Discuss the pathogenesis of WE?

• Caused by acute and severe CNS deficiency of thiamine (chronic def lead to Beri beri)
• Thiamine is a cofactor for several key enzymes important in energy metabolism and production of ATP
• Alcohol withdrawal causes CNS over activity leading to increased need for thiamine.
• Thiamine deficiency cause brain cell death by inhibiting metabolism in brain regions with high metabolic requirements and high thiamine turnover.
• WE may be precipitated in susceptible patients by administration of intravenous glucose before thiamine supplementation (glucose lead to utilisation of thiamine)
• Thiamine deficiency in alcohol abusers results from inadequate intake and reduced GI absorption. Thiamine absorption is significantly reduced in malnourished alcoholic abusers. Thus parenteral treatment is needed.

Discuss the clinical features of WE?

• Mental changes- confusion, disorientation, inattentiveness, drowsiness, obtundation, semi coma, coma. Mental changes are most common and may be the only sign of WE. These changes are however non specific and may be caused by alcohol intoxication or withdrawal.
• Oculomotor- nystagmus, lateral rectus palsy, conjugate gaze palsy
• Gait- wide based gait with small steps. When severe- walking may not be possible
• Hypotension and hypothermia

Discuss the diagnosis of WE?

• The classic triad of WE includes acute confusion, ataxia and ophthalmoplegia. However the triad is present in only 10% of patients with WE. Thus if the classic triad is used for diagnosis, WE will be missed or the diagnosis will be delayed till the classic triad becomes obvious.
• A high index of suspicion is therefore needed and the presence of only one sign should be sufficient to assign a diagnosis and commence treatment.
• Untreated WE- most patients progress to coma and death. IV thiamine is safe and effective. Thus treatment takes priority over diagnosis. Response to thiamine may be diagnostic.
• The diagnosis should be based on the presence of any one or more of the following signs:
  • Acute confusion
  • Decreased consciousness level including unconsciousness or coma
  • Memory disturbance
  • Ataxia/unsteadiness
  • Ophthalmoplegia
  • Nystagmus
  • Unexplained hypotension with hypothermia.

Discuss treatment?
Treatment is required where WE is suspected or as prophylaxis in patients at high risk. All patients undergoing alcohol withdrawal or treatment for AWS should be treated prophylactically.

• Treatment of WE
  • Oral B-vitamin replacement is both inadequate and ineffective owing to limited gastrointestinal absorption in alcohol misusers. Parenteral B-vitamin replacement is therefore required
  • Dosage Pabrinex (2 ampoule pairs) tds for 2 – 3 days followed by:
    • Pabrinex OD for 3 to 5 days
    • Then Thiamine Oral 100mg TDS for 1 week then thiamine 100mg OD
    • Multivitamin (One a day) OD
• Prophylaxis against WE
  • Dosage Pabrinex OD for 3 to 5 days (each paired ampoule of pabrinex contains 250 mg of thiamine beside other vitamins)
  • Then Thiamine Oral 100mg TDS for one week , then thiamine 100mg OD
  • Multivitamin (One a day) OD
• There are no RCT to support any particular dosing regimen. However high doses are justified based on reports of failed clinical improvement in WE with low doses.
• 100mg OD of thiamine should be continued after discharge until patients are no longer considered at risk. (NB- dietary requirement of thiamine is only 1-2 mg daily)
• There is a small risk (1 in 1 million IV doses) of anaphylaxis with parenteral thiamine.

Discuss laboratory abnormalities in WE?

Atrophy of the mamillary bodies on MRI is a highly specific finding in WE and Korsakoff syndrome and is present in most cases and can be detected within a week of onset of WE.

Who would you consider for treatment?

• Patients having symptoms of AWS as listed above.
• Patients should also be considered for treatment, if they do not have symptoms of AWS but are at risk of developing severe AWS. The risk factors are:
  • High alcohol intake ( > 15 units/day)
  • Previous history of severe withdrawal, seizures and/or DTs
  • Concomitant use of other psychotropic drugs
  • Poor physical health
  • High levels of anxiety
  • Other psychiatric disorders
  • Hypoglycaemia
  • Hypokalaemia
  • Hypocalcaemia
  • Fever
  • Sweating
  • Insomnia
  • Tachycardia.

Discuss the role of benzodiazepine in the treatment of AWS?

• Benzodiazepines are used to control psychomotor agitation and prevent progression to more severe withdrawal.
• The oral long-acting benzodiazepines, chlordiazepoxide and diazepam, are preferred as they have both a long half-life and a smoother more protracted effect.
• Oral chlordiazepoxide is the drug of choice as it has a lower potential for abuse than diazepam.
• Chlordiazepoxide 5mg is approximately equivalent to diazepam 2mg.
• Oxazepam and lorazepam are benzodiazepines with shorter half life that are not significantly metabolised by the liver so are preferred for patients with liver failure as there is a lower risk of accumulation.
• 0.5 mg of lorazepam is roughly equivalent to 5 mg of diazepam

Discuss the management of AWS?

• Baseline tests- All patients should have FBC, U&E, LFT, Magnesium, phosphate, Blood glucose, clotting, B12 and folate.
• Chlordiazepoxide- The aim of treatment is that the patient is calm and sedated but easily aroused. The dose should be tailored to each patient dependent upon symptoms. A total daily dose of 120mg chlordiazepoxide (given at 6-hourly intervals) on day one is usually appropriate, with additional prn (5mg to 10mg) doses available for breakthrough symptoms. The total daily dose is then steadily reduced to zero over a number of days (5-10 days). Use the regime applicable to your trust. Some patients may need massive doses of benzodiazepines while other agitated patients may need intravenous benzodiazepines. A few patients with refractory DTs may need intubation and ventilation. Diazepam can also be administered rectally.
• Thiamine- All patients undergoing alcohol withdrawal or treatment for AWS should be treated prophylactically for WE. If any signs of WE is present, treatment doses of thiamine should be administered (see WE below). Multivitamin tablet should also be started.
• Seizures- use IV benzodiazepines. There is little evidence to support the use of conventional anti-epileptics in the prophylaxis or treatment of seizures arising as a result of acute alcohol withdrawal.
• Supportive care
  • Hydration- most patients are hypovolemic as a result of sweating, hyperthermia, vomiting, and tachypnea. Patients with DTs may lose up to 6 litres of fluid in a day.
  • Electrolytes-Low K, Mg and PO4 is common and should be corrected
  • Alcoholic Ketoacidosis- may occur in a non-diabetic alcohol abuser who is malnourished. Restoration of fluid balance with glucose-containing saline solution is usually effective
  • Patients should be placed in a quiet environment. Mechanical restraint may be temporarily needed to protect the patients and staff.

Wernicke’s encephalopathy (WE)
Discuss WE?
WE is a reversible biochemical lesion of the CNS caused by overwhelming metabolic demands being made upon depleted B-vitamin reserves, in particular thiamine (B1). Although, usually associated with chronic alcoholism, WE can occur in the setting of poor nutrition caused by any other condition. It has been shown to occur in 12.5% of alcohol misusers. It is fatal in 17% of inappropriately managed patients. Permanent brain damage (Korsakoff’s psychosis) occurs in 85% of inappropriately managed survivors, 25% of whom require long-term institutionalisation.

Discuss the pathogenesis of WE?

• Caused by acute and severe CNS deficiency of thiamine (chronic def lead to Beri beri)
• Thiamine is a cofactor for several key enzymes important in energy metabolism and production of ATP
• Alcohol withdrawal causes CNS over activity leading to increased need for thiamine.
• Thiamine deficiency cause brain cell death by inhibiting metabolism in brain regions with high metabolic requirements and high thiamine turnover.
• WE may be precipitated in susceptible patients by administration of intravenous glucose before thiamine supplementation (glucose lead to utilisation of thiamine)
• Thiamine deficiency in alcohol abusers results from inadequate intake and reduced GI absorption. Thiamine absorption is significantly reduced in malnourished alcoholic abusers. Thus parenteral treatment is needed.

Discuss the clinical features of WE?

• Mental changes- confusion, disorientation, inattentiveness, drowsiness, obtundation, semi coma, coma. Mental changes are most common and may be the only sign of WE. These changes are however non specific and may be caused by alcohol intoxication or withdrawal.
• Oculomotor- nystagmus, lateral rectus palsy, conjugate gaze palsy
• Gait- wide based gait with small steps. When severe- walking may not be possible
• Hypotension and hypothermia

Discuss the diagnosis of WE?

• The classic triad of WE includes acute confusion, ataxia and ophthalmoplegia. However the triad is present in only 10% of patients with WE. Thus if the classic triad is used for diagnosis, WE will be missed or the diagnosis will be delayed till the classic triad becomes obvious.
• A high index of suspicion is therefore needed and the presence of only one sign should be sufficient to assign a diagnosis and commence treatment.
• Untreated WE- most patients progress to coma and death. IV thiamine is safe and effective. Thus treatment takes priority over diagnosis. Response to thiamine may be diagnostic.
• The diagnosis should be based on the presence of any one or more of the following signs:
  • Acute confusion
  • Decreased consciousness level including unconsciousness or coma
  • Memory disturbance
  • Ataxia/unsteadiness
  • Ophthalmoplegia
  • Nystagmus
  • Unexplained hypotension with hypothermia.

Discuss treatment?
Treatment is required where WE is suspected or as prophylaxis in patients at high risk. All patients undergoing alcohol withdrawal or treatment for AWS should be treated prophylactically.

• Treatment of WE
  • Oral B-vitamin replacement is both inadequate and ineffective owing to limited gastrointestinal absorption in alcohol misusers. Parenteral B-vitamin replacement is therefore required
  • Dosage Pabrinex (2 ampoule pairs) tds for 2 – 3 days followed by:
    • Pabrinex OD for 3 to 5 days
    • Then Thiamine Oral 100mg TDS for 1 week then thiamine 100mg OD
    • Multivitamin (One a day) OD
• Prophylaxis against WE
  • Dosage Pabrinex OD for 3 to 5 days (each paired ampoule of pabrinex contains 250 mg of thiamine beside other vitamins)
  • Then Thiamine Oral 100mg TDS for one week , then thiamine 100mg OD
  • Multivitamin (One a day) OD
• There are no RCT to support any particular dosing regimen. However high doses are justified based on reports of failed clinical improvement in WE with low doses.
• 100mg OD of thiamine should be continued after discharge until patients are no longer considered at risk. (NB- dietary requirement of thiamine is only 1-2 mg daily)
• There is a small risk (1 in 1 million IV doses) of anaphylaxis with parenteral thiamine.

Discuss laboratory abnormalities in WE?

Atrophy of the mamillary bodies on MRI is a highly specific finding in WE and Korsakoff syndrome and is present in most cases and can be detected within a week of onset of WE.

The spectrum of alcohol-related liver injury is often grouped into three histological stages of ALD: fatty liver or simple steatosis, alcoholic hepatitis, and chronic hepatitis with hepatic fibrosis or cirrhosis.

Fatty liver- develops in the majority with alcohol consumption of > 60g/day (8 g is 1 unit) of alcohol, but may also occur in individuals who drink less. Fatty liver is usually asymptomatic and self limited, and may be completely reversible with abstinence after about 4-6 weeks. However, progression to fibrosis and cirrhosis occurs in 5%-15% of patients despite abstinence.

A subset of patients with ALD will develop severe alcoholic hepatitis (AH), which has a substantially worse short-term prognosis (discussed separately)

Discuss conversion of alcohol in units?

Grams of alcohol consumed= percentage of alcohol X specific gravity of alcohol (0.79g/ml) X volume consumed

A unit is defined as the equivalent of 8 g of ethanol

Discuss alcohol as a hepatotoxin?
Unlike many other hepatotoxins, the likelihood of developing progressive liver disease is not completely dose-dependent, because it occurs in only a subset of patients. The risk of developing cirrhosis increases with the ingestion of >60-80 g/day of alcohol for 10 years or longer in men, and >20 g/day in women. Yet, even drinking at these levels, only 6%-41% develop cirrhosis. Thus liver disease should not be presumed to be alcoholic in nature in a person with excess alcohol intake
Based on epidemiological evidence, a suggested “safe” limit of alcohol intake had been 21
units per week in men and 14 units per week in women who have no other chronic liver disease (where).

Discuss the diagnosis of ALD?

• The diagnosis of ALD is based on a combination of features, including a history of significant alcohol intake, clinical evidence of liver disease, and supporting laboratory abnormalities.
• No single laboratory marker definitively establishes alcohol to be the aetiology of liver disease.
• A combination of raised GGT and mean corpuscular volume may improve the sensitivity for diagnosing alcohol abuse.
• Levels of AST more than 500 IU/L or an ALT) >200 IU/L are uncommonly seen with alcoholic hepatitis. In about 70% of patients, the AST/ALT ratio is higher than 2, but this may be of greater value in patients without cirrhosis. Ratios greater than 3 are highly suggestive of ALD.
• Physical exam findings more commonly observed in ALD are parotid enlargement, Dupuytren’s contracture, and especially those signs associated with feminization
• Other alcohol related diseases like cardiomyopathy, skeletal muscle wasting, pancreatic dysfunction, and alcoholic neurotoxicity may co exist and evidence of these must be sought during the clinical examination, so that appropriate treatment may be provided.

Discuss the treatment of ALD?

Abstinence is the most important therapeutic intervention. It has been shown to improve the histology, decrease progression to cirrhosis, and to improve survival at all stages in patients with ALD. The improvement can be relatively rapid, and in 66% of patients abstaining
from alcohol, significant improvement was observed in 3 months.

Discuss the management of recidivism?

Recidivism is a major risk in all patients at any time following abstinence. Options:

Disulfiram- little evidence that disulfiram enhances abstinence, and based on its poor tolerability, its use has been largely supplanted by newer agents.

Naltrexone- is a pure opioid antagonist and controls the craving for alcohol. A Cochrane systematic review concluded that short-term treatment with naltrexone lowers the risk of relapse.

Acamprosate- has been shown to reduce withdrawal symptoms, including alcohol craving. Its effect is more pronounced in maintaining rather than inducing remission when used in combination with counselling and support. In detoxified alcoholics, it has been shown to
decrease the rate of relapse, maintain abstinence, and decrease severity of relapse when it occurs.

Ref

1. AASLD Practice Guidelines: Alcoholic Liver Disease (archived copy at Webcite)

Can Alcoholic hepatitis be diagnosed clinically?
Suggested criterion:

• History of recent excessive alcohol ingestion
• Serum bilirubin more than 80umol/l
• ALT <300 IU (or AST<500 IU)
• Exclusion of autoimmune, chronic viral or malignant liver disease

NB- Characteristic features of alcoholic hepatitis (but not necessary for diagnosis) include pyrexia, hepatomegaly, a hepatic bruit, ascites, encephalopathy, an AST: ALT ratio greater than 1.5, and a peripheral leucocytosis.

How accurate is a clinical diagnosis of Alcoholic hepatitis?
An accuracy of about 80% has been quoted for the clinical diagnosis of alcoholic hepatitis when compared with histology. However if only those studies with a minimum level of bilirubin (>80 umol/l) as a criterion for diagnosis are looked at, the accuracy rises to nearly 100%.

Does alcoholic hepatitis with co-existing cirrhosis alters the prognosis or treatment?
Whilst nearly all patients who fulfil these criteria will have features of alcoholic hepatitis on biopsy, approximately 50-60% will also have established cirrhosis. There is no evidence that co-existing cirrhosis worsens the short term outcome of patients with alcoholic hepatitis, indicating that it is the acute inflammatory process which is primarily responsible for the poor prognosis of these patients. The presence of cirrhosis (confirmed or suspected) should therefore not prevent consideration of specific treatment for alcoholic hepatitis.

How do you assess the severity of Alcoholic Hepatitis?
American College of Gastroenterology defines severity as a modified Discriminant Function (mDF)> 32 and/or hepatic encephalopathy.

• mDF = 4.6 (PTpatient–PTcontrol)+ serum bilirubin (µmol/l)/17.1

This is based on recent studies where a mDF> 32 and/or hepatic encephalopathy was associated with a 65% 28-day survival in placebo treated patients. While those with a score less than 32 had a survival of 93%.

Where would you use steroids?
American College of Gastroenterology recommends prednisolone should be used in patients with severe alcoholic hepatitis in whom the diagnosis is certain. Severity is defined as a DF> 32 and/or hepatic encephalopathy.
Histologic confirmation of alcoholic hepatitis optimizes the selection of those patients being considered for corticosteroid therapy. However, if the risk of performing liver biopsy is considered too great, the diagnosis can usually be made reliably by clinical and laboratory evaluation in the majority of patients.
The efficacy of steroids has not been adequately evaluated in patients with severe alcoholic hepatitis who also have concomitant pancreatitis, gastrointestinal bleeding, renal failure, and active infection.
Patients with mDF >32 and treated with steroids had a 28 day survival of 84.6% compared with 65.1% for placebo treated patients.

Is there any other clinical guide to help us better direct our treatment?
A GAHS (Glasgow alcoholic hepatitis score) has been recently developed. The authors of GAHS points out a few shortcomings of mDF;

• Calculation of mDF relies on the absolute value of the PT & there exists significant variation in the absolute values of PT obtained using different assays in different countries. This may thereby affect the validity of the mDF score in countries such as the UK where a greater severity score will be generated based on the PT. This creates a definite inaccuracy in the mDF value and limits its translation between different facilities.
• The presence of encephalopathy has often been included when making a treatment decision, in addition to just calculating the mDF. This is problematic, as encephalopathy is very subjective in its milder forms.
• Apart from the positive reports on the relevance of an mDF cut off value of 32, its accuracy in predicting survival has been repeatedly questioned.
• In their analysis, mDF was highly sensitive in the prediction of death from alcoholic hepatitis but lacked specificity. This was dramatic as it incorrectly predicted the outcome at 28 days after admission in 51% of cases.
• They also suggests that even with a mDF greater than or equal to 32, patients with a GAHS less than nine do not benefit from such treatment.

What is GAHS?

Discuss GAHS Vs mDF?

Thus GAHS of 9 or more is much more discriminatory in identifying patients most at risk of death. A score of 9 or more can be used either on day 1 (admission day) or day6-9.

What is the steroid dose and duration?
Prednisolone 40 mg daily for four weeks followed by a taper.
Careful monitoring for evidence of infection, gastrointestinal bleeding, glucose intolerance, or renal failure is essential while the patient is on prednisolone therapy.

How do you assess response?
Any fall in serum bilirubin after one week of corticosteroid treatment is indicative of treatment response and good prognosis.

Are there any other treatments for Alcoholic Hepatitis?
The role for pentoxifylline whilst promising is as yet unproven. It acts by inhibiting TNF alpha.

What other supportive care can patients with Alcoholic hepatitis be provided?

• These patients are at risk of sepsis. Close vigilance for sepsis and a low threshold for the use of antibiotics is required.
• These patients have significant protein energy malnutrition. Nutritional support is vital for these patients.

Summary
Patients with severe disease (mDF > 32, or more specifically GAHS > 9) benefit from corticosteroids, and perhaps pentoxifylline.

References

1. McCullough AJ, O’Connor, JF. Alcoholic liver disease: Proposed recommendations for the American College of Gastroenterology. Am J Gastroenterol 1998; 93:2022.
2. Forrest EH. A clinical approach to alcoholic hepatitis. J R Coll Physicians Edinb 2007; 37:3-8 (archived copy at webcite)
3. Forrest EH et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut 2005; 54; 1174-1179 (archived copy at webcite)