Nitrogen economy in alcoholic patients without liver disease

Nitrogen

Economy in Alcoholic D.Bunout,

Nitrogen

M. Petermann,

balance was studied in five alcoholic patients

Patients

G. Ugarte,

Without Liver Disease

G. Barrera,

and H. lturriaga

during alcohol consumption

and after

1 or 2 weeks

of abstinence,

under metabolic ward conditions. Patients had a history of excessive ethanol intake for five years or more. They were intoxicated and otherwise asymptomatic on admission and had been drinking 150 g or more of ethanol daily, for at least one month. Subjects consumed a diet providing vitamins and minerals exceeding RDA values, 45 kcal/kg of body weight and 0.6 g/kg of proteins (as egg protein), for 33 days. During the first 11 days patients received 200 g of ethanol that were isocalorically substituted later by dietary fat and carbohydrates. The results of this study show that, in alcoholic patients while drinking and after seven days of alcohol withdrawal, nitrogen balance is significantly decreased compared to that performed after two weeks of abstinence. Ethanol metabolic rate was found to be increased, compared to controls. It was lower in four of five patients after the second week of abstinence. These results suggest that alcohol abuse increases protein requirements in chronic alcoholic patients even without histologic liver disease or clinical signs of gastroenterologic disorders. o 1987 by Grune & Stratton, Inc.

S

HORT PERIODS of excessive alcohol intake in normal volunteers receiving a marginal normal protein diet do not alter significantly nitrogen (N) balance.’ However, prolonged alcohol intake in the rat, induces an increased urinary N excretion, producing a negative balance.‘-4 Chronic alcoholism in humans is often associated with failure, intestinal malabsorption5.6 and liver or pancreatic which may also alter significantly N economy.’ The metabolic effects of chronic alcoholism on N balance, independent of liver and pancreatic failure or gastrointestinal disease have not been studied in alcoholic patients. To what extent chronic alcoholism can generate protein catabolism despite a normal protein, calorie, vitamin, and mineral supply is also not known. The

present

study

aims

to test

the

hypothesis

that

N

economy is altered in chronic inveterate alcoholics without signs of gastroenterologic disease while drinking. Subjects were studied during ethanol administration and in subsequent periods of abstinence in a metabolic ward. MATERIALS

AND METHODS

Subjects Five chronic alcoholic patients admitted to the Alcoholism Ward of Paula Jaraquemada Hospital were studied. They had a history of alcoholism for at least five years and were all intoxicated on admission. Subjects had drunk more than 150 g of ethanol daily during the previous month or quarter. Their body weight was normal and they did not have clinical or laboratory signs of overt liver damage or other diseases. Experimental

Design

After admission and upon receipt of a written informed consent from the patient and a close relative. the patients were transferred to a metabolic ward and studied during 33 days, divided in three periods of I 1 days each (Fig 1). They were allowed to perform light physical activity. Patients consumed a diet that provided Efhanol ndminisrration. 45 kcal/kg body weight including calories provided by 200 g of ethanol (20%, w/v solution) given in six divided doses and 0.6 g/kg of protein as egg protein. The diet was supplemented with vitamins and minerals to comply generously with recommended dietary allowances.’ Abstinence. Ethanol calories were replaced by fat and carbohydrates maintaining the same energy and protein intake of the first Metabolism,

Vol 36. No 7 IJuly). 1987: pp 651-653

period. To assess the effects of alcohol withdrawal on nitrogen balance, patients were studied during the first and after the second week of ethanol abstinence. A short withdrawal syndrome was observed in some patients. Symptoms were dealt with diazepam orally. Subjects LF and CG received 20 to 60 mg/d during three days, while subject CV took only 20 mg during the first day. The other two patients were managed with supportive care. Diazepam was administered immediately after alcohol abstinence and suspended before the second EMR and N balance. Clinical

and Laboratory

Studies

Routine laboratory tests included total bilirubin, aspartate amino transferase (SCOT), gamma glutamyl transferase ($T). prothrombin time, serum albumin, and fasting blood sugar. These tests were performed on admission (Table I). Nitrogen balance was assessed on the last five days of the ethanol administration period and after five and I7 days of abstinence. This timing was chosen to avoid blood sampling during balance periods and to prevent an immediate effect of this possible stressful situation. Twenty-four-hour urine samples were collected each day in acidified containers; accuracy was controlled by simultaneous creatinine measurements. A fecal marker was given at the beginning and at the end of each period and stools were pooled for N measurement. Kjeldahl’s method was used for urinary and fecal N determinations9 For balance calculations, insensible losses were estimated as 8 mg/kg/d.“’ Ethanol metabolic rate (EMR) was studied after two and I6 days of abstinence. One gram of ethanol/kg body weight was infused IV in 20 minutes and six blood samples were taken thereafter at 30-minute intervals for ethanol enzymatic determination.” EMR was calculated according to Widmark.” The value for EMR in nonalcoholics in our laboratory is 98 + 6.4 mg/kg/h. Liver biopsies were performed at the end of the period of ethanol intake using a Menghini needle. Histologic slides were read. Statistical

Analysis

Results are expressed as mean *SE of the mean. between mean values were compared using two-tailed

Differences Student’s

t

From the Institute of Nutrition and Food Technology, University of Chile, Santiago. Supported by University of Chile DIB Grant M 1.512-8214. Address reprint requests to Daniel Bunout. MD, Box 15138, Santiago Il. Chile. ~1987 by Crune & Stratton, Inc. 0026-0495/87/3607-0008$03.00/O 651

652

BUNOUT ET AL

Table 2. Ingested and Excreted Nitrogen in the Three Five-Day Study Periods Subject

Period*

IngestedN

Urin.wyN

1

4.5

2.8

2a

4.7

2.8

1.03

2b

4.8

2.8

0.84 0.75

LF

Fig 1. Experimental design showing periods of ethanol consumption CXNJg/d) and abstinence. Chronogram of nitrogen (NI balance and ethanol metabolic rate determination (EMRJ. Patients were kept on a diet that provided 45 kcalfkgld and 0.6 g/kg/d of proteins.

test. For differences within the same individual, one-tailed paired f test was used. This protocol was accepted by the Ethics Committee of the Institute of Nutrition and Food Technology, University of Chile.

CG

cu

SG

LM

RESULTS

On admission, none of the patients gave a history or suffered from jaundice, diarrhea, bleeding, ascites or edema. No important laboratory abnormalities were found (Table I). Fasting blood sugar and serum albumin were normal in all subjects. There were no significant changes at the end of the study except for a mean weight gain of 0.56 rt 0.20 kg (P < .OS). Minimal or moderate steatosis or minimal necrosis were the only pathologic findings observed in liver biopsies. No significant change in fecal N was observed in the three periods; urinary N was significantly higher in the ethanol intake period (P < .OS) (Table 2). Estimated N balance was significantly lower during alcohol intake and during the first week of abstinence. It increased significantly only after two weeks of alcohol withdrawal (Fig 2). Ethanol metabolic rate measured two days after ending alcohol consumption was significantly higher than that of nonalcoholic individuals (P < .Ol), and decreased in four of the five subjects after 16 days of abstinence (Table 3). DISCUSSION

The results of this study show that chronic alcoholics, studied while drinking 200 g of ethanol/d and during the first week of abstinence, exhibit a significant derangement in N economy. This disorder in N balance is not dependent on hepatic damage since all the patients showed no clinical, laboratory, or histologic signs of liver disease. The negative N balance does not seem to be due to dietary imbalance. During the study, the patients ingested a diet that

FecalN 0.96

1

4.7

3.4

2a

4.8

3.7

1.12

2b

4.8

3.1

0.98

1

4.6

4.7

1.11

2a

4.9

3.8

0.91

2b

4.9

2.1

0.56

1

6.8

4.4

0.80

2a

6.8

3.1

0.78

2b

6.8

3.1

1.21

1

5.7

5.1

0.70

2a

5.7

4.3

1.34

2b

5.7

3.1

1.23

Values are given as g/d. *Periods: 1, ethanol intake; 2a. first abstinence period; 2b. second abstinence period.

complied with recommended dietary allowances* for proteins, vitamins, and with an energy content similar to that found by dietary surveys in our alcoholic population.‘3 Only carbohydrate and fat calories were replaced by ethanol. Thus, there were no minor vitamin or mineral deficiencies or differences in calories or protein intake, but 2 weeks of alcohol abstinence corrected the N balance disturbances. During the first days of alcohol withdrawal, N balance did not differ from that of the drinking period. Previous studies in our metabolic ward with nonalcoholic subjects of similar low socioeconomic level have not shown consistent improvement of N balance after a prolonged stay.‘4S’sThus, it is unlikely that the better quality of life and nutrition during the study period may have improved N balance in our subjects. An effect of diazepam on N balance in these patients seems highly improbable. Diazepam was administered in low doses before and not during the second balance

Table 1. Clinical and Laboratory Data on Admission Subiects LF

Age (~1 Height (ml

46 1.57

CG

49 1.65

cu

34 1.71

cc

28 1.66

LM

27 1.63

Weight (kg)

47

50

51

71

60

Prothrombin time (46)

70

100

82

100

100

Total bilirubin (mg/dL)

0.67

0.42

0.70

0.34

0.17

Hematocrit (%I

45

42

45

49

SGOT (IU/L)

37

30

42

33

8

y GT (IU/Lj

46

57

35

46

26

49

Fig 2. Nitrogen balance of five alcoholic patients during ethanol intake and after 1 end 2 weeks of abstinence. (Alcohol: ethanol administration. Short abst: first week of alcohol abstinence. Late abst: last week of abstinence). Nitrogen balance during late abstinence is significantly higher than those of alcohol and short abstinence (P < .05).

653

NITROGEN ECONOMY IN ALCOHOLIC PATIENTS

Table 3. Ethanol Metabolic

excessive alcohol drinking in experimental animals has induced a negative N balance.3S4In these studies, as in ours, no increase in fecal N was observed but the alteration Prolonged

Rate After Two and Sixteen

Days of Abstinence Patients

Short Abstinence

Late Abstinence

LF

166.7

156.8

CG

142.4

126.1

cu

159.4

99.6

SC

124.0

110.4

LM

118.0

240.4

Values are 9wen as mg/kg/h.

in this second period, N balance and did not change significantly. Alcoholics usually have a low protein intake. If an adaptation to such intake would have occurred while drinking before admission, it should have been expressed as a low urinary N excretion.16 How excessive ethanol intake decreases N balance is not clear from these observations. It seems though that chronic alcohol abuse is needed, considering that periods of five days of excessive alcohol intake do not modify N balance in man.’ period.

Furthermore,

urinary excretion

in N economy was dependent on increased urinary N excretion3 In man there is only a preliminary report in four chronic alcoholics in whom 2 weeks of ethanol administration induced a decrease in nitrogen balance. Patients’ liver, pancreatic, or gastrointestinal functions were not stated in the abstract.” Our patients showed an increased rate of ethanol metabolism that decreased only after 2 weeks of abstinence in four out of five of them. A significant decrease in EMR with prolonged abstinence has been observed by us and others.‘8*‘9 The negative N balance induced by chronic alcoholism, as the increase in EMR, persists after several days of abstinence. This high EMR may be reflecting a systemic hypermetabolic state leading to a negative N balance. Whatever the mechanism responsible for the negative N balance may be in chronic alcoholics during ethanol intake or recent abstinence, our results suggest that these subjects have higher protein requirements than healthy individuals.

REFERENCES

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