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Alcohol abuse and hematologic disorders.docx

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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
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  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 patient’s social and economic status, can lead to anemia via the following: ●If the patient also has a chro nic 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 pr  esence 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, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written  in plain language, at the 5 th  to 6 th  grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th  to 12 th  grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of 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 po rtal 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.)
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