William E. Thornton. M.D. Bonnie J. Pray. R.N.
Lowered serum folate and alcohol-withdrawal syndromes The work of biochemists and internists has generated a body of literature concerned with the folic acid deficiency anemia of alcoholism. I - 6 Thus far. several mechanisms appear to share the responsibility for the effects of alcohol in producing lowered serum folate levels. Some investigators have suggested that the depletion of folate body stores in chronic alcoholism may be caused by malnutrition. hepatocellular damage. intestinal malabsorption. and hepatic enzyme induction. 6 - 14 Additionally.Eichner and Hillman l6 present evidence that alcohol abuse appears to make normal folate stores unavailable for the support of serum levels by interfering with mechanisms necessary for conversion and delivery of the stored form to the circulation. Concomitantly. a growing and controversial body of psychiatric information indicates a relationship between abnormalities of folic acid
metabolism and a variety of mental and emotional disturbances. including confusion. irritability. disorientation. sleep disturbance. depression. and psychosis.1 6 - 26 Since altered mental functions associated with alcohol-withdrawal syndromes include similar items. we have reason to survey patients for evidence of an association between lowered serum folate concentrations and psychophysiologic manifestations of alcohol withdrawal.
Method One hundred thirty-one patients were admitted to a private hospital medical service in a middle-class resort community for treatment of physical dependence on alcohol. All had ingested alcohol persistently and excessively for more than one year. and in each case hospitalization was recommended because the history of alcohol use prompted concern for the
Dr. Thornton is all associate professor in psychiatry and associate professor in family practice at the Medical University of South Carolina. Ms. Pray is a psychiatric nurse and research associate in private practice. Reprint requests to Dr. Thornton. 171 Ashley Avenue. Charleston. SC 29403.
32
dangers of an acute physical withdrawal syndrome. The patients-60 men and 71 womenranged from 28 to 69 years of age. The mean ages for the men and women were 47 and 48 years. respectively. All patients received a standard chemotherapeutic regimen. On the first day. they received 50 mg chlordiazepoxide intramuscularly (I.M.) every 6 hours. I gm magnesium sulfate I.M. and 100 mg thiamine hydrochloride I.M. Beginning with the second hospital day and continuing through discharge. each received 50 mg thiamine orally per day. and 50 to 75 mg chlordiazepoxide orally every 6 hours. Alternatives to this regimen were a flexible and progressively decreasing chlordiazepoxide dosage schedule as symptoms allowed. and intramuscular chlordiazepoxide as required for behavioral management. Intravenous diazepam was used to treat convulsions. Medical history taken on admission included questions concerning the use of drugs thought to influence folate ab-
DECEM BER 1977
sorption and metabolism. such as estrogen compounds, anticonvulsants. and barbiturates. Laboratory screening tests of liver function were done on admission and again at clinically indicated intervals when compromised hepatic function was evident. Fasting serum folate values were estimated within 24 hours of admission. Blood samples were analyzed by Archibald's29 technique. using a radioisotopic competitive binding method. Serum values of less than 5 ng per ml were considered low. although some patients with serum values in the 3 to 5 ng per ml range may have no evidence of folate deficiency or may be borderline.
Nurses' technique A nurses' alcohol-withdrawal observation and classification technique was specifically developed for use by a psychiatric nurse. who evaluated patients directly once every day and also reviewed daily nursing notes on the patients' charts. The nurses' classification technique was designed to facilitate transformation of assembled observations descriptive of alcohol-withdrawal behavior (as clinically observed and characterized in the literature) into classical medical withdrawal syndromes. 3o •31 The nurse observer assessed clinical symptoms and signs during alcohol withdrawal. and then derived an intelligent and uniform diagnosis. Table I itemizes the types of behavior observed among the 131 patients during the process of alcohol withdrawal. Table 2 categorizes the clinical observations into five basic behavioral groups: autonomic. psychological. perceptual. confusional.
PSYCHOSOMATICS
Table 1-0bservations descriptive of behavior Intention tremor Weakness Perspiration Nausea Anorexia Vomiting Diarrhea Anxiety Apprehension Irritability Gross tremulousness Hostility Insomnia illusions Ideas of reference
P ychomotor agitation Blood pr ure elevation Tachycardia Fever Grand mal Izures Incontinence (fecal or urinary) Confusion Disorientation Social Incompetence
self-care Incompetence Garbled speech Delu Ion Hallucination Stereotyped-repetitive motor activity
Table 2-Categorization of clinical observations Intention tremor Weakness Perspiration Nausea Anorexia Vomiting
all ( Anxiety Apprehen Ion Irritability
Diarrhea Gross tremulousn Incontinence (fecal or urinary) Blood pressure elevation Tachycardia Fever
I) Hostility Psychomotor agitation Insomnia
illusions Ideas of reference Delusions
Hallucination (visual. olfactory auditory. tactile)
Garbled speech Confusion Disorientation
Social Incompetence Self-care Incompetence Stereotyped-repetitive motor activity
Grand mal seizures
33
Serum folate and convulsive. Table 3 shows the final conversion of the nursing observations into four medically traditional diagnostic withdrawal syndromes: alcoholic tremor. alcoholic hallucinosis. delirium tremens. and withdrawal seizures (rum fits). The diagnosis of withdrawal seizures assumes that a medical evaluation has excluded causes other than the direct effect of alcohol withdrawal. Early in the study. it became obvious that the differentiation of alcoholic tremor from no significant manifestations of alcohol withdrawal required more definition than the nurses' classification device would allow. Accordingly. it was determined that for a nurse to make a diagnosis of alcoholic tremor. a minimum of three items each from the autonomic and psychological observation categories would be required.
Results Among the 131 patients admitted for treatment of prob-
able physical dependency on alcohol. 95 were diagnosed by the nurses' observation and classification device to have experienced an alcohol-withdrawal syndrome. Thirty-five of the 131 patients did not experience sufficient symptoms and signs of alcohol withdrawal to allow a traditional medical diagnosis. Table 4 summarizes the diagnoses and the numbers of patients with serum folate values of less than 5 ng per ml. None of these patients had used barbiturates. anticonvulsants. or estrogen compounds. Abnormal liver function tests. as determined by serum glutamic oxaloacetic transaminase (SGOT) values of greater than 60 international milliunits. were found in 61 of the 131 patients. Of these 61 patients. 23 (38%) had serum folate values of less than 5 ng per ml. When the elevated liver function tests were assigned to the diagnostic categories. it was found that 30 of the 36 patients diagnosed as having delirium
tremens also had elevated hepatic enzymes. Of the 6 patients with withdrawal seizures. 4 had liver-enzyme elevations: of the 3 with alcoholic hallucinosis. 2 did: of the 51 with alcoholic tremor. 15 did: and of the 35 with no withdrawal syndrome. 12 had liver enzyme elevations. The mean age of the total patient population was 48 years. but the mean age of the 36 patients diagnosed as having delirium tremens was 55 years.
Discussion These results provide additional incentive for studying the relevance of lowered serum folate values to the prevalence and severity of alcohol-withdrawal syndromes. Specifically. the data indicate an increased likelihood of psychophysiologic abstinence manifestations in the presence of lowered serum folate levels. If these patients indeed suffer from a biochemical folate deficiency state. the controversial role of folate deficiency as a cause of mental dys-
Table 3-Conversion of categorized clinical observations into medically traditional diagnostic withdrawal syndromes
34
DECEMBER 1977
I
I
Table 4-Alcohol withdrawal diagnosis and serum folate values
None Alcoholic tremor Alcoholic halluclno Dellrlumtremen Withdrawal selzur Total
35 51 3 38 8 131
28 33 2 28 8
(80%)
(85%) (87%) (72%) (100%)
95 (73%)
7 18 1 10
o
(20%) (35%) (33%) (28%) (0%) (27%)
• ng .. nanograms .. 10' om
functions would be given additional support. The data support the clinical merits of examining the serum of alcohol-dependent patients for lowered folate concentrations and administering parenteral folic acid as part of the medical management of alcohol detoxification. The lack of withdrawal seizures among low folate patients is in keeping with Reynolds'32 reports of increased seizure frequency among folate-treated epileptic patients: however, the seizure patient sample is obviously too small to warrant further consideration. Additionally. the prevalence of abnormal liver-function chemistries and advanced age among the delirium tremens patients may serve a predictive value in management of similar patient populations. The nurses' alcohol-withdrawal observation and classification technique proved instructive to nursing personnel. as they were able to develop more precise mechanisms for translating behavioral observation to uniform diagnosis. Also. the de-
PSYCHOSOMA TICS
vice was useful in its assessment of severity along a continuum of alcohol withdrawal. By observing the continuum of alcoholwithdrawal states. the needs and timing of treatment adjustments become increasingly predictable. The nurses observation technique supports the importance of viewing alcohol withdrawal from a severity-continuum perspective.33
REFERENCES I. Sullivan LW. Herbert V: Suppression of hematopoiesis by ethanol. J ('/ill 11It"I!Jt 43( II ):2048-2062. 1964. ~ Leevy CM et al: B-complex vitamins in liver disease of the alcoholic. Am J Clill NUlr 16(4):339346. 1965. 3. Eichner. ER: The hematologic disorders of alcoholism. Am J Med 54:621-630. 1973. 4. Straus DJ: Hematologic aspects of alcoholism. Sl!minars ill HemaIIIlol(Y 10: 183-194. 1973. 5. Davis RE. Smith BK: Pyridoxal and folate deficiency in alcoholics. Med J Au.Hralia 2:357-360. 1974. 6. Klipstein FA. Lindenbaum J: Folate deficiency in chronic liver disease. Blood 25(4):443-456. 1965. 7. Dellcr DJ. Kimber CL. Ibbotson RN: Folic acid deficiency in cirrhosis of the liver. Nek' SerieJ 10( I ):35-42. 1965.
K. Herbert V. Zalusky R. Davidson
CS: Correlillion of folate deficiency with alcoholism and associated macrocytosis. anemia. and liver disease. Alln 1111 Med 5K(6):977-988. 1963. 9. Cherrick GR et al: Observations on hepatic avidity for folate in Laennec's cirrhosis. J Lab Clin Med 66(3):446-451. 1965. 10. Longstreth GF. Newcomer AD: Subject review: Drug-induced malabsorption. Mayo C/inic Proc 50: 284-292. 1975. II. Halsted CH et al: Intestinal malabsorption in folate-deficient alcoholics. Cia.Hwelllewlog.r 64:526-532. 1973.
12. Latham AN et al: Liver enzyme induction by anticonvulsant drugs and its relationship to disturbed calcium and folic acid metabolism. J Clin Pharm 33:337-342. 1973. 13. Richens A: Enzyme induction and folate deficiency. Brit Med J 1:567. 1972. 14. Scott J: Macrocytosis of chronic alcoholism. Lancet I: 1297. June 22. 1974. 15. Eichner ER. Hillman RS: Effect of alcohol on serum folate level. J C/in 11I~·e.\·t 52:584-591. 1973. 16. Herbert V: Experimental nutritional folate deficiency in man. Trans A Am Phy.,idam 75:307-320. 1972. 17. Strachan RW. Henderson JG: Dementia and folic acid deficiency. Quart J M I!d 36: 189-704. 1967. 18. Kallstrom T: Serum B'7 and folate concentrations in mental patients.
.'·;a/lllljiJ/ale A,·ta Psrchiat Scand 45: 19-36. 1969. 19. Reynolds EH. Preele JM. Bailey J. et al: Folate deficiency in depressive illness. Brit J Psychiat 117:2117-292. 1970. 20. Hunter R. Jones M. Jones TG. et al: Serum B" and folate concentrations in mental patients. Brit J Psychiat 113:1291-1295.1967. 21. Carney MWP: Serum folate values in 423 psychiatric patients. Brit Med J 4:512-516.1967. " Reynolds EH: Schizophrenia-like psychosis of epilepsy and disturhances of folate and vitamin B" meta holism induced hy anticonvulsant drugs. Brit J Psychiat 113:911919. 1967. 23. Reynolds EH. Preece J. Johnson AO: Folate metaholism in epileptic and psychiatric patients. J Neural N"urtJsurlf P.
Lowered serum folate and alcohol-withdrawal syndromes The work of biochemists and internists has generated a body of literature concerned with the folic acid deficiency anemia of alcoholism. I - 6 Thus far. several mechanisms appear to share the responsibility for the effects of alcohol in producing lowered serum folate levels. Some investigators have suggested that the depletion of folate body stores in chronic alcoholism may be caused by malnutrition. hepatocellular damage. intestinal malabsorption. and hepatic enzyme induction. 6 - 14 Additionally.Eichner and Hillman l6 present evidence that alcohol abuse appears to make normal folate stores unavailable for the support of serum levels by interfering with mechanisms necessary for conversion and delivery of the stored form to the circulation. Concomitantly. a growing and controversial body of psychiatric information indicates a relationship between abnormalities of folic acid
metabolism and a variety of mental and emotional disturbances. including confusion. irritability. disorientation. sleep disturbance. depression. and psychosis.1 6 - 26 Since altered mental functions associated with alcohol-withdrawal syndromes include similar items. we have reason to survey patients for evidence of an association between lowered serum folate concentrations and psychophysiologic manifestations of alcohol withdrawal.
Method One hundred thirty-one patients were admitted to a private hospital medical service in a middle-class resort community for treatment of physical dependence on alcohol. All had ingested alcohol persistently and excessively for more than one year. and in each case hospitalization was recommended because the history of alcohol use prompted concern for the
Dr. Thornton is all associate professor in psychiatry and associate professor in family practice at the Medical University of South Carolina. Ms. Pray is a psychiatric nurse and research associate in private practice. Reprint requests to Dr. Thornton. 171 Ashley Avenue. Charleston. SC 29403.
32
dangers of an acute physical withdrawal syndrome. The patients-60 men and 71 womenranged from 28 to 69 years of age. The mean ages for the men and women were 47 and 48 years. respectively. All patients received a standard chemotherapeutic regimen. On the first day. they received 50 mg chlordiazepoxide intramuscularly (I.M.) every 6 hours. I gm magnesium sulfate I.M. and 100 mg thiamine hydrochloride I.M. Beginning with the second hospital day and continuing through discharge. each received 50 mg thiamine orally per day. and 50 to 75 mg chlordiazepoxide orally every 6 hours. Alternatives to this regimen were a flexible and progressively decreasing chlordiazepoxide dosage schedule as symptoms allowed. and intramuscular chlordiazepoxide as required for behavioral management. Intravenous diazepam was used to treat convulsions. Medical history taken on admission included questions concerning the use of drugs thought to influence folate ab-
DECEM BER 1977
sorption and metabolism. such as estrogen compounds, anticonvulsants. and barbiturates. Laboratory screening tests of liver function were done on admission and again at clinically indicated intervals when compromised hepatic function was evident. Fasting serum folate values were estimated within 24 hours of admission. Blood samples were analyzed by Archibald's29 technique. using a radioisotopic competitive binding method. Serum values of less than 5 ng per ml were considered low. although some patients with serum values in the 3 to 5 ng per ml range may have no evidence of folate deficiency or may be borderline.
Nurses' technique A nurses' alcohol-withdrawal observation and classification technique was specifically developed for use by a psychiatric nurse. who evaluated patients directly once every day and also reviewed daily nursing notes on the patients' charts. The nurses' classification technique was designed to facilitate transformation of assembled observations descriptive of alcohol-withdrawal behavior (as clinically observed and characterized in the literature) into classical medical withdrawal syndromes. 3o •31 The nurse observer assessed clinical symptoms and signs during alcohol withdrawal. and then derived an intelligent and uniform diagnosis. Table I itemizes the types of behavior observed among the 131 patients during the process of alcohol withdrawal. Table 2 categorizes the clinical observations into five basic behavioral groups: autonomic. psychological. perceptual. confusional.
PSYCHOSOMATICS
Table 1-0bservations descriptive of behavior Intention tremor Weakness Perspiration Nausea Anorexia Vomiting Diarrhea Anxiety Apprehension Irritability Gross tremulousness Hostility Insomnia illusions Ideas of reference
P ychomotor agitation Blood pr ure elevation Tachycardia Fever Grand mal Izures Incontinence (fecal or urinary) Confusion Disorientation Social Incompetence
self-care Incompetence Garbled speech Delu Ion Hallucination Stereotyped-repetitive motor activity
Table 2-Categorization of clinical observations Intention tremor Weakness Perspiration Nausea Anorexia Vomiting
all ( Anxiety Apprehen Ion Irritability
Diarrhea Gross tremulousn Incontinence (fecal or urinary) Blood pressure elevation Tachycardia Fever
I) Hostility Psychomotor agitation Insomnia
illusions Ideas of reference Delusions
Hallucination (visual. olfactory auditory. tactile)
Garbled speech Confusion Disorientation
Social Incompetence Self-care Incompetence Stereotyped-repetitive motor activity
Grand mal seizures
33
Serum folate and convulsive. Table 3 shows the final conversion of the nursing observations into four medically traditional diagnostic withdrawal syndromes: alcoholic tremor. alcoholic hallucinosis. delirium tremens. and withdrawal seizures (rum fits). The diagnosis of withdrawal seizures assumes that a medical evaluation has excluded causes other than the direct effect of alcohol withdrawal. Early in the study. it became obvious that the differentiation of alcoholic tremor from no significant manifestations of alcohol withdrawal required more definition than the nurses' classification device would allow. Accordingly. it was determined that for a nurse to make a diagnosis of alcoholic tremor. a minimum of three items each from the autonomic and psychological observation categories would be required.
Results Among the 131 patients admitted for treatment of prob-
able physical dependency on alcohol. 95 were diagnosed by the nurses' observation and classification device to have experienced an alcohol-withdrawal syndrome. Thirty-five of the 131 patients did not experience sufficient symptoms and signs of alcohol withdrawal to allow a traditional medical diagnosis. Table 4 summarizes the diagnoses and the numbers of patients with serum folate values of less than 5 ng per ml. None of these patients had used barbiturates. anticonvulsants. or estrogen compounds. Abnormal liver function tests. as determined by serum glutamic oxaloacetic transaminase (SGOT) values of greater than 60 international milliunits. were found in 61 of the 131 patients. Of these 61 patients. 23 (38%) had serum folate values of less than 5 ng per ml. When the elevated liver function tests were assigned to the diagnostic categories. it was found that 30 of the 36 patients diagnosed as having delirium
tremens also had elevated hepatic enzymes. Of the 6 patients with withdrawal seizures. 4 had liver-enzyme elevations: of the 3 with alcoholic hallucinosis. 2 did: of the 51 with alcoholic tremor. 15 did: and of the 35 with no withdrawal syndrome. 12 had liver enzyme elevations. The mean age of the total patient population was 48 years. but the mean age of the 36 patients diagnosed as having delirium tremens was 55 years.
Discussion These results provide additional incentive for studying the relevance of lowered serum folate values to the prevalence and severity of alcohol-withdrawal syndromes. Specifically. the data indicate an increased likelihood of psychophysiologic abstinence manifestations in the presence of lowered serum folate levels. If these patients indeed suffer from a biochemical folate deficiency state. the controversial role of folate deficiency as a cause of mental dys-
Table 3-Conversion of categorized clinical observations into medically traditional diagnostic withdrawal syndromes
34
DECEMBER 1977
I
I
Table 4-Alcohol withdrawal diagnosis and serum folate values
None Alcoholic tremor Alcoholic halluclno Dellrlumtremen Withdrawal selzur Total
35 51 3 38 8 131
28 33 2 28 8
(80%)
(85%) (87%) (72%) (100%)
95 (73%)
7 18 1 10
o
(20%) (35%) (33%) (28%) (0%) (27%)
• ng .. nanograms .. 10' om
functions would be given additional support. The data support the clinical merits of examining the serum of alcohol-dependent patients for lowered folate concentrations and administering parenteral folic acid as part of the medical management of alcohol detoxification. The lack of withdrawal seizures among low folate patients is in keeping with Reynolds'32 reports of increased seizure frequency among folate-treated epileptic patients: however, the seizure patient sample is obviously too small to warrant further consideration. Additionally. the prevalence of abnormal liver-function chemistries and advanced age among the delirium tremens patients may serve a predictive value in management of similar patient populations. The nurses' alcohol-withdrawal observation and classification technique proved instructive to nursing personnel. as they were able to develop more precise mechanisms for translating behavioral observation to uniform diagnosis. Also. the de-
PSYCHOSOMA TICS
vice was useful in its assessment of severity along a continuum of alcohol withdrawal. By observing the continuum of alcoholwithdrawal states. the needs and timing of treatment adjustments become increasingly predictable. The nurses observation technique supports the importance of viewing alcohol withdrawal from a severity-continuum perspective.33
REFERENCES I. Sullivan LW. Herbert V: Suppression of hematopoiesis by ethanol. J ('/ill 11It"I!Jt 43( II ):2048-2062. 1964. ~ Leevy CM et al: B-complex vitamins in liver disease of the alcoholic. Am J Clill NUlr 16(4):339346. 1965. 3. Eichner. ER: The hematologic disorders of alcoholism. Am J Med 54:621-630. 1973. 4. Straus DJ: Hematologic aspects of alcoholism. Sl!minars ill HemaIIIlol(Y 10: 183-194. 1973. 5. Davis RE. Smith BK: Pyridoxal and folate deficiency in alcoholics. Med J Au.Hralia 2:357-360. 1974. 6. Klipstein FA. Lindenbaum J: Folate deficiency in chronic liver disease. Blood 25(4):443-456. 1965. 7. Dellcr DJ. Kimber CL. Ibbotson RN: Folic acid deficiency in cirrhosis of the liver. Nek' SerieJ 10( I ):35-42. 1965.
K. Herbert V. Zalusky R. Davidson
CS: Correlillion of folate deficiency with alcoholism and associated macrocytosis. anemia. and liver disease. Alln 1111 Med 5K(6):977-988. 1963. 9. Cherrick GR et al: Observations on hepatic avidity for folate in Laennec's cirrhosis. J Lab Clin Med 66(3):446-451. 1965. 10. Longstreth GF. Newcomer AD: Subject review: Drug-induced malabsorption. Mayo C/inic Proc 50: 284-292. 1975. II. Halsted CH et al: Intestinal malabsorption in folate-deficient alcoholics. Cia.Hwelllewlog.r 64:526-532. 1973.
12. Latham AN et al: Liver enzyme induction by anticonvulsant drugs and its relationship to disturbed calcium and folic acid metabolism. J Clin Pharm 33:337-342. 1973. 13. Richens A: Enzyme induction and folate deficiency. Brit Med J 1:567. 1972. 14. Scott J: Macrocytosis of chronic alcoholism. Lancet I: 1297. June 22. 1974. 15. Eichner ER. Hillman RS: Effect of alcohol on serum folate level. J C/in 11I~·e.\·t 52:584-591. 1973. 16. Herbert V: Experimental nutritional folate deficiency in man. Trans A Am Phy.,idam 75:307-320. 1972. 17. Strachan RW. Henderson JG: Dementia and folic acid deficiency. Quart J M I!d 36: 189-704. 1967. 18. Kallstrom T: Serum B'7 and folate concentrations in mental patients.
.'·;a/lllljiJ/ale A,·ta Psrchiat Scand 45: 19-36. 1969. 19. Reynolds EH. Preele JM. Bailey J. et al: Folate deficiency in depressive illness. Brit J Psychiat 117:2117-292. 1970. 20. Hunter R. Jones M. Jones TG. et al: Serum B" and folate concentrations in mental patients. Brit J Psychiat 113:1291-1295.1967. 21. Carney MWP: Serum folate values in 423 psychiatric patients. Brit Med J 4:512-516.1967. " Reynolds EH: Schizophrenia-like psychosis of epilepsy and disturhances of folate and vitamin B" meta holism induced hy anticonvulsant drugs. Brit J Psychiat 113:911919. 1967. 23. Reynolds EH. Preece J. Johnson AO: Folate metaholism in epileptic and psychiatric patients. J Neural N"urtJsurlf P.
