Alcohol-related liver disease

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The main goal of treatment is to reduce liver injury due to excessive alcohol use and prevent progression of liver disease.

Other treatment goals are to reduce symptoms and prevent complications related to ARLD. It is important that clinicians consider the continuous long-term management of ARLD in addition to treatment of the acute symptomatic episodes of alcohol-related hepatitis.

Treatment by a multi-disciplinary team is the ideal approach.[1][37] A medicine specialist (internist, gastroenterologist, or hepatologist), a mental health specialist (psychiatrist, substance misuse expert), and a nutrition expert (dietician, gastroenterologist) should work together to improve the long-term prognosis of the patient.[80]

Alcohol abstinence and alcohol withdrawal

The importance of alcohol abstinence needs to be continually emphasised in the management of ARLD. Abstinence or even reducing the amount of alcohol consumed improves projected survival in ARLD, even in the presence of cirrhosis with decompensation.[1][41][81][82] Alcohol abstinence reduces steatosis, fibrosis, and possibly the risk of hepatocellular carcinoma.[81][83] Complete alcohol abstinence is associated with improved long-term survival in patients with alcohol-related hepatitis.[84]

Abstinence from alcohol may lead to the development of alcohol withdrawal syndrome (AWS). Light or moderate AWS can develop within 6-24 hours after the patient's last alcoholic drink, and may progress to more severe forms.[1][41] Alcohol withdrawal symptoms include:

Mild AWS
- Hypertension and tachycardia
- Anorexia, anxiety, emotional lability, insomnia, irritability, diaphoresis, headache, and fine tremor
Moderate AWS (worsening mild AWS, plus):
- Agitation and coarse tremor
Severe AWS/delirium tremens (worsening moderate AWS, plus):
- Confusion/delirium
- Generalised tonic-clonic seizures (this may be the first manifestation of AWS for some patients)
- Auditory, visual, or tactile hallucinations
- Hyperthermia subsequent to psychomotor agitation.

AWS should be assessed and managed as per the Clinical Institute Withdrawal Assessment Alcohol-revised (CIWA-Ar) protocol. Clinicians should be able to differentiate AWS from hepatic encephalopathy and acknowledge that both conditions can co-exist.[1]

Pharmacotherapy for AWS

Benzodiazepines are the most commonly used drugs to treat AWS.[1] Long-acting benzodiazepines (e.g., diazepam) provide greater protection against seizures and delirium; shorter-acting benzodiazepines (e.g., oxazepam, lorazepam) are safer in older adults and those with hepatic dysfunction.[1] High doses of benzodiazepines may trigger or worsen hepatic encephalopathy.[1] Once abstinence has been achieved, the combination of counselling plus pharmacotherapy may be considered to improve the likelihood of long-term abstinence. See Alcohol withdrawal.

Pharmacotherapy for alcohol use disorder

The American College of Gastroenterology recommends baclofen (a GABA-B receptor agonist) for the treatment of alcohol use disorder in patients with compensated ARLD. Baclofen has been studied the most in these patients.[1] Other suggested drug options for this patient group include acamprosate, naltrexone, gabapentin, or topiramate.[1] Naltrexone is not recommended for patients currently taking opioids. It may be used in early ALRD and patients with compensated cirrhosis, but should be avoided in patients with decompensated cirrhosis or liver failure.[1] Gabapentin may be misused by some patients with substance use disorders and should be used with caution. The guideline recommends against the use of disulfiram for the treatment of alcohol use disorder.[1] See Alcohol-use disorder.

Weight reduction

Weight reduction is important in patients with obesity to slow the progression of ARLD.[18][85]

Caution is required if using orlistat to reduce weight in ARLD, due to reports of acute liver failure, and other significant complications such as cholelithiasis and cholestatic hepatitis.[86][87]

Smoking cessation

Smoking cessation is beneficial in reducing the progression of ARLD.[41] Smoking cessation is also helpful in initiating alcohol abstinence and maintenance.

Cessation may be facilitated by efforts as modest as a simple recommendation by a physician during routine consultation with the patient.

Immunisations

Influenza and pneumococcal vaccines are recommended in patients with chronic ARLD. If hepatitis B surface antibody and hepatitis A immunoglobulin G (IgG) antibody are negative, then hepatitis A and hepatitis B immunisation should be considered in all stages of ARLD.[88]

Nutrition

The prevalence of malnutrition is extremely high in ARLD. ARLD is associated with a high risk of complications, including infection, ascites, encephalopathy, hepatorenal syndrome, and overall mortality.[89][90][91]

Guidelines recommend evaluation of nutritional status, with consideration for nutritional supplementation to ensure sufficient caloric intake and to correct specific deficits.[37][41][1] Nutritional therapy should be instituted during hospitalisations for acute decompensation of ARLD, including calories, vitamins, and micronutrients (including zinc).[41] These patients require frequent-interval feeds; nitrogen balance can be improved by a night-time snack and a morning feed.[92][93]

Nutritional supplementation

May reduce overall mortality in some malnourished patients with ARLD, especially those with alcohol-related hepatitis or cirrhosis, but a consistent improvement in survival has not been demonstrated.[94][95][96][97]

Systematic reviews indicate that adjunctive nutritional support (parenteral or enteral nutrition, or nutritional supplements) does not confer a survival benefit in patients with ARLD, but encephalopathy may be ameliorated.[98][99][100][101] Randomised controlled clinical trials are required.

If the patient cannot achieve adequate caloric intake orally, enteral nutrition support should be considered.[1][37][41]

Routine use of specialised formulations

Not indicated, unless standard formulations cannot be tolerated at amounts necessary to satisfy nutritional requirements.[102][103] Branched chain amino acid (BCAA) formulations are used for patients who cannot tolerate the necessary amount of standard amino acids without precipitating encephalopathy.

Protein feeding

Is usually well tolerated, and there is no reason to routinely restrict protein in patients with alcohol-related hepatitis. Patients with severe alcohol-related hepatitis need a daily protein intake of 1.2 to 1.5 g/kg and caloric intake of 35 kcal/kg.[1] Caloric and protein intake is vital for improving outcomes in patients with ARLD.[104]

Refeeding syndrome

Patients who misuse alcohol are at high risk of developing refeeding syndrome and should have close surveillance for development of severe hypokalaemia, hypophosphataemia, and hypomagnesaemia.

Micronutrient supplementation

Long-term oral zinc supplementation for patients with cirrhosis due to ARLD has shown beneficial effects on both nutritional parameters and liver metabolic function including in liver fibrosis (cirrhosis).

Thiamine and other vitamin supplements should be considered if necessary.[1]

Pharmacotherapy

Clinical trials have focused on patients with alcohol-related hepatitis.

Corticosteroids

Meta-analysis of individual patient data from four controlled studies of severe alcohol-related hepatitis found that corticosteroid reduced risk of death within 28 days compared with placebo (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48 to 0.86) or pentoxifylline (HR 0.64; 95% CI 0.43 to 0.95).[105] Corticosteroid efficacy reduced with time; 6-month mortality did not differ between corticosteroid and placebo or corticosteroid and pentoxifylline.[105]

One subsequent meta-analysis found that corticosteroids did not statistically reduce mortality in patients with alcohol-related hepatitis compared with placebo or no intervention (relative risk 0.90, 95% CI 0.70 to 1.15) up to 3 months following randomisation.[106] [ ] However, in a subgroup of patients with poor prognosis (Maddrey discriminant function score 32 or hepatic encephalopathy), corticosteroid use improved short-term survival, but there was no long-term health benefit.[107][108] [ Modified Maddrey's Discriminant Function Opens in new window ]

An early decline in serum bilirubin at day 7 of treatment is a strong prognostic factor for a response to corticosteroids and a higher survival rate at 6 months after treatment.[109] Along with prothrombin time, and other parameters, it is included in the calculation of the Lille score used to identify patients who are not responding to corticosteroids.[110] In one meta-analysis, the only patients who benefited from corticosteroids (28-day survival) were those with Lille scores of ≤0.16 (complete responders) or between 0.16 and 0.56 (partial responders).[108] Those with higher Lille scores should discontinue corticosteroids.[37] The American College of Gastroenterology recommends discontinuing corticosteroids in patients with a Lille score >0.45, while the European Association for the Study of the Liver recommends discontinuation in patients with a Lille score ≥0.56.[41][1]

Prednisolone is preferred to prednisone in acute alcohol-related hepatitis. Intravenous methylprednisolone is an alternative for patients who cannot take oral drugs.[1][37] Corticosteroids should be avoided in patients with gastrointestinal bleeding requiring transfusion, in active infection, and in hepatorenal syndrome.[111][112]

Corticosteroids do not appear to increase the occurrence of, or mortality from, bacterial infections in patients with severe alcohol-related hepatitis.[113]

The American College of Gastroenterology recommends treatment with intravenous acetylcysteine for 5 days as an adjuvant to corticosteroids because it provides the best survival benefit at 28 days with 85% risk reduction of death from alcohol-related hepatitis, based on the results of one systematic review and network meta-analysis and its excellent safety profile.[1][114] However, other guidelines have not included such a recommendation, and additional trials are ongoing.

Pentoxifylline

Guidelines do not recommend pentoxifylline for the treatment of severe alcohol-related hepatitis.[1][37][41]

Prospective studies are required to determine if subgroups of patients with alcohol-related hepatitis may potentially benefit from pentoxifylline. There are insufficient data to assess whether other anti-tumour necrosis factor (TNF) therapies are beneficial in ARLD.[115][116]

Treatment of ascites

Patients with ascites should undergo diagnostic paracentesis to exclude spontaneous bacterial peritonitis.[117]

The kidneys avidly retain sodium in patients with alcohol-related hepatitis and cirrhosis. The goal of treatment is to attain negative sodium balance. Patients with less-severe disease may respond to moderate dietary salt restriction alone (2 g of sodium daily). More severe restriction usually leads to compliance problems, as the diet will be unpalatable and the patient may reduce food intake.[117][118][119] Only 10% to 15% of patients respond to diet management alone.[117]

As liver function deteriorates, patients need diuretics in combination with a sodium-restricted diet in order to induce adequate sodium excretion in the urine. The most commonly used diuretic regimen is a combination of furosemide and spironolactone.[117] Using this combination, successful therapy can be reached in up to 90% of patients.[117] In patients who are refractory to salt restriction and diuretics (usually <10% of those with cirrhosis), large-volume paracentesis or transjugular intrahepatic portosystemic shunt (TIPS) therapy may be required.[42][117][118][119]

Abdominal paracentesis animated demonstration

Demonstrates how to perform diagnostic and therapeutic abdominal paracentesis.

Primary prophylaxis with antibiotics should be considered in appropriate high-risk (ascites fluid protein <15 g/L [<1.5 g/dL]) patients with alcohol-related cirrhosisto reduce the risk of developing a first episode of spontaneous bacterial peritonitis. Antibiotics for primary prophylaxis should be used judiciously, taking into account adverse effects and risk of promoting resistance.[125] Due to concerns with antibiotic resistance, it is better to restrict primary antibiotic prophylaxis to hospitalised patients with the highest risk; this includes patients with ascites protein concentration <1 g/L and patients with cirrhosis and low protein (<1.5 g/L) ascites with renal dysfunction (serum creatinine level >106.08 micromol/L [>1.2 mg/dL], blood urea nitrogen level >8.92 mmol/L [>25 mg/dL], or serum sodium level <130 mmol/L [<130 mEq/L]) or liver failure (Child‐Turcotte‐Pugh score >9 and bilirubin >51.31 micromol/L [>3 mg/dL]).[117]

The use of an oral fluoroquinolone in selected high-risk patients with cirrhosis with low ascites fluid protein (<1.5 g/dL) has been shown to reduce the risk of developing first episode of spontaneous bacterial peritonitis and risk of mortality in one meta-analysis.[126] AASLD guidelines currently recommend ciprofloxacin for primary prophylaxis.[117]

Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycaemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behaviour.[127]

Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability).
Consult your local guidelines and drug information source for more information on suitability, contraindications, and precautions.

Due to safety issues associated with fluoroquinolones, there is emerging evidence for other antibiotic prophylaxis options. Trimethoprim/sulfamethoxazole or rifaximin may be used as alternatives in some patients, and in some centers they may actually be used in preference to ciprofloxacin.[117][128][129]

Intravenous ceftriaxone may be used in patients with cirrhosis and gastrointestinal haemorrhage as it decreases the rate of infections, re-bleeding rate, transfusion needs, and improves survival.[117][130]

In terms of which antibiotic regimen is more efficacious, the AASLD does not recommend any antibiotic, but two more recent meta-analyses (one has been published since those guidelines) have suggested rifaximin as potentially being more efficacious.[131][129]

Treatment of co-existing hepatitis C

The decision to use antiviral therapy in patients with ARLD with hepatitis C infection should be determined on an individual basis. Use of antiviral agents in patients with active alcohol use cannot generally be recommended because efficacy may be reduced.[132] Alcohol abstinence followed by antiviral therapy may potentially improve the efficacy of antiviral therapy.[133]

Current treatment for chronic hepatitis C in abstinent patients is almost exclusively with combinations of direct antiviral agents. Recommended regimens for the treatment of hepatitis C are frequently updated by the American Association for the Study of Liver Diseases. AASLD: HCV guidance Opens in new window

End-stage disease

Patients with end-stage ARLD should be considered for liver transplantation. Patients with ARLD must be screened for alcohol-related comorbid disease, and are required by most transplant centres to have at least a 6-month period of confirmed abstinence.[134][135] Other criteria should be taken into consideration.[1][11][41][136][137]

Priority for receiving liver transplantation depends on the model for end-stage liver disease (MELD) score. [ MELDNa scores (for liver transplantation listing purposes, not appropriate for patients under age 12 years) (SI units) Opens in new window ] Other factors include acuteness of liver disease, associated complications, other medical and psychiatric comorbidities, family support, alcohol dependence, and risk of recidivism. The model is based on a composite scoring of serum creatinine, serum bilirubin, and international normalised ratio. A higher score indicates worse prognosis. It has been validated as an independent predictor of patient survival in candidates for liver transplantation. A MELD score of 21 had a sensitivity of 75% and a specificity of 75% in predicting 90-day mortality in acute alcohol-related hepatitis.[138]

Patients with acute alcohol-related hepatitis are usually not considered for transplantation until they have recovered from the acute illness and can demonstrate rehabilitation and sustained abstinence. However, there is growing evidence that, using stringent criteria, liver transplantation can be successful in a select group of patients with alcohol-related hepatitis.[139][140] Risk of alcohol relapse does not differ significantly between patients with alcohol-related hepatitis and patients with alcohol-related cirrhosis who underwent elective liver transplantation.[139]

Patients with severe alcohol-related hepatitis not responding to medical therapy have a mortality rate as high as 70% at 6 months.[110]

One multi-centre retrospective US study of 147 patients with severe alcohol-related hepatitis as first decompensation event, median MELD score of 39, who underwent liver transplantation before 6 months of abstinence (median abstinence of 55 days) from 2006 to 2017 at 12 US centres found that cumulative patient survival after liver transplantation was 94% at 1 year and 84% at 3 years, with cumulative incidence of sustained alcohol use of 10% at 1 year (95% CI 6% to 18%) and 17% at 3 years (95% CI 10% to 27%) after liver transplantation.[141]

American Association for the Study of Liver Diseases guidelines suggest considering liver transplantation in carefully selected patients with favourable psychosocial profiles in severe alcohol-related hepatitis not responding to medical therapy.[37]

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