Alcohol abuse and hematologic disorders

Literature review current through: Aug 2014. | This topic last updated: Jun 13, 2013.

INTRODUCTION
Alcohol abuse is generally defined as chronic consumption of more than 80 grams of alcohol per
day.
This translates into a daily intake of one of the following: approximately 250 mL of hard liquor,
more than 500 mL of fortified wine, one bottle (750 mL) of table wine, or 1.5 liters of beer (four 12
ounce cans or bottles).
Alcohol abuse can have a variety of effects on the hematologic system, including macrocytosis
with or without anemia, leukopenia, and/or thrombocytopenia.
How this occurs is not completely understood.
A direct toxic effect on hematopoietic cells, abnormalities in membrane phospholipids, and
interference with folate utilization all may be involved [2,3].
MECHANISM OF ALCOHOL TOXICITY
The adverse effects of alcohol on hematopoiesis may be mediated in part by metabolites of
alcohol (ethanol).
Ingested ethanol is metabolized in the liver in part by alcohol dehydrogenase, which oxidizes
alcohol to acetaldehyde, while reducing NAD to NADH
It has been suggested that acetaldehyde accounts for some of the hematologic toxicity of alcohol
Acetaldehyde can produce RBC protein-acetaldehyde adducts [4], which may generate immune
responses against these modified proteins.
Indeed, IgA and IgM anti-acetaldehyde-protein adducts have been found in alcoholics with
macrocytic red cells.
MANIFESTATIONS OF HEMATOLOGIC TOXICITY
The clinical manifestations of alcohol-induced hematologic disorders are profoundly influenced by
the patient's social and economic status, and the presence or absence of other factors, such
nutritional deficiency or alcoholic cirrhosis.
Most of these changes result, either directly or indirectly, in anemia.
As an example, if extensive liver disease is present, the patient may develop an abnormally
functioning fibrinogen or other coagulation disorders, which may initiate or exacerbate bleeding.
(See "Disorders of fibrinogen", section on 'Liver disease' and "Coagulation abnormalities in
patients with liver disease", section on 'Hypocoagulability in cirrhosis'.)
ANEMIA Alcohol abuse, coupled with the patients social and economic status, can lead to
anemia via the following:
If the patient also has a chronic infection (eg, tuberculosis), the anemia of chronic disease may
be present. (See "Anemia of chronic disease (anemia of [chronic] inflammation)".) Treatment of
the underlying infection(s) will reverse this component of the patient's anemia.
The presence of cirrhosis can lead to bleeding from esophageal and gastric varices; bleeding
can also occur from alcoholic gastritis. Continued bleeding may eventually lead to iron deficiency
anemia. (See "Causes and diagnosis of iron deficiency anemia in the adult".)
The presence of portal hypertension may lead to congestive splenomegaly (hypersplenism), with
splenic trapping of red cells, white cells, and/or platelets and resulting cytopenia(s). (See "Extrinsic
nonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis and
hypersplenism".)
Alcohol abuse is probably the most common cause of nutritional folate deficiency in the United
States, leading to a megaloblastic anemia [1,2]. (See "Etiology and clinical manifestations of
vitamin B12 and folate deficiency".)
Alcohol directly interferes with erythropoiesis and blocks the response to folate in subjects who are
folate deficient. Both macrocytosis (see below) and stomatocytosis are regular features on the
peripheral blood smear [6,7]. (See "Stomatocytosis", section on 'Etiology'.)
Macrocytosis Even before anemia appears, approximately 90 percent of alcoholics have a
macrocytosis (mean corpuscular volume [MCV] between 100 to 110 femtoliters [fL]) which is easily
detected by automated counters [1,2,8]. Alcohol-induced macrocytosis occurs even though
patients are folate and cobalamin replete and do not have liver disease. The mechanism is
unknown, but it takes two to four months for the macrocytosis to disappear after the patient
becomes abstinent.
Attribution of macrocytosis to alcohol abuse requires the exclusion of other causes of this
abnormality. The most common are megaloblastic anemia (eg, B12 or folate deficiency), liver
disease, hypothyroidism, use of antimetabolite drugs, and myelodysplastic syndromes (table 1).
(See "Macrocytosis", section on 'Alcoholism'.)
As an example, in a study of 300 patients in a New York City hospital who had a MCV >100 fL, the
most common causes were drugs (frequently for treatment of HIV) and alcohol abuse [9]. Less
common causes were liver disease and elevated reticulocytes. Megaloblastic anemia accounted
for less than 10 percent of cases.
Alcoholism can sometimes be difficult to distinguish from megaloblastic anemia due to folate or
cobalamin deficiency. The latter diagnoses are suggested by the findings of an MCV above 110 fL,
macroovalocytosis of the circulating red cells, teardrop-shaped red cells, and hypersegmented
neutrophils on the blood smear (ie, more than 5 percent of neutrophils having five lobes) (picture
1A-B) [8,9]. Measurement of the serum cobalamin level and red blood cell folate levels will usually
establish the appropriate diagnosis. Measurement of serum folate is not used in this setting, since
alcohol lowers the folate level even in patients who are not truly deficient. (See "Diagnosis and
treatment of vitamin B12 and folate deficiency".)
Treatment of alcohol-induced macrocytosis, with or without anemia, is abstinence. Return of the
MCV to normal also confirms the diagnosis.
Decreased red cell production As noted above, anemia in alcoholic patients is often
multifactorial [1]. In addition to the direct toxic effect of alcohol, iron deficiency due to
gastrointestinal bleeding, nutritional folate deficiency from the effects of a poor diet, and the
anemia of chronic disease may be present. Each of these disorders impairs RBC production,
which should be associated with a low or low normal reticulocyte count. (See "Anemias due to
decreased red cell production".)
Hemolysis Although decreased red cell production is generally responsible for the anemia,
there may also be a hemolytic component in some alcoholic patients. Two factors may contribute
to this problem [2]:
Splenic sequestration due to an enlarged spleen (see "Extrinsic nonimmune hemolytic anemia
due to mechanical damage: Fragmentation hemolysis and hypersplenism")
Spur cell hemolysis in severe alcoholic cirrhosis (see "Extrinsic nonimmune hemolytic anemia
due to systemic disease"). In an interesting case report, orthotopic liver transplant cured the spur
cell anemia, which recurred when the patient resumed alcohol abuse and the liver graft failed,
implicating both liver failure and alcohol abuse as causes of spur cell anemia [6].
Bone marrow examination A bone marrow aspiration and biopsy are usually unnecessary in
the anemia associated with alcohol abuse. If obtained, approximately one-fourth of patients will
show the presence of ringed sideroblasts in erythroid precursors (picture 2) [1]. Very heavy alcohol
consumption may also be associated with the appearance of vacuoles in proerythroblasts and
granulocytic precursors, the cause of which is unknown [2]. As an example, in a series of 144
patients from Finland, 24 percent of severe alcohol abusers had vacuolated proerythroblasts [7].
(See "Causes of congenital and acquired sideroblastic anemias", section on 'Alcohol'.)
The marrow may also become distinctly hypoplastic [10] and even aplastic with pancytopenia [11].
Abstinence results in reversal of the hypoplasia.
LEUKOPENIA Alcoholics appear to be immunocompromised and are susceptible to recurrent
infections [2]. Leukopenia, due to a fall in the neutrophil count, occurs in approximately 8 percent
of hospitalized alcoholics, and there may also be a hard-to-characterize defect in neutrophil
function. The presence of alcoholic cirrhosis, portal hypertension, and splenomegaly can further
lower the white blood cell count (ie, hypersplenism).
THROMBOCYTOPENIA In some series, as many as 80 percent of hospitalized alcoholics have
mild thrombocytopenia, defined as a platelet count below 150,000/microL [2]. An enlarged spleen
in the patient with alcoholic cirrhosis is thought to play an important role, but alcohol also has a
direct toxic effect on megakaryocytes [2]. The platelet count rarely falls below 10,000/microL; as a
result, splenectomy to control thrombocytopenic bleeding is almost never necessary [2]. In some
patients, platelet function may also be abnormal. (See "Congenital and acquired disorders of
platelet function", section on 'Liver disease' and "Coagulation abnormalities in patients with liver
disease", section on 'Platelet level and function'.)
Rebound thrombocytosis The combination of alcohol abstinence and ingestion of a
reasonable diet (typically occurring after hospitalization) often results in a platelet "rebound" at one
to two weeks, with the platelet count often reaching 600,000 to 900,000/microL. This is a normal
and transient response to the prior episode of thrombocytopenia, and does not require
hematologic consultation or treatment. The platelet count returns to normal levels within another 7
to 10 days without further therapy [2].
IRON OVERLOAD Although the mechanism(s) involved are unclear, excess ingestion of
alcohol leads to increased absorption of iron from the gastrointestinal tract, with deposition in the
liver. The resulting accumulation of iron can lead to oxidative damage, cell death, fibrogenesis,
and such complications as fatty liver, alcoholic hepatitis, cirrhosis, and an increased risk for
hepatocellular carcinoma [12,13]. (See "Pathophysiology and diagnosis of iron overload
syndromes", section on 'Iron toxicity' and "Clinical manifestations and diagnosis of alcoholic fatty
liver disease and alcoholic cirrhosis".)
As a result, those who abuse alcohol may have increased serum ferritin concentrations, often
making it difficult to distinguish this pattern of hepatic iron overload from that seen in patients with
hereditary hemochromatosis (HH). Determination of hepatic iron via quantitative phlebotomy, liver
biopsy, and/or use of noninvasive T2* MRI techniques indicates that, although increased, hepatic
iron levels in those with alcoholic liver disease are significantly lower than that seen in patients
with HH. (See "Pathophysiology and diagnosis of iron overload syndromes", section on 'MRI and
SQUID techniques' and "Pathophysiology and diagnosis of iron overload syndromes", section on
'Distinction from alcoholic liver disease'.)
Interaction with existing genetic abnormalities Excess alcohol intake, with or without
hepatic iron accumulation, is a risk factor for the worsening of a number of genetic disorders, such
as the following:
Acute intermittent porphyria Ethanol is a known inducer of hepatic delta-aminolevulinic acid
synthase (ALAS1), the rate-limiting enzyme for heme synthesis in the liver. As a result, alcohol is a
risk factor for provoking neurovisceral episodes in the acute porphyrias. (See "Pathogenesis,
clinical manifestations, and diagnosis of acute intermittent porphyria", section on 'Ethanol and
smoking'.)
Hereditary hemochromatosis The increased iron absorption associated with excess alcohol
ingestion is an additive risk factor for hepatic iron overload in patients with hereditary
hemochromatosis, especially those with underlying liver disease. (See "Treatment of hereditary
hemochromatosis", section on 'Avoidance of excessive ethanol'.)
Porphyria cutanea tarda Alcohol abuse has been reported as being an important and
common susceptibility factor in many series of patients with porphyria cutanea tarda. (See
"Porphyria cutanea tarda and hepatoerythropoietic porphyria", section on 'Alcohol'.)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials,
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Here are the patient education articles that are relevant to this topic. We encourage you to print or
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subjects by searching on patient info and the keyword(s) of interest.)
Basics topics (see "Patient information: Vitamin B12 deficiency and folate (folic acid) deficiency
(The Basics)")
SUMMARY AND RECOMMENDATIONS
Definition of alcohol abuse Alcohol abuse has been defined as chronic consumption of more
than 80 grams of ethanol per day, or a daily intake of approximately 250 mL of hard liquor, 500 mL
of fortified wine, 750 mL of table wine, or 1.5 liters of beer (four 12 ounce cans or bottles).
Manifestations The hematologic consequences of alcohol abuse include any or all of the
following:
Anemia, often macrocytic, with components due to decreased red cell production and/or
increased red cell destruction. (See 'Anemia' above.)
Leukopenia, most often due to trapping of leukocytes in an enlarged spleen (ie, hypersplenism).
(See 'Leukopenia' above.)
Thrombocytopenia, often due to hypersplenism, although platelet dysfunction may be present in
some individuals. (See 'Thrombocytopenia' above.)
Increased bleeding due to an acquired coagulopathy. (See "Coagulation abnormalities in patients
with liver disease", section on 'Hypocoagulability in cirrhosis'.)
Complicating factors Additional factors which may affect the degree of hematologic
derangement in the subject with alcohol abuse include the following:
Poor diet, with resulting folate deficiency
Coexisting infection
Advanced liver disease, with bleeding varices, hypersplenism, acquired coagulopathy
Differential diagnosis The differential diagnosis in a patient with varying degrees of
macrocytic anemia and cytopenias includes the following:
Deficiencies of folate and/or cobalamin
Myelodysplastic syndrome
Drug toxicity
Treatment There is no effective treatment for the hematologic consequences of alcohol abuse
other than cessation of alcohol intake along with resumption of an adequate diet.
Macrocytic anemia may take many months to disappear after cessation of alcohol intake.
The hematologic manifestations secondary to portal hypertension and hypersplenism (eg,
bleeding varices, cytopenias) may remain unchanged.
Alcohol abstinence and ingestion of a reasonable diet may result in a temporary period of
rebound thrombocytosis. (See 'Rebound thrombocytosis' above.)