2. IntroductionIntroduction
Chronic and excessive alcohol ingestion is oneChronic and excessive alcohol ingestion is one
of the major causes of liver disease. Theof the major causes of liver disease. The
pathology of alcoholic liver disease comprisespathology of alcoholic liver disease comprises
three major lesions, with the injury rarelythree major lesions, with the injury rarely
existing in a pure form: (1) fatty liver, (2)existing in a pure form: (1) fatty liver, (2)
alcoholic hepatitis, and (3) cirrhosis.alcoholic hepatitis, and (3) cirrhosis.
Fatty liver is present in >90% of binge andFatty liver is present in >90% of binge and
chronic drinkers. A much smaller percentagechronic drinkers. A much smaller percentage
of heavy drinkers will progress to alcoholicof heavy drinkers will progress to alcoholic
hepatitis, thought to be a precursor to cirrhosis.hepatitis, thought to be a precursor to cirrhosis.
3. Risk FactorsRisk Factors
Quantity and duration of alcohol intake are theQuantity and duration of alcohol intake are the
most important risk factors involved in themost important risk factors involved in the
development of alcoholic liver disease. Thedevelopment of alcoholic liver disease. The
roles of beverage type(s), i.e. wine, beer, orroles of beverage type(s), i.e. wine, beer, or
spirits, and pattern of drinking are less clear .spirits, and pattern of drinking are less clear .
Progress of the hepatic injury beyond the fattyProgress of the hepatic injury beyond the fatty
liver stage seems to require additional riskliver stage seems to require additional risk
factors that remain incompletely defined.factors that remain incompletely defined.
4. Risk factorsRisk factors
In general, the time it takes to develop liver disease isIn general, the time it takes to develop liver disease is
directly related to the amount of alcohol consumed. Itdirectly related to the amount of alcohol consumed. It
is useful in estimating alcohol consumption tois useful in estimating alcohol consumption to
understand that one beer, four ounces of wine, or oneunderstand that one beer, four ounces of wine, or one
ounce of 80% spirits all contain ~12 g of alcohol.ounce of 80% spirits all contain ~12 g of alcohol.
The threshold for developing alcoholic liver diseaseThe threshold for developing alcoholic liver disease
in men is an intake of >60–80 g/d of alcohol for 10in men is an intake of >60–80 g/d of alcohol for 10
years, while women are at increased risk foryears, while women are at increased risk for
developing similar degrees of liver injury bydeveloping similar degrees of liver injury by
consuming 20–40 g/d. Ingestion of 160 g/d isconsuming 20–40 g/d. Ingestion of 160 g/d is
associated with 25–fold increased risk of developingassociated with 25–fold increased risk of developing
alcoholic cirrhosis.alcoholic cirrhosis.
5. Risk FactorsRisk Factors
Quantity: In men, 40–80 g/d of ethanol produces fattyQuantity: In men, 40–80 g/d of ethanol produces fatty
liver; 160 g/d for 10–20 years causes hepatitis orliver; 160 g/d for 10–20 years causes hepatitis or
cirrhosis. Only 15% of alcoholics develop alcoholiccirrhosis. Only 15% of alcoholics develop alcoholic
liver disease.liver disease.
Gender: Women exhibit increased susceptibility toGender: Women exhibit increased susceptibility to
alcoholic liver disease at amounts >20 g/d.alcoholic liver disease at amounts >20 g/d.
Hepatitis C: HCV infection concurrent with alcoholicHepatitis C: HCV infection concurrent with alcoholic
liver disease is associated with younger age forliver disease is associated with younger age for
severity, more advanced histology, decreased survival.severity, more advanced histology, decreased survival.
Even moderate alcohol intake of 20–50 g/d increasesEven moderate alcohol intake of 20–50 g/d increases
the risk of cirrhosis and hepatocellular cancer in HCV-the risk of cirrhosis and hepatocellular cancer in HCV-
infected individuals.infected individuals.
6. Risk FactorsRisk Factors
Genetics: Alcoholism is more common inGenetics: Alcoholism is more common in
monozygotic than dizygotic twins. However,monozygotic than dizygotic twins. However,
polymorphisms in the genes involved in alcoholpolymorphisms in the genes involved in alcohol
metabolism, such as aldehyde dehydrogenase (ALD),metabolism, such as aldehyde dehydrogenase (ALD),
have yet to be linked to alcoholic liver disease.have yet to be linked to alcoholic liver disease.
Malnutrition: Alcohol injury does not requireMalnutrition: Alcohol injury does not require
malnutrition, but obesity and fatty liver from themalnutrition, but obesity and fatty liver from the
effect of carbohydrate on the transcriptional controleffect of carbohydrate on the transcriptional control
of lipid synthesis and transport may be factors.of lipid synthesis and transport may be factors.
Patients should receive vigorous attention.Patients should receive vigorous attention.
7. Metabolism of AlcoholMetabolism of Alcohol
Alcohol is metabolised almost exclusively by theAlcohol is metabolised almost exclusively by the
liver via one of two main pathways.liver via one of two main pathways.
Eighty per cent of alcohol is metabolised toEighty per cent of alcohol is metabolised to
acetaldehyde by the mitochondrial enzyme,acetaldehyde by the mitochondrial enzyme,
alcohol dehydrogenase (ADH). Acetaldehydealcohol dehydrogenase (ADH). Acetaldehyde
forms adducts with cellular proteins informs adducts with cellular proteins in
hepatocytes which activate the immune system,hepatocytes which activate the immune system,
leading to cell injury. Acetaldehyde is thenleading to cell injury. Acetaldehyde is then
metabolised to acetyl-CoA and acetate by ALD.metabolised to acetyl-CoA and acetate by ALD.
This generates NADH from NAD (nicotinamideThis generates NADH from NAD (nicotinamide
adenine dinucleotide), which changes the redoxadenine dinucleotide), which changes the redox
potential of the cell.potential of the cell.
8. Metabolism of AlcohalMetabolism of Alcohal
The remaining 20% is metabolised by the mixed functionThe remaining 20% is metabolised by the mixed function
oxidase enzymes of the smooth endoplasmic reticulum.oxidase enzymes of the smooth endoplasmic reticulum.
Cytochrome CYP2E1 is an enzyme which oxidises ethanol toCytochrome CYP2E1 is an enzyme which oxidises ethanol to
acetate. It is induced by alcohol, and during metabolism ofacetate. It is induced by alcohol, and during metabolism of
ethanol it releases oxygen free radicals, leading to lipidethanol it releases oxygen free radicals, leading to lipid
peroxidation which can induce mitochondrial damage. Theperoxidation which can induce mitochondrial damage. The
CYP2E1 enzyme also metabolises acetaminophen and henceCYP2E1 enzyme also metabolises acetaminophen and hence
chronic alcoholics are more susceptible to hepatotoxicity fromchronic alcoholics are more susceptible to hepatotoxicity from
low doses of paracetamol.low doses of paracetamol.
It is thought that pro-inflammatory cytokines may also beIt is thought that pro-inflammatory cytokines may also be
involved in inducing hepatic damage in alcoholic hepatitis,involved in inducing hepatic damage in alcoholic hepatitis,
since endotoxin is released into the blood because of increasedsince endotoxin is released into the blood because of increased
gut permeability, leading to release of TNF-α, IL-1, IL-2 andgut permeability, leading to release of TNF-α, IL-1, IL-2 and
IL-8 from immune cells. All of these cytokines have beenIL-8 from immune cells. All of these cytokines have been
implicated in the pathogenesis of liver fibrosis.implicated in the pathogenesis of liver fibrosis.
9. PathologyPathology
Alcohol can produce a wide spectrum of liverAlcohol can produce a wide spectrum of liver
disease from fatty change to hepatitis anddisease from fatty change to hepatitis and
cirrhosis.cirrhosis.
10. Pathology- Fatty liverPathology- Fatty liver
The metabolism of alcohol invariably produces fat in the liver.The metabolism of alcohol invariably produces fat in the liver.
This is minimal with small amounts of alcohol, but with largerThis is minimal with small amounts of alcohol, but with larger
amounts, the cells become swollen with fatamounts, the cells become swollen with fat (steatosis(steatosis) giving) giving
eventually, a Swiss-cheese effect on haematoxylin and eosineventually, a Swiss-cheese effect on haematoxylin and eosin
stain. Steatosis can also be seen in obesity, diabetes, starvationstain. Steatosis can also be seen in obesity, diabetes, starvation
and occasionally in chronic illness . There isand occasionally in chronic illness . There is no liver cellno liver cell
damagedamage. The fat disappears on stopping alcohol.. The fat disappears on stopping alcohol.
In some cases collagen is laid down around the central hepaticIn some cases collagen is laid down around the central hepatic
veins (perivenular fibrosis) and this can sometimes progress toveins (perivenular fibrosis) and this can sometimes progress to
cirrhosis without a preceding hepatitis. Alcohol directly affectscirrhosis without a preceding hepatitis. Alcohol directly affects
stellate cells, transforming them into collagen-producingstellate cells, transforming them into collagen-producing
myofibroblast cells. Cirrhosis might then develop if there is anmyofibroblast cells. Cirrhosis might then develop if there is an
imbalance between degradation and production of collagen.imbalance between degradation and production of collagen.
11. Pathology- Alcoholic HepatitisPathology- Alcoholic Hepatitis
In addition to fatty change there is infiltration byIn addition to fatty change there is infiltration by
polymorphonuclear leucocytes and hepatocytepolymorphonuclear leucocytes and hepatocyte
necrosis. Dense cytoplasmic inclusions callednecrosis. Dense cytoplasmic inclusions called
Mallory bodiesMallory bodies are sometimes seen in hepatocytesare sometimes seen in hepatocytes
andand giant mitochondriagiant mitochondria are also a feature.are also a feature.
Mallory bodies are suggestive of, but not specific for,Mallory bodies are suggestive of, but not specific for,
alcoholic damage as they can be found in other liveralcoholic damage as they can be found in other liver
disease, such as Wilson's disease and Primary Biliarydisease, such as Wilson's disease and Primary Biliary
Cirrhosis. If alcohol consumption continues,alcoholicCirrhosis. If alcohol consumption continues,alcoholic
hepatitis may progress to cirrhosis.hepatitis may progress to cirrhosis.
12. Pathology- Alcoholic CirrhosisPathology- Alcoholic Cirrhosis
This is classically of the micronodular type,This is classically of the micronodular type,
but a mixed pattern may also be seenbut a mixed pattern may also be seen
accompanying fatty change, and evidence ofaccompanying fatty change, and evidence of
pre-existing alcoholic hepatitis may be present.pre-existing alcoholic hepatitis may be present.
13. Clinical Features- Fatty liverClinical Features- Fatty liver
There are often no symptoms or signs. VagueThere are often no symptoms or signs. Vague
abdominal symptoms of nausea, vomiting andabdominal symptoms of nausea, vomiting and
diarrhoea are due to the more general effectsdiarrhoea are due to the more general effects
of alcohol on the gastrointestinal tract.of alcohol on the gastrointestinal tract.
Hepatomegaly, sometimes huge, can occurHepatomegaly, sometimes huge, can occur
together with other features of chronic livertogether with other features of chronic liver
disease.disease.
14. Clinical Features- Alcoholic HepatitisClinical Features- Alcoholic Hepatitis
The clinical features vary in degree:The clinical features vary in degree:
The patient may be well, with few symptoms, the hepatitis onlyThe patient may be well, with few symptoms, the hepatitis only
being apparent on the liver biopsy in addition to fatty change.being apparent on the liver biopsy in addition to fatty change.
Mild to moderate symptoms of ill-health, occasionally withMild to moderate symptoms of ill-health, occasionally with
mild jaundice, may occur. Signs include all the features ofmild jaundice, may occur. Signs include all the features of
chronic liver disease. Liver biochemistry is deranged and thechronic liver disease. Liver biochemistry is deranged and the
diagnosis is made on liver histology.diagnosis is made on liver histology.
In the severe case, usually superimposed on patients withIn the severe case, usually superimposed on patients with
alcoholic cirrhosis, the patient is ill, with jaundice and ascites.alcoholic cirrhosis, the patient is ill, with jaundice and ascites.
Abdominal pain is frequently present, with a high feverAbdominal pain is frequently present, with a high fever
associated with the liver necrosis. On examination there is deepassociated with the liver necrosis. On examination there is deep
jaundice, hepatomegaly, sometimes splenomegaly, and ascitesjaundice, hepatomegaly, sometimes splenomegaly, and ascites
with ankle oedema.with ankle oedema.
15. Clinical Features- Alcoholic cirrhosisClinical Features- Alcoholic cirrhosis
This represents the final stage of liver diseaseThis represents the final stage of liver disease
from alcohol abuse. Nevertheless, patients canfrom alcohol abuse. Nevertheless, patients can
be very well with few symptoms. Onbe very well with few symptoms. On
examination, there are usually signs of chronicexamination, there are usually signs of chronic
liver disease. The diagnosis is confirmed byliver disease. The diagnosis is confirmed by
liver biopsy.liver biopsy.
Alcohol-induced cirrhosis often presents withAlcohol-induced cirrhosis often presents with
a serious complication such as variceala serious complication such as variceal
haemorrhage or ascites.haemorrhage or ascites.
16. Laboratory InvestigationLaboratory Investigation
The typical laboratory abnormalities seen in fattyThe typical laboratory abnormalities seen in fatty
liver are nonspecific and include modest elevations ofliver are nonspecific and include modest elevations of
the aspartate aminotransferase (AST), alaninethe aspartate aminotransferase (AST), alanine
aminotransferase (ALT), and gamma-glutamylaminotransferase (ALT), and gamma-glutamyl
transpeptidase (GGTP), accompanied bytranspeptidase (GGTP), accompanied by
hypertriglyceridemia, hypercholesterolemia, andhypertriglyceridemia, hypercholesterolemia, and
occasionally hyperbilirubinemia.occasionally hyperbilirubinemia.
In alcoholic hepatitis and in contrast to other causesIn alcoholic hepatitis and in contrast to other causes
of fatty liver, the AST and ALT are usually elevatedof fatty liver, the AST and ALT are usually elevated
two- to sevenfold. They are rarely >400 IU, and thetwo- to sevenfold. They are rarely >400 IU, and the
AST/ALT ratio >1AST/ALT ratio >1
17. Laboratory InvestigationLaboratory Investigation
Hyperbilirubinemia is common and is accompaniedHyperbilirubinemia is common and is accompanied
by modest increases in the alkaline phosphatase level.by modest increases in the alkaline phosphatase level.
Derangement in hepatocyte synthetic functionDerangement in hepatocyte synthetic function
indicates more serious disease. Hypoalbuminemiaindicates more serious disease. Hypoalbuminemia
and coagulopathy are common in advanced liverand coagulopathy are common in advanced liver
injury.injury.
Ultrasonography is useful in detecting fattyUltrasonography is useful in detecting fatty
infiltration of the liver and determining liver size. Theinfiltration of the liver and determining liver size. The
demonstration by ultrasound of portal vein flowdemonstration by ultrasound of portal vein flow
reversal, ascites, and intraabdominal collateralsreversal, ascites, and intraabdominal collaterals
indicates serious liver injury with less potential forindicates serious liver injury with less potential for
complete reversal of liver disease.complete reversal of liver disease.
18. ManagementManagement
Complete abstinence from alcohol is the cornerstoneComplete abstinence from alcohol is the cornerstone
in the treatment of alcoholic liver disease. Improvedin the treatment of alcoholic liver disease. Improved
survival and the potential for reversal of histologicsurvival and the potential for reversal of histologic
injury regardless of the initial clinical presentation areinjury regardless of the initial clinical presentation are
associated with total avoidance of alcohol ingestion.associated with total avoidance of alcohol ingestion.
Referral of patients to experienced alcohol counselorsReferral of patients to experienced alcohol counselors
and/or alcohol treatment programs should be routineand/or alcohol treatment programs should be routine
in the management of patients with alcoholic liverin the management of patients with alcoholic liver
disease.disease.
19. ManagementManagement
Attention should be directed to the nutritional andAttention should be directed to the nutritional and
psychosocial states during the evaluation andpsychosocial states during the evaluation and
treatment periods. Because of data suggesting that thetreatment periods. Because of data suggesting that the
pathogenic mechanisms in alcoholic hepatitis involvepathogenic mechanisms in alcoholic hepatitis involve
cytokine release and the perpetuation of injury bycytokine release and the perpetuation of injury by
immunologic processes, glucocorticoids have beenimmunologic processes, glucocorticoids have been
extensively evaluated in the treatment of alcoholicextensively evaluated in the treatment of alcoholic
hepatitis.hepatitis.
Patients with severe alcoholic hepatitis, defined as aPatients with severe alcoholic hepatitis, defined as a
discriminant function > 32, were given prednisolone,discriminant function > 32, were given prednisolone,
32 mg/d, for 4 weeks followed by a steroid taper .32 mg/d, for 4 weeks followed by a steroid taper .
20. ManagementManagement
Pentoxifylline, which has a weak anti-TNF action,Pentoxifylline, which has a weak anti-TNF action,
may also be beneficial and is alternative to themay also be beneficial and is alternative to the
corticosteroid in severe alcoholic hepatitis. It appearscorticosteroid in severe alcoholic hepatitis. It appears
to reduce the incidence of hepatorenal failure and itsto reduce the incidence of hepatorenal failure and its
use is not complicated by sepsis.use is not complicated by sepsis.
In the acute presentation of alcoholic liver disease itIn the acute presentation of alcoholic liver disease it
is also important to identify and anticipate alcoholis also important to identify and anticipate alcohol
withdrawal and Wernicke's encephalopathy, whichwithdrawal and Wernicke's encephalopathy, which
need treating in parallel with the liver diseaseneed treating in parallel with the liver disease
21. ManagementManagement
Treatment for complications of cirrhosis, suchTreatment for complications of cirrhosis, such
as variceal bleeding, encephalopathy andas variceal bleeding, encephalopathy and
ascites, may also be needed.ascites, may also be needed.
A trial of abstention to establish if liver diseaseA trial of abstention to establish if liver disease
can improve is mandatory, but transplantationcan improve is mandatory, but transplantation
should not be denied if the patient continues toshould not be denied if the patient continues to
deteriorate.deteriorate.
22. Liver TransplantationLiver Transplantation
The role of liver transplantation in the management ofThe role of liver transplantation in the management of
alcoholic liver disease remains controversial. In manyalcoholic liver disease remains controversial. In many
centres, however, alcoholic liver disease is a commoncentres, however, alcoholic liver disease is a common
indication for liver transplantation. The challenge isindication for liver transplantation. The challenge is
to identify patients with an unacceptable risk ofto identify patients with an unacceptable risk of
returning to harmful alcohol consumption.returning to harmful alcohol consumption.
Many programmes require a 6-month period ofMany programmes require a 6-month period of
abstinence from alcohol before a patient is consideredabstinence from alcohol before a patient is considered
for transplantationfor transplantation
23. Liver TransplantationLiver Transplantation
Although this relates poorly to the incidence ofAlthough this relates poorly to the incidence of
alcohol relapse after transplantation, liver functionalcohol relapse after transplantation, liver function
may improve to the extent that transplantation is nomay improve to the extent that transplantation is no
longer necessary.longer necessary.
The outcome of transplantation for alcoholic liverThe outcome of transplantation for alcoholic liver
disease is good (if the patient remains abstinent)disease is good (if the patient remains abstinent)
because minimal immunosuppression is oftenbecause minimal immunosuppression is often
required and there is no risk of disease recurrence.required and there is no risk of disease recurrence.
Transplantation for alcoholic hepatitis has a poorerTransplantation for alcoholic hepatitis has a poorer
outcome than for complications of alcoholic cirrhosis.outcome than for complications of alcoholic cirrhosis.
24. PrognosisPrognosis
Critically ill patients with alcoholic hepatitis haveCritically ill patients with alcoholic hepatitis have
short-term (30 day) mortality rates >50%. Severeshort-term (30 day) mortality rates >50%. Severe
alcoholic hepatitis is heralded by coagulopathyalcoholic hepatitis is heralded by coagulopathy
(prothrombin time > 5 s), anemia, serum albumin(prothrombin time > 5 s), anemia, serum albumin
concentrations <25 g/L (2.5 mg/dL), serum bilirubinconcentrations <25 g/L (2.5 mg/dL), serum bilirubin
levels > 137 mol/L (8 mg/dL), renal failure, andlevels > 137 mol/L (8 mg/dL), renal failure, and
ascites.ascites.
AA discriminant functiondiscriminant function calculated as 4.6 xcalculated as 4.6 x
[prothrombin time control (seconds)] + serum[prothrombin time control (seconds)] + serum
bilirubin (mg/dL) can identify patients with a poorbilirubin (mg/dL) can identify patients with a poor
prognosis (discriminant function > 32).prognosis (discriminant function > 32).
25. PrognosisPrognosis
The presence of ascites, variceal hemorrhage,The presence of ascites, variceal hemorrhage,
deep encephalopathy, or hepatorenal syndromedeep encephalopathy, or hepatorenal syndrome
predicts a dismal prognosis. The pathologicpredicts a dismal prognosis. The pathologic
stage of the injury can be helpful in predictingstage of the injury can be helpful in predicting
prognosisprognosis
Liver biopsy should be performed wheneverLiver biopsy should be performed whenever
possible to confirm the diagnosis, to establishpossible to confirm the diagnosis, to establish
potential reversibility of the liver disease, andpotential reversibility of the liver disease, and
to guide the therapeutic decisions.to guide the therapeutic decisions.
26. ReferencesReferences
Harrison’s Principle of Internal Medicine 17Harrison’s Principle of Internal Medicine 17thth
editionedition
Davidson’s Principle and Practice of MedicineDavidson’s Principle and Practice of Medicine
2121stst
editionedition
Kumar and Clark Clinical Medicine 6Kumar and Clark Clinical Medicine 6thth
editionedition