A 52 year old Caucasian man was brought to the emergency room in an inebriated state by the Medical Emergency Service who found him lying in the street. The history was not initially obtainable and physical examination revealed the following: blood pressure, 100/70; pulse 110/min; respiration 28/min, temp. 990 F. He was lethargic but arousable. He was markedly pale and cachectic with icteric (jaundiced) conjunctiva and skin. Pupils were reactive and fundoscopic (retinal) examination was normal. His tongue was depapillated and dry. His neck was supple and there was no lymphadenopathy (enlarged lymph nodes). His lungs were clear. The heart appeared slightly enlarged by percussion. There was moderate tachycardia with a grade II apical systolic murmur. His abdomen was distended and there was shifting dulness indicating ascites. The liver was enlarged ~ 4 cm below the right costal margin and tender. The spleen could not be palpated. There was 2+ bilateral edema of his legs and feet. There were no apparent focal neurologic defects.
Laboratory Findings:
Hemogram: hemoglobin, 10 g/dl; hematocrit, 34%; red cells, 2.8 x 106/l; mean corpuscular volume (MCV), 121 fl (normal 80-96); mean corpuscular hemoglobin (MCH), 36 pg/cell (normal, 27-33); mean corpuscular hemoglobin concentration (MCHC), 32 % (normal 28-34 %); red cell distribution width, 23 % (normal, 11.5-14.5 %); leukocyte count, 15,000/l (normal 4000-10,000) with 85 % neutrophils, 10 % lymphocytes, 5 % monocytes; platelets, 80,000/l; (normal 150,000-40,000/l). The peripheral blood smear contained macro-ovalocytes, tear-drop red cells, small schizocytes (abnormal shape) and reduced platelets.
Blood chemistries: glucose, 50 mg/dl (normal, 60-110). Electrolytes, blood urea nitrogen (BUN), creatinine, calcium and phosphorous were normal. Total protein: 5.0 G/dl; albumin, 2.3 G/dl (normal 4.0 G/dl); globulin, 2.7 G/dl bilirubin, 7.5 mg/dl with 5.0 mg/dl conjugated and 1.7 mg/dl unconjugated; liver enzymes were elevated with lactic dehydrogenase extremely high (>2000 units); Urinalysis: positive for bilirubin.
Stool: negative for blood.
Serum folate: 0.5 ng/ml (normal>5.0 ng/ml); red cell folate, 50 ng/ml (normal >200 ng/ml). Serum vitamin B12, 1,500 pg/ml (normal, 200-800 pg/ml).
Intravenous fluids containing glucose and normal electrolytes constituted initial treatment. When the patient became coherent after a few days, a more complete history indicated that he was a heavy alcohol drinker for several years, consuming at least a pint of whisky daily on periodic binges. During these periods, his food intake was reduced and limited to bread and occasionally chicken but no fresh vegetables and rarely red meat or fish.
Discussion:
1.The hypoglycemia is an expression of the interference of excess alcohol ingestion on glucose metabolism.
2.The role of chronic alcoholism on protein malnutrition is indicated by the cachexia and low serum albumin.
3.The toxic effect of alcohol on the liver is indicated by the clinical evidence for hepatitis (i.e., jaundice, enlarged tender liver and elevated hepatic enzymes).
4. A key problem for this patient is is an inadequate intake of folate because the alcohol substitutes for an adequate diet. Other vitamin deficiencies may also occur depending on the severity of the malnutrition.
Click here to read background in folate metabolism.
Impaired folate uptake. The most important cause of impaired folate absorption in chronic alcoholics is secondary to the defective replication of the epithelial mucosa as a consequence of the vitamin deficiency. Abnormal epithelial membranes extending from the oral cavity through the small intestine have been observed in folate deficiency (and vitamin B12 deficiency) and this abnormal "megaloblastic" cellular replication is the same as that which occurs in hematopoiesis and which is responsible for the macrocytic anemia.
There has also been some evidence for impaired absorption of folates from food in alcoholism. Folic acid contains, as part of its structure, a glutamic acid residue -- the main serum form of folate is the monoglutamate. The gamma-carbon of folate can form amide bonds with other glutamates and the dietary form of folic acid is polyglutamyl folic acid. This form is poorly transported by cells of lgut or liver. In order for such folates to be absorbed from the proximal small intestine, the glutamate residues must be hydrolyzed. A membrane-bound gamma-glutmayl hydrolase on the brush borders catlyzes this hydrolysis. Only the folyl monoglutamates are efficiently absorbed. This enzyme may be deficient in chronic alcoholism.
The anemia in folate (and vitamin B12) deficiency is characterized by macrocytic erythrocytes secondary to abnormal proliferation and maturation of the erythroid precursors (called megaloblasts) in the bone marrow. There is early death of such cells (apoptosis) that is referred to as intramedullary hemolysis (or ineffective erythropoiesis). Actually, in severe deficiency, defective development of the myeloid and megakaryocytic cell lines may also occur. This "ineffective hematopoiesis" is responsible for the high lactic dehydrogenase in the plasma because the apoptotic cells release this enzyme.
Alcohol may also have a direct toxic effect on folate metabolism but the precise mechanism has not been defined. Whereas patients who are folate deficient may respond to as little as 25-50 g of folic aciddaily, if they are given alcohol at the same time, a therapeutic response to folate requires a higher dose of the vitamin.
Review of nutritional requirement. The daily requirement for folate varies with age, gender, pregnancy, lactation etc. The recommended intake for an adult is 200 g of "free" (absorbable folate). This means the folyl polyglutamates in the diet have to be converted to the monoglutamate to provide the "free" folate of which ~ 50 % should be absorbed.
The daily biological turnover of folate is ~ 50 g/day. If total stores approximate ~ 510,000 g, the lack of folate in the diet (as in this patient) will result in clinical evidence of folate deficiency in 200 days. If stores are lower, clinical folate deficiency will occur more rapidly.
Vitamin B12 deficiency is not usually seen as a consequence of chronic alcoholism. The liver injury secondary to alcohol usually raises the serum B12 concentration because the injury to the liver results in the release of the vitamin into the plasma.
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