Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

all patients

1st line – alcohol abstinence ± alcohol withdrawal management

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1st line – 

alcohol abstinence ± alcohol withdrawal management

Measures include alcohol abstinence counselling, brief intervention psychotherapy, Alcoholics Anonymous, alcohol rehabilitation programmes, and behaviour modification for cessation of alcohol, smoking, and drug use. Also close monitoring for, and treatment of, symptoms of alcohol withdrawal.

Benzodiazepines are the most commonly used drugs to treat alcohol withdrawal syndrome.[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 in those with hepatic dysfunction.​​[1][41]​​​ 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.

Primary options

oxazepam: 15-30 mg orally three to four times daily

OR

diazepam: 10 mg intravenously initially, followed by 5-10 mg every 3-4 hours when required

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Secondary options

lorazepam: 2-6 mg/day orally given in 2-3 divided doses

Plus – alcohol use disorder management

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Plus – 

alcohol use disorder management

Treatment recommended for ALL patients in selected patient group

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.

See Alcohol use disorder.

Primary options

baclofen: 5 mg orally three times daily initially, increase gradually according to response, maximum 45-60 mg/day

Secondary options

acamprosate: 666 mg orally three times daily

OR

naltrexone: 50 mg orally once daily

Tertiary options

gabapentin: 300-600 mg orally three times daily

OR

topiramate: 100-150 mg orally (immediate-release) twice daily

Plus – weight reduction + smoking cessation

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Plus – 

weight reduction + smoking cessation

Treatment recommended for ALL patients in selected patient group

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 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 simple recommendation by a physician during routine consultation with the patient.

Plus – nutritional supplementation + multivitamins

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Plus – 

nutritional supplementation + multivitamins

Treatment recommended for ALL patients in selected patient group

The prevalence of malnutrition is extremely high in ARLD.[89][90][91]

Guidelines recommend evaluation of nutritional status, with consideration for nutritional supplementation to ensure sufficient caloric intake and to correct specific deficits.[1][37][41]​​​​ 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][142]​​ 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, then enteral nutrition support should be considered.[1][37][41]​​

Routine use of specialised formulations is 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]​​

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.

Long-term oral zinc supplementation for patients with alcohol-related cirrhosis 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]​​

Plus – immunisation

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Plus – 

immunisation

Treatment recommended for ALL patients in selected patient group

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]

Consider – corticosteroid

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Consider – 

corticosteroid

Additional treatment recommended for SOME patients in selected patient group

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]

Suitable for patients with ARLD with a Maddrey's discriminant function (MDF) score of 32 or more, or hepatic encephalopathy.

MDF is based on a composite scoring of prothrombin time and total bilirubin.[107][108] [ Modified Maddrey's Discriminant Function Opens in new window ]

If bilirubin falls during the first week, treatment is continued until acute decompensation resolves.

Corticosteroids are stopped if there is no improvement in serum bilirubin on the seventh day of treatment. 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 of ≥0.56.​​[1][41]

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]

Primary options

prednisolone: 40 mg orally once daily

Secondary options

prednisone: 40 mg orally once daily

Tertiary options

methylprednisolone sodium succinate: 32 mg intravenously every 24 hours

Consider – acetylcysteine

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Consider – 

acetylcysteine

Additional treatment recommended for SOME patients in selected patient group

The American College of Gastroenterology recommends treatment with intravenous acetylcysteine 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.

Primary options

acetylcysteine: consult specialist for guidance on intravenous dose

Consider – sodium restriction ± diuretic

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Consider – 

sodium restriction ± diuretic

Additional treatment recommended for SOME patients in selected patient group

For patients with less severe ascites a 2 g daily sodium diet is required. Commonly prescribed 'no added' salt diets usually contain about 4 g sodium daily. The target weight loss should be no more than 0.5 kg per day in patients without peripheral oedema (those with oedema may lose up to 1 kg per day).

As liver function deteriorates, patients will 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. 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]

Abdominal paracentesis animated demonstration
Abdominal paracentesis animated demonstration

Demonstrates how to perform diagnostic and therapeutic abdominal paracentesis.

Primary options

furosemide: 40-160 mg orally once daily in the morning

and

spironolactone: 100-400 mg orally once daily in the morning

Consider – antibiotic prophylaxis

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Consider – 

antibiotic prophylaxis

Additional treatment recommended for SOME patients in selected patient group

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 cirrhosis to 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][143]​ Due to concerns for antibiotic resistance, it is better to restrict primary antibiotic prophylaxis to hospitalised patients with the highest risk; this includes patients with ascites protein concentration less than 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 options. Trimethoprim/sulfamethoxazole or rifaximin may be used as alternatives in some patients, and in some centres they may actually be used in preference to ciprofloxacin.[117][128][129][144]

Intravenous ceftriaxone may be used in patients with cirrhosis and gastrointestinal haemorrhage as it decreases the rate of infections, rebleeding 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]

Primary options

ciprofloxacin: 500 mg orally once daily

OR

trimethoprim/sulfamethoxazole: 160 mg orally once daily

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OR

rifaximin: 550 mg orally twice daily

OR

ceftriaxone: 1 g intravenously every 24 hours

2nd line – liver transplant + continued alcohol abstinence

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2nd line – 

liver transplant + continued alcohol abstinence

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]

Alcohol abstinence and management of alcohol use disorder should continue after transplant.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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