was supported by grants from the Swiss National Funds and the Swiss Foundation for Alcohol Research (SSA) to Felix Stickel.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

More From Forbes

Aspirin shows promise in treating common liver disease.

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Daily low dose aspirin reduced the amount of fat in the liver according to a new study.

Daily, low-dose aspirin may be an effective treatment for a common type of liver disease, according to a new study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by fat buildup in the liver, affecting its function. Also called non-alcoholic fatty liver disease, it is commonly associated with factors such as type 2 diabetes and obesity, but is not related to alcohol consumption.

Up to a third of Americans have fat build up in the liver and in about 2-5% that fat build up has already caused inflammation and liver cell damage. Although symptoms can take years to develop after the initial fat build-up, with fatty liver disease sometimes being called "silent," they include fatigue, weight loss, weakness, itching and yellowing of the skin or eyes. Permanent, irreversible liver damage called cirrhosis can result and people who are badly affected may develop liver failure where the only suitable treatment is a transplant.

Once fat buildup in the liver has begun to damage the organ, no approved treatments are available to reverse it, but some lifestyle changes such as lowering cholesterol, losing weight and medication to control blood pressure and diabetes may be effective.

Now a new clinical trial led by researchers at Harvard has tested whether low-dose daily aspirin might be an effective treatment for fat build up in the liver.

“Since MASLD is estimated to affect up to a third of U.S. adults, aspirin represents an attractive potential low-cost option to prevent progression to cirrhosis or liver cancer, the most feared complications of MASLD,” said Andrew T. Chan, lead author of the work and a gastroenterologist and professor at Harvard Medical School in Boston, MA.

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The study, published in the Journal of the American Medical Association involved 80 people with MASLD who were split equally into those who received the daily aspirin and those who received a placebo instead. The participants were aged between 18 and 70 years old and did not know whether they were getting the real drug or not. At the beginning of the trial and 6 months after the aspirin, or placebo, the participants had their quantity of liver fat measured. Participants who had received the aspirin had their liver fat reduce by 6.6% on average, whereas those who received the placebo had an increase of 3.6% on average. Other tests of liver function also showed improvement in people who had received the aspirin.

“Multiple noninvasive blood and imaging-based tests for liver fat, inflammation, and fibrosis all showed a similar direction of benefit that favored aspirin treatment,” said Tracey G. Simon, hepatologist and instructor at Harvard Medical School who was lead author of the work. “Together, these data support the potential for aspirin to provide benefits for patients with MASLD," added Simon.

The researchers think aspirin works to reduce liver fat by decreasing inflammation and also affecting fat metabolism. However, they stress that further studies are needed to determine whether the result holds up in a larger number of people and also whether the benefits of aspirin use on liver fat persist long term.

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Recent advances in the prevention and treatment of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) and the role of biomarkers

Affiliations.

• 1 Department of Internal Medicine B, University of Münster, Munster, Germany [email protected].
• 2 European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.
• 3 Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.
• 4 VA HSR&D Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas, USA.
• 5 Gastroenterology, Baylor College of Medicine, Houston, Texas, USA.
• 6 Institute of Liver Studies, Kings College London, London, UK.
• 7 Department of Medicine II, University Hospital LMU, Munich, Germany.
• PMID: 38527788
• DOI: 10.1136/gutjnl-2023-330584

The progression of cirrhosis with clinically significant portal hypertension towards decompensated cirrhosis remains clinically challenging and the evolution towards acute-on-chronic liver failure (ACLF), with one or more extrahepatic organ failures, is associated with very high mortality. In the last decade, significant progress has been made in the understanding of the mechanisms leading to decompensation and ACLF. As portal hypertension advances, bacterial translocation across an impaired gut barrier culminates in endotoxaemia, systemic inflammation and cirrhosis-associated immune dysfunction (CAID). Gut-derived systemic inflammation and CAID have become the logical targets for innovative therapies that prevent hepatic decompensation episodes and the progression to ACLF.Furthermore, classification of disease and biomarker discovery to personalise care have advanced in the field. This review discusses progress in biomarker discovery and personalisation of treatment in decompensated cirrhosis and ACLF.

Keywords: CIRRHOSIS; CLINICAL DECISION MAKING; LIVER FAILURE.

© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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