Introduction

Alcoholic liver disease (ALD) is the term used to describe the manifestations of alcohol overconsumption, leading to inflammation and scarring of the liver tissue as a result of progressive destruction and regeneration of liver parenchyma. The spectrum of alcoholic liver disease includes three subtypes which can overlap, including alcoholic fatty liver disease, alcoholic hepatitis, and cirrhosis. It is an increasingly common condition, accounting for over a third of liver disease related deaths in the UK and rising. In the early phases of disease it is often silent with no symptoms, however without early action and cessation of alcohol consumption, it is progressive and can be fatal.

Epidemiology

  • Incidence: 20.00 cases per 100,000 person-years
  • Peak incidence: 40-50 years
  • Sex ratio: more common in males 2:1
Condition Relative
incidence
Non-alcoholic fatty liver disease16.50
Alcoholic liver disease1
Hepatitis C0.80
Haemochromatosis0.06
Autoimmune hepatitis0.05
Wilson's disease0.01
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Pathophysiology

Alcoholic liver disease is an umbrella term used to refer to a spectrum of liver injuries caused by alcohol overconsumption, including alcoholic fatty liver disease, alcoholic hepatitis, and cirrhosis.

Alcohol metabolism
  • Alcohol is primarily metabolised in the liver, which is why alcohol overconsumption can lead to such devastating effects on the hepatic system
  • Alcohol dehydrogenase (ADH) is the primary system which converts alcohol to acetaldehyde, and this cannot be up-regulated once it reaches its limit
  • Cytochrome P450 2E1 (CYP2E1) also converts alcohol to acetaldehyde, and this enzyme tends to be up-regulated in heavy alcohol consumers
    • CYP2E1 also forms large amounts of reactive oxygen species which results in oxidative damage to hepatic tissue
  • Acetaldehyde is a highly reactive toxic metabolite which contributes to progressive liver damage as alcohol consumption increases
    • Acetaldehyde is a known carcinogen and is thought to contribute to the development of hepatocellular carcinoma independent from the effects of liver cirrhosis

Alcoholic fatty liver disease
  • Triglycerides accumulate amongst liver tissue as a result from two processes which are enhanced in alcohol over-consumption:
    • Reduction in fat export due to a decrease in liver fatty acid oxidation and lipoprotein reduction
    • Increased input of lipids to hepatic tissue due to increased peripheral lipolysis and triglyceride synthesis
  • This process can be enhanced if a person is also overweight/obese, leading to compounding non-alcoholic related fatty deposition in the liver
  • At this stage of ALD, it is potentially reversible if managed effectively

Alcoholic hepatitis
  • This is a stage where there is combined liver steatosis and inflammation, with focal regions of liver necrosis

Alcoholic cirrhosis
  • A progressive process of hepatic tissue inflammation, degeneration and regeneration leads to excessive fibrogenesis and scarring of the liver
  • Existing liver tissue is replaced by excess extra-cellular matrix and collagen
  • This reduces the functional capacity of the liver, as well as distorting the normal architecture, leading to micronodules in the liver (and rarely, macronodules)

Clinical features

Early on in the disease, patients with alcoholic fatty liver often show no abnormal physical symptoms or signs, or present with non-specific symptoms including:
  • Fatigue
  • Malaise
  • Abdominal pain
  • Anorexia
  • Weakness
  • Nausea and/or vomiting

As alcoholic liver disease is a spectrum, the signs and symptoms can differ depending on the severity of disease. Alcoholic hepatitis occurs in 30% of patients with excessive alcohol consumption, with symptoms including:
  • Jaundice (common)
  • Right upper quadrant pain (common)
  • Hepatomegaly (common, present in 70% of patients with ALD)
    • Generally an enlarged and smooth edge, but rarely tender to palpation
  • Palmar erythema
  • Peripheral oedema
  • Clubbing
  • Dupuytren's contracture (present in 30% of patients with alcoholic liver disease)
  • Pruritis
    • If there is cholestasis leading to bile salt deposition in skin
  • Xanthomas
  • Spider angiomas
    • Multiple spider angiomas are characteristic of chronic liver disease, while solitary angiomas are seen in other systemic disease
    • Presence of spider angiomas correspond with a higher risk of ALD related mortality
    • The reported prevalence of spider angiomas in patients with liver cirrhosis is 31%

As the liver metabolises estrogen, with progressive liver damage estrogen levels rise which can lead to a variety of estrogenic effects including:
  • Gynaecomastia and testicular atrophy (in males)
  • Loss of body hair
  • Amenorrhoea (in females)
  • Loss of libido

As inflammation and scarring occurs, alcoholic cirrhosis progresses and can lead to portal hypertension resulting in its own variety of features including:
  • Ascites (within 10 years of the diagnosis of cirrhosis, >50% of patients will develop this)
  • Dilated veins (e.g. caput medusae)
  • Variceal bleeding and haemorrhage
  • Splenomegaly

Investigations

Commonly, alcoholic liver disease is first identified following routine or screening liver function tests. ALD diagnosis is difficult, as there is no single diagnostic test which will distinguish that the liver damage was caused by alcohol itself.

Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
  • ALT
    • Raised in hepatocellular pattern of liver injury, including ALD
    • Occasionally also raised in skeletal muscle injury
  • AST
    • Raised in hepatocellular pattern of liver injury, including ALD
    • May also be raised in acute cardiac or skeletal muscle injury

The ratio of AST:ALT is of benefit in acute alcoholic hepatitis.
  • AST: typically 100-200IU/L
  • ALT: May be normal or only mildly raised, even in severe cases.
  • Ratio of AST:ALT is normally >2, a ratio of >3 is strongly suggestive of acute alcoholic hepatitis

Serum gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP)
  • GGT
    • Raised in association with chronic heavy alcohol consumption (>70% of individuals)
    • Not specific to ALD as it may also be raised in other pathologies such as obesity, non-alcoholic fatty liver disease, biliary obstruction, and hepatocellular carcinoma
  • ALP
    • Raised in cholestatic pattern of liver injury
    • May be normal, or if raised, may indicate cholestasis related to ALD

It is possible in ALD for all four markers (AST, ALT, ALP, GGT) to be raised. However it is important to consider the rise relative to their respective upper limit of normal.
  • In ALD, the AST and/or ALT levels will be raised much more compared to the ALP and/or GGT levels.
  • For example, if the AST is 160IU/mL (normal <40IU/mL), and the ALP is 150IU/mL (normal <130IU/mL), this would represent a hepatocellular injury, as the AST is 4x the upper normal limit, while the ALP is only slightly raised.
  • In alcoholic fatty liver disease (AFLD), normally there is a solitary mild increase in AST and ALT.

Serum bilirubin
  • May be elevated in liver disease, whether caused by ALD or otherwise.
  • Not useful to categorise a case as hepatocellular, cholestatic or infiltrative
  • Conjugated and unconjugated bilirubin fraction is useful to distinguish rise in bilirubin caused by liver disease versus haemolysis or Gilbert's syndrome
    • Liver disease (many types, including ALD) will have elevated conjugated bilirubin
    • Haemolysis or Gilbert's syndrome will have elevated non-conjugated bilirubin, more than 90% of total bilirubin will be unconjugated

Serum albumin
  • Reduced serum albumin
  • Liver synthesises albumin, therefore low levels indicates diminished synthetic function

Serum prothrombin time, INR
  • Elevated prothrombin time/INR
  • Indicates diminished synthetic function of liver

Liver ultrasound
  • May be used to differentiate abnormal liver function tests caused by other pathologies e.g. hepatocellular carcinoma, cholestasis, liver mass/abscess
  • If known ALD and cirrhosis, is useful to screen for hepatocellular carcinoma development

Liver biopsy
  • Not usually necessary for ALD due to invasiveness of procedure
  • If performed, may be percutaneous or transjugular
  • Histological findings vary depending on stage of ALD
StageHistological findings
Steatosis (early ALD)Fat droplets, mostly in peri-venular areas
Alcoholic hepatitisMallory-Denk bodies, neutrophil-rich inflammation with necrosis, hepatocyte ballooning
Steatofibrosis (cirrhosis)Peri-venular and peri-cellular fibrosis, fibrous septa, micronodular fibrosis (Laennec's cirrhosis)

Other investigations to consider
  • Normally, investigations may be used in order to distinguish between causes of liver damage, as often the signs/symptoms are non-specific
  • Viral hepatitis serology
  • Serum ceruloplasmin
  • Serum iron, transferrin and ferritin
  • Anti-mitochondrial antibody
    • To rule out primary biliary cirrhosis
  • Alpha-1 antitrypsin levels
    • To rule out alpha-1 antitrypsin deficiency

Management

Ideally, the aim of treatment in ALD is to prevent and/or slow the progression of liver damage, which can be fatal.

General measures
  • Alcohol abstinence
    • Likely the most important part of management is the complete cessation of alcohol consumption
    • This not only slows the progression of disease, but improves the long-term survival for patients, even in the late stages of disease where there is existing cirrhosis with de-compensation
  • Weight loss
    • This is particularly important in overweight or obese patients, where a component of liver disease may be caused by non-alcoholic fatty liver
  • Vaccinations
    • In the absence of past or current infection, hepatitis A and B immunisations should be provided to reduce likelihood of infection and compounding liver damage
  • Nutrition
    • A high protein dit should be instituted, particularly in those with alcoholic hepatitis (1-1.5g of protein/kg for adequate recovery)
    • Consider feeding tube for enteral feeding if anorexia or altered mental status

Alcohol withdrawal
  • The standard for treating acute alcohol withdrawal is benzodiazepines (e.g. diazepam)
  • Quick-acting benzodiazepine (e.g. lorazepam) for alcohol withdrawal seizures
  • Oral lorazepam is the first-line treatment for delirium tremens in alcohol withdrawal

Acute alcoholic hepatitis
  • While there is no single approved therapy for ALD, glucocorticoids (e.g. prednisolone) are considered the standard of care for acute alcoholic hepatitis and are often used
  • May improve short-term survival, but are unlikely to show a long-term benefit
  • The NICE guidelines suggest the use of Maddrey's discriminant function (DF) to identify patients with severe acute alcoholic hepatitis
    • DF of >32 predicts a high mortality within 90 days, and means a liver biopsy should be considered, with corticosteroid treatment initiation
  • Pentoxifylline can be used as an alternative to glucocorticoids if they are contraindicated (e.g. hepatitis B viral infection, tuberculosis, other serious infection)

End-stage ALD
  • In patients with end-stage ALD (cirrhosis with decompensation), liver transplantation can be considered
  • Usually must be alcohol free for >6 months

Complications

Hepatic encephalopathy
In severe cases, hepatic encephalopathy can occur as a result of significant toxin build-up (ammonia), characterised by symptoms and signs including:
  • Confusion
  • Drowsiness
  • Hyperventilation
  • Asterixis
  • Fetor hepaticus
This should be managed with supportive care plus lactulose until laxative effect is achieved.

Portal hypertension
  • This complication occurs once liver cirrhosis is established.
  • If the blood vessels in the liver are blocked due to severe liver fibrosis, a high pressure develops in the portal venous system.
  • This leads to large varices within the venous system in the esophagus, stomach, rectum and umbilicus.
    • This results in secondary complications such as variceal haemorrhage which can be life-threatening, ascites and splenomegaly.
    • Ascites can be complicated by spontaneous bacterial peritonitis (suspect in patients with abdominal distention, pain +/- fever)
  • This can be managed with a transjugular intrahepatic portal-systemic shunt (TIPSS) if there is acute bleeding, particularly if gastric varices are present

Hepato-renal syndrome
  • As a result of portal hypertension, there is widespread splanchnic vasodilation
  • This leads to a reduction in the effective circulating volume, which can reduce the blood flow to the kidneys, compromising the renal system and potentially leading to a life-threatening acute kidney failure

Hepatocellular carcinoma
  • Once liver cirrhosis is established, there is a significantly increased risk in development of hepatocellular carcinoma
  • Hepatic ultrasound should be undertaken serially approximately every 6 months to yearly to screen for liver cancer development