ALCOHOL-INDUCED HYPOGLYCEMIA

and (_ ALCOHOLIC KETOACIDOSIS

- A REVIHJ -

LEONARD L. MADISON

j l ., c A L C 0 H 0 L I C H Y P 0 G L Y C E M I A

I. INTRODUCTION AND HISTORICAL REVIEW

It has been kn01~n for years that hypoglycemia may mimic the clinical picture l of acute alcoholic intoxication. However, until relatively recently it has escaped general recognition that alcohol can induce profound,and at times fatal, hypoglycemia. 1. In 1941, Brown and Harvey first described as a distinct clinical syndrome the occurrence of profound hypoglycemi a following ingestion of alcoholic beverages in six malnourished alcoholics. Athough they erroneously attributed the ensuing hypoglycemia to contaminants

(methanol 4.3%, gasolene 0.8%, ethyl acetate 3.s:n in the denatured .. ( alcohol ("smoke") which their patients ingested, their report served l two important purposes. First, it focused attention on the problem of hypoglycemic coma in alcoholics. Second, it defined many of the

salient clinical features of the syndrome (1).

2. In 1949 Bottura, Neves, et al described eleven cases of profound hypoglycemia following alcoholic debauches. This was the first good clinical evidence that the hypoglycemia was secondary to the ethanol

~ 3 since the local brandy consumed by their patients was s ho1~n to • •I be free of contaminating toxic substances (1).

3. In 1950, eighteen additional cases were reported from Brazil (Neves,

et al~ including the first documented occurrence of ethanol-induced hypoglycemia in a child following accidental inges tion of brandy. l -2- .,

Between 1958-1961, seven additional cases were reported in children I· c 1 between the ages of three to six years after accidental consumption of wine, brandy and gin (1).

5. Convulsions as a major manifestation of ethanol-induced hypoglycemia was evident from the report of Cummins in the USA and Talis in Greece.

6. Final proof confirming the clini ca l impression that ethanol per se rather than any toxic contaminants was responsible for the ensuing hypoglycemia came in 1963 from the experimental production of the syndrome with pure ethanol by Field et al, by Freinkel et al in

chronic al coho lics and by Lochner and Madison in dogs (1).

II. AHARErJESS OF THE CLINICAL SYNDROME OF ETHANOL-INDUCED HY POGLYCEt1IA AS J ( EVIJENCED BY REPORTED CASES (REF 1) 1 REPORTS OF ETHANOL-INDUCED HYPOGLYCEMIA (Cumulative) · YEAR TOTAL ADULTS CHILDREN NO . OF COUNTRIES J 1940- 49 24 24 0 2 -r To 1959 54 51 3 5 i To 1965 101 89 12 9

COUNTRIES AND NUMBER OF CASES REPORTED TO 1965

l. Antilles- 1 6. Rep. S. Africa - 23* 2. Brazi 1 - 29* 7. Sweden - 2 3. England - 2 8. Uraguay - 2 4. France - 2 9. USA - 36* 5. Greece - 4 *87 % from 3 countries

l -3- .. ( CONCLUSIONS FROM LITERATURE REVIEW TO 1965 l. The paucity of reports belied the true frequency of this potentially lethal disturbance of carbohydrate metabolism. The infrequent reports from England, France and Sweden and the absence of reports from Germany, Spain, Portugal, Austria and other countries where per capita alcohol consumption is significant (15-25 L/yr/adult) suggested not that ethanol-induced hypoglycemia was rare or absent in these areas but rather that the familiarity with the syndrome was lacking and cases were being misdiagnosed or undiagnosed (1).

2. Where physicians have been alert to its occurrence and aware of its manifold and often bizarre manifestations, large numbers of cases have been observed in short periods of time as evidenced by the ( fo l lowing:

a. 29 cases reported from Brazil by Bottura and Neves within a two year period.

b. 23 cases were described by Neame and Joubert ( 1961) •li thin a 10 month period of time in South Africa. By 1965 Neame per­ sonally had studied 52 cases which he used as a basis for his dissertation. c. By 1965 only 3 cases were reported from France. Hithin another two years the tota l increased to 18, twelve of which were reported from the Hotel-Dieu i n Paris by one group of investigators (Dorf, Bour and colleagues).

( o . d. From 1964-67 about 18-24 cases per year were seen in the PMH emergency room. Kreisberg cl aims it is the one of most frequent forms of hypoglycemia found in a large metropolitan emergency room. t~eame and Joubert stated that it was the commonest cause of fasting hypoglycemia in South Africa .

(_ 1 -4- .,

INCREASED (?} A~JAREi~ESS OF ALCOHOL- INDUCED HYPOGL YCEmA ( FROM 1965 - 1975

REPORTS OF ALCOHOL-INDUCED HYPOGLYCEMIA (ref 1-16) (Cumulative)

YEARS TOTAL ADULTS CHILDREN NO. OF CO U ~ TRIE S 1940-49 24 24 0 2 To 1959 54 51 3 5 To 1965 101 89 12 C) TO 1975 237 202 35 15

COUNTRIES REPORTI NG CASES TO 1975 (ref 1-16 )

l. Anti 11 es 6. Greece 11. Rep . S. Africa (52 }* 2. Argentina 7 . . Hungary 12. S11eden 3. Brazil (29)* 8. Italy 13 . S~titzer 1and 4. England 9. Japan 14. Uraguay 5. France (18)* 10. Portuga 1 15. USA (49}* * 62% from 4 Countries .J ( ] III. SETTING IN WHICH ETHANOL-INDUCED HYPOGLYCEMIA OCCURS x 2> A. OCCURREflCE OF ETHANOL-INDUCED HYPOGLYCEMIA 1. Chronic malnourished vitamin-depleted alcohol ic 2. Weekend or binge drinker 3. Occassional drinker - social drinker 4. Children after accidental ingestion. l1 B. HYPERSUSCEPTIBI LITY TO ETHANOL-INDUCED HYPOGLYCEMIA

1. Infants and children 2. Adolescents 3. Following muscular exercise J 4. Endocrine disorders Addison's Disease 1 Pituitary Deficiency Hyperthyroidism Diabetics on Insulin or oral agents c. PREREQUISITE - FA STING-+ LIVER GLYCOGEN DEPLETION Clinical ly in adults a variabl e period of fasting of at least 14-24 hours but often longer precedes the development of hypogl ycemia after imbibing alcoholic beverages. In the hypersusceptible group an over­ ( night fast or less is sufficient. Deglycogenation of the liver is prerequisite and this takes variable amounts of time depending on the patients' age, and underlying clinical condition. 1 -5- ,, ( D. LATENT PERIOD FROM LAST DRINK TO HYPOGLYCEMIC CO MA 1. Hypoglycemia may occur during drinking spree. 2. Hypoglycemia often appears 5-20 hours after last ingestion of alcohol. 3. In many patients the transition from alcoholi c stup or to hvoo ­ gl ycem ic coma is imperceptible. The drunk one puts to bed at night may be ne xt morning's corpse from hypoglycemia. 4. Alternatively, the patient may awaken from alcoholic stupor and have a lucid in terval for minutes to 7 ho urs only to pass again into uncons ciousness from hypoglycemia. 5. Young children and adolescents seem espec ially hypersusceptible to ethanol-induced hypoglycemia. Both the previous period of fa sti ng and the latent period from the time of ingestion of ethanol to hypoglycemic coma are significantly foreshortened in this group of patients. SUr1MARY .I WHEN HYPOGLYCEMIA OCCURS DEPENDS UPON : a. The state of liver glycogen at start of drinking spree b. The duration of drinking spree (and t he conti nued fast) c. The magnitude of blood alcohol at end of drinking spree d. Continued fasting after drinking has stopped .I ( IV. CLINICAL FEATURES OF ETHANOL-INDUCED HYPOGLYCEMIA ' The clinical features that characterize ethanol-induced hypoglycemia are no different from those produced by hypoglycemia of any etiology. Hypo glycemia may masquerade as almost any neurologic sy ndrome and mimic any psyc hiatric disorder. Its manifestations may vary from subtle mental changes to bizarre neurological changes with coma, convulsions and death.

SYMPTOMS AND SIGNS OF HYPOGLYCEMIA

I. Changes in Appetite - Driven Hunger or Nau sea and .Anorexia II. Hypothermia

l -6- .,

I I I. Sympathetic Discharge - Hyperepinephrinemia 1 c Restlessness Sweating Anxiety Tachycardia Palpitations Tremulousness IV. CNS- Inadequate Cerebral Delivery of Glucose j Mental Disturbances- Personality Changes Slow cerebration Negativism Irritability Bizarre behavior Aggressiveness Disorders of speech and gait Somnolent-Agitated State Somnolence alternating with agitated states (tumbling, writhing, ye lling) Monoplegias, hemipl.egias, blindness Incoordination of eye muscles Positive Babinski Deep Coma Flaccidity or decerebrate rigidity Cold moist skin .l Hypothermia Trismus l Extensor rigidity Convulsions

MOST COMMON NEUROLOGICAL FINDINGS IN ALCOHOL-INDUCED HYPOGLYCEMIA COMA -I l. Hypothermia 2. Trismus 3. Convulsions (especially in children) 4. Conjugate deviation of the eyes 5. Extensor rigidity of the extremities 6. Babinski - unilateral or bilateral The clinical picture on admission frequently suggests cerebra- vascular accidents, encephalitis, tetanus, meningitis, brain tumor, epilepsy, subarachnoid hemorrhage or trauma to the bra in . Especially in infants and children are convulsions a frequent complication, occurring in more than half of the reported cases. -7- .,

DIFFERENTIAL DIAGNOSIS OF COMA, COfNULSIOrlS AND NEUROLOGIC DISORDERS 1:-\ c ALCOHOLICS

I. Metaboli c a. Acute alcoholic intoxication b. Alcohol ~1ithdrawal Synd·romes - tremulous, halluci na tory, convul s ive and delerious states c. Wernicke 's Encephalopathy - Cerebral Beri Beri d. Pellagra e. Acute dilution hyponatremia f. Hepatic encephalopathy g. PoisQnings - methanol, isopropyl alcohol, glycols, etc. h. Hypogl ycem ia i. Hypophosphatemia II. Non-metabolic - Brain Trauma Subdural hematoma, concussion, meningeal artery bleeding, etc.

Remember that alcohol-induced hypoglycemi a may occur co ncurrently with acute alcoholic intoxication, early withdrawal symptoms or Wernicke's ( encephalopathy.

In all cases a plasma glucose should be obtained and unless hyp erglycemia or glycosuria are present, IV glucose should be administered.

CAUSES OF HYPOGLYCEMIA IN ALCOHOLICS (ref l) l . Al coho l-induced 2. Hepatic Necrosis 3. Hepatic venou s congestion 4. Hepatoma ,in cirrhotics J. 5. Iatrogenic - large IV amounts of glucose stopped abruptly ) i BLOOD ALCOHOL VS BLOOD GLUCO SE In only 35 cases were simultaneous data on blood glucose and blood ethanol concentrations reported. -8- ., BLOOD GLUCOSE VS BLOOD ETHANOL ( •(482) •(312) E 0 • 0 '- • ) 0'1 E • _J 180 0 • • z 160 .. • <( 140 ., I 1- 120 • w 100 • • • • 80 ' • 0 . • 0 60 • 0 • • _J 40 • • (]) • 20 •• • • 10 15 20 25 30 35 40 45 ( BLOOD GLUCOSE (mg/100 ml)

1. No correlation between blood glucose and ethanol concentrations was · apparent. This is in accord with the clinical histories. 2. In all but 4 instances blood ethanol levels were too low to account for coma from ethanol per se.

3. T~o-thirds of the patients had blood ethanol levels below 150 mg / 100 ml. 4. Profound hypoglycemia with blood glucose values below 25 mg/100 ml occurred with blood ethanol levels less than 60 mg %. .J 5. Lochner and Madison showed that ethanol-induced hypoglycemia can be produced in dogs with blood ethanol levels between 10 and 20 mg / I 100 ml. In the 52 patients studied by Neame, most had only slightly elevated blood alcohol levels.

Acidosi s in Ethanol-Induced Hypoglycemia - Status as reported in 1968 (Madison- ref 1) Plasma bicarbonate was recorded in only a small fraction of the reported 1 -9-

cases. However where it was measured, plasma bicarbonate was less than l c 15 mEq / L in l/3 of the cases. In about 17 % of the cases plasma bicarbonate ' was below 9 mEq/L. Since urinary ketones were frequently positive, ketonemic

acidosis was suspected. However because ECF volume frequently was de pleted, a~ J element of lactic acidosis was also suspected (1). In addition, the acetic acid resulting from hepatic metabolism of ethanol was considered to add to the systemic acidosis since more than 80% of the acetate formed in the liver appeared in hepatic venous effluent. j It was concluded that only further studies could define the frequency, . magnitude and cause of the metabolic acidosis which may accompany alcoho l­ induced hypoglycemia . This will be discussed in detail in the section on Alcoholic Ketoacidosis. ( VI. RESPONSE TO THERAPY (ref l) l. In about 85% of the cases the administration of glucose intravenously results in a prompt and often dramatic cessation of all the neuro­ logical manifestations of the hypoglycemia and in an equally rapid return of consciousness . 2. About 10-15% show a delayed, partial or incomplete response to t intravenous glucose. This is an ominous prognostic sign since about 70% of these patients died within hours to days with clinical evidence r of irreversible brain dama ge. 3. In untreated patients, about 45% recovered spo ntaneously but 55% di ed . Death in more than one-half of the untreated subjects serves to emphasize the necessity for immediate therapy.

VII. MORTALITY IN ALCOHOL-INDUCED HYPOGLYCEMIA (ref l-16)

Cases Death s Mortality

1975 Total 237 30 13% Adults 202 23 ll% Children 35 7 20% 1 -10-

( PATHOGENESIS OF ALCOHOL INDUCED HYPOG LYCEMIA (ref l, 24- 45)

I. Introduction The clinical evidence indicatinQ that deglycogenation of the livel' is

a prerequisite for ethanol-induced hypoglycemia suppo rts the ~vitro

and ~vivo experimental evidence indicating that the hypoglycemia is th e consequence of ethanol-induced suppression of hepatic gluconeogenesis. The bulk of the experimental evidence indicates that the reduction in

hepatic gluconeogenesis is not the result of ethanol~~ but rather is secondary to the metabolic alteration within the hepatocyte produced by the oxidation of ethanol to acetate within these cells.

II. Metabolic Changes in Hepatic Cells Secondary to the Oxidation of Etha nol This subject recently has been reviewed in detail at Medical Grand Rounds ( by Dr. Athol Ware (Alcohol, the Liver .. . and You, January 27, 1977) . Only the highlights immediately pertinent to the suppression of gluconeogenesis will be reviewed today.

1. In mammals the liver is the major site of ethanol oxida t ion ( > 90 ~ ) 2. Within the cytoplasmic portion of the liver ce lls the oxidation of ethanol to acetaldehyde and then to acetate is catalyzed respectively by alcohol and acetaldehyde dehydrogenase. Since there are multiple

form ~ of acetaldehyde dehydrogenase in multiple locations i.e. cytoplasm, mitochondria, and endoplasmic reticulum, so me acetaldehyde may enter the mitochondria where it is oxidized to acetate. -11- .,

J OXIDATION OF ETHANOL IN THE HEPATOCYTE 1 (

{ ' '""~ ,., ..., ...., ...... ····· ,. I) CYTOPLASM :"i MI TOCHONDRION r:: .l "('"T ~:: ASPTTATE ~ OXAL.O- \ Hz ETHANOL. ACETATE ;;

OIHYOROXYACETONE - P 0

ACETATE

c 3. The oxidation of alcohol and acetaldehyde both require NAD as a

hydrogen acceptor and thereby generate NADH 2.

Alcohol ------~ Acetaldehyde Acetate NAD NAD NADH ~ 2 I 4. The NADH 2 generated in the cytoplasmic portion of the liver cell can be reoxidized to NAD by a variety of reactions.

a) Pyruvate---~ lactate

NADHz~..l NAD

b) Dihydroxyacetone phosphate ----7 a-g lycerophosphate NADH ..--.) NA D 2 c) Oxaloacetate -----) Malate

NADH 2 ~ NAD J,

-12- ., I ( 5. The major route for the reoxidation of NADH 2 is the intramito­ 1 chondri a l flavoprotein cytochrome system. The i r:1 permeabil ity of the mitrochondrial membrane to extramitochondrial NADH 2 is bypass ed I functionally by means of metabolites that freely pass through the mitochondrial membrane and are capable of acting as electron

carriers from extramitochondrial NADH 2 to the in tramitochondri al electron. transport system (shuttles).

6. Despite all these potential avenues for the reoxidation of NADH 2 generated by the oxidation of ethanol, marked increases in the NADH /NAD ratio within the Jiver cell accompany hepatic ethanol 2 oxidation as evidence by j__ll vitro measurements of hepatic NADH 2/

NAD ratios and by j__ll vivo changes in paired metabo lites which

reflect changes in cytoplasmic and mitochondrial NADH 2(NAD ratio. Lactate t c Cytosol /pyruvate

BOH j Mitochondria /AcAc

I [.

l I ) I -13- I ., I III. THE PATHWAYS FOR GLUCONEOGENES IS DURING FASTING ARE DEPICTED BELOW (ref l)

GLUCOSE 0 I GLUCOS E· S· P It FRU CTOS E·6·P (;\' ) FRU..-CTOSE 1,6, - ~ H OIHYOROXYACETONE·P---- GLYCERA LOEH YO E -:3-P I ,-"'"))i t "-t> NA011l 1 ,3, ~ ·G.LYCEAATE PHOSPHO[ NOLPYRUVAT E ( > PY_RUVATE ~- ~A CE TYL CoA ; ~ lf ,,,; '"D H, j \~~~ :o:~O ACETATE \ y//( AodJ MALA TE CITRATE ~ t t \ I (

Pathways of hepatic gluconeogenesis during starvation. Th e ~pe c iii c er. tymes upon which gluconeog enesis is d e pendent are num bered wi th in th e l., rge drrows. The NAO-dependent poinh in the pathway of gluconeo­ genesis are shown by the bold solid arrows. Th e direc­ tion of reactions in the presence of an elevated NADH:/ NAD ratio is depicted by the stippled curved •Hrow s.

Pyruvate carbo xylase which, by C0 2 fixation, converts pyruvate to oxaloacetate. 2. Pho sphoeno lpyruvate carboxyk inase which converts oxaloacetate to I phosphoenolpyruvate. rI 3. Fructose-1 ,6-diphosphatase which hydro lyzes fructose-] .~-diphosphate to fructose-6-phosphate. 4. Glucose-6-phosphatase which hydro lyzes glucose-6-phosphate to free glycose. l

-14- ., c VI . ALCOHOL HAS THE FOLLOWING EFFECTS WHICH REDUCE THE RATE OF HEP ATIC GLUCOt/EOGEr~ESIS ( l, 24-45)

A. SHUNTING GLUCONEOGENIC PRECURSORS A\·JAY FR OM GLUCONEOGENIC PATH\>IAYS

BY INCREASED NADH 2/NAD RATIO

Precursor Pathwa~ to Glucose Effect of Alcohol

l. AMINO ACIDS via a-ketoglutarate a-ketoglutarate Glutamic Acid converted to Proline Glutamate -. Arginine 2. AMIIW ACIDS via Pyruvate Pyruvate reduced Alanine to Lactate Serine Glycine 3. AMINO ACID via Malate to Oxalo- Oxa l oacetate is Phenylalanine acetate reduced to Malate t1ethionine ( Proline Aspartate via Oxaloacetate 4. LACTATE via Pyruvate Pyruvate reduced to Lactate

5. GLYCEROL via a-g lycerophosphate Dihydroxyacetone to dihydroxyacetone phosphate reduced phosphate to a-g lycerophosphate

B. DECR EAS ING HEPATIC UPTA KE OF GLUCONEOGENIC PRECURSOR 1. Decreased Hepatic Uptake of Lactate (39) 2. Decreased Hepatic Uptake of Glycero l (3 1)

C. IMPAIRMENT OF GLU CONEOGENESIS BY DECREASING THE RATE OF FATTY ACID OXIDATION (32) According to the studies of Williamson, the rate of gluconeogenesis is in part regulated by the rate of fatty acid oxidation within the mitochondria. During the metabolism of alcohol, fatty acid oxidation is inhibited, t hereby decreasing gluconeogenesis. -15- ., c ETHANOL ON HEPATIC GLUCOSE OUTPUT

Hepatic

Blood olucose mg% 40 ~g ~ I m1~~r. ~~~ ~~ 1 -20 0 '20 40 60 so 100 120 Time (min)

Effect of ethanol on hepatic glucose output and on peripheral glucose utilization during fasting. In this study, despite an ethanol·inducP.d inhibition of peripheral glucose utilization which averaged 47 mg per minute, severe arterial hypoglycemia ensued as a consequence of the greater mean fall (67 mg per minute) in hepatic glucose output during ethanol administration. ( ETHANOL ON HEPATIC GLUCOSE OUTPUT ------

HEPATIC so GLUCOSE 60 OUTPUT 40 mg/min 2o 0

/"HEPATIC VENOUS .BLOOD 1oono~ GLUCOSE 90 ,_~tff:~t'-~-~~~~ mg~o 80 10 "-....ARTERIAL

EHBF J ml/min mf~-~~ -30 -zo -10 o 10 20 30 40 so 60 TIME (minutes) Effect of ethanol on hepatic glucose output a. nd on peripherxl glucose utilization during fasting. In thi3 study ethanol adrruni.~tration produced a rise in blood glucose concentration from 81.7 to 85 .S mg/ 100 ml de.pite the 75% decrease in mean hepatic glucose output from 60.3 to 21.3 mg per minute. Arterial glucose .. concentration increased as a result of an ethanol-induced inhibition of mean periph­ eral glucose utilization ~f 50 mg per minute. -16- ( .,

J EFFECT OF FRUCTOSE ON HEPATIC OUTPUT ( ll

ETHANOL ETHANOL PLUS CONTROL ALON E FRUCTOSE 60 30 mM/hr. 60 mM /hr

HEPATIC GLUCOSE OUTPUT mglmin

TIME (minutes)

EHcd of frudos:-, a non·NAD-depend en+ pre cu .-s., r oi glucose, on hepatic glucose output during . e_thanol­ induced suppression of he patic gluconeogenam lil fast­ ed dogs {mean changes in she studies). (

EFFECT OF a-KETOGLUTERATE ON HEPATIC GLUCOSE OUTPUT DURING ETHANOL INDUCED DECREASE IN GLUCONEOGENESIS

ETHANOL PLUS oe-KET0- 30mMihr. GLUTARATE 60 IOOmM/ hr.

50

40 HEPATIC GLUCOSE 30 OUTPUT mglmin 20

tO

0 30 30 90 90 150 TIME (minutes)

Effect .of ~-ketoglutarate, a NAO-dependent precu;-so r of glucose, on hepatic glucose output during ethanol­ induced !Oppression of hepatic glucon'? ogenesis in fasted dogs {mean changes in sill stud ies). -17- ( ., / ETHANOL PLUS METHYLENE BLUE ON HEPATIC GLU CON EOGENESIS r ( ETHANOL ETHANOL CONTROL ALONE PLUS 1 30 Mlh METHYLENE: 50 m r. BLUE I J 40 I HEPATIC J GLUCOSE 30 OUTPUT mg/min 20

TIME (minutes)

Effect of methylen'e bh~. a redox dye capa!:. !!J of o':i­ dizing NAOH:J tv NAD and thereby dec r ea~ing t!-t~ elevated NADH.. / NAD ratio generated in the liver c~ · l during ethanol oxidation, on hepatic glucose output during ethanol-induced supprenion of l;epa!':c gluco­ neogenesis in fasted dogs !m ea n c!-1anges in six ~tudies} .

(

All the preceding studies are consonant with the hypothesis that alterations in hepatocyte NADHz/NAD ratio during the oxidation of ethanol results in a suppression of hepatic gluconeogenesis. These

data are supported by ~vivo studies from our laboratory indicating that ethanol infusion does not impair the augmented renal gluconeo­ genesis induced by hypoglycemia since the renal content of alcohol dehydrogenase per gram of renal tissue is only 1/100 that of the 1 iver.

Krebs suggested that the major site of decrease of gluconeogenesis wa s the consequence of impairment in utili za tion of all substrates that enter the gluconeogenic pathway via pyruvate (lactate, alanine, "I

-18- .,

( serine, etc) (35). He indicated that when the equilibrium of the lactate/pyruvate redox pair was changed in favor of lactate, the hepatic concentrations of pyruvate decreased and thereby diminished the flow through the first gluconeogenic step whereby pyruvate is converted to oxaloacetate by pyruvate carboxylase. Since the Km value of pyruvate carboxylase is rather high (0.4 mM) and above the

usual co~centration of pyruvate, a fall in pyruvate concentration will cause a proportionate fall in oxaloacetate formation (35).

THE PYRUVATE CARBOXYLASE REACTION DURING STARVATION

Alanine~

Serine~ Pyruvate---~) Oxaloacetate --~) Glucose p .c. Lactate--+ 'f ( "INHIBITION" OF PYRUVATE CARBOXYLASE BY ETHANOL -·· Alanine~ Serine~ Pyruvate ---+----) Oxaloacetate ------) Glucose Lactate~ ~ Lactate

This was tested experimentally~ vivo in our laboratory by mea?uring changes in lactate balance during ethanol-induced suppression of hepatic gluconeogenesis and found to account for only 25 % of the total suppression in hepatic gluconeogenesis. The remaining 75% of the total suppression of gluconeogenesis was considered to be the result of interference with gluconeogenesis at other NAD dependent steps. -;

-19- .,

( Further studies showed this was not the case and that only 50 ~ of the suppression of gluconeogenesis could be attributed to changes

in the NADH 2/NAD ratio.

Acetate, the end product of ethanol oxidation,was shown in j_!l_ vi vo studies in our laboratory to account for 50% of the total suppressi on of hepatic .gluconeogenesis. The precise mechanism whereby ace t ate depresses hepatic gluconeogenesis is unknown at the present time. It is also re?ponsible for the major part of suppression of pe rip heral

glucose utilization produced by ethanol (l). ---In vitro studies of Williamson on the perfused rat heart confirm these effects on peri pheral glucose utilization (43). I ' In support of this evidence that changes in the NA DH 2/NAD ratio do J ( not account for all the suppression of gluconeogenesis is the foll 01vi ng. t Hyperthyroid subjects have been shown to be especially susceptible to ethanol-induced hypoglycemia yet the redox changes produced by ethanol I in hyperthyroid rats is smaller than that produced in control rats

(41, 42) 0

FROM YLI KAHRI ( 41) 1 Ethanol did not change the L/P ratio or the NADH 2/NAD ratio in hype r­ i thyroid rats yet caused a greater fall in blood glucose than did t he 1 admj nistration of ethanol to euthyroid rats (41, 42). LACTATE PYRUV ill NADH z tJAD NORt1AL 2. 00 0.16 12 .7 99 636 0.1 6

NO RMAL + ETOH 2.56 0 . 11 23.3 203 535 0. 38

HYPERTHYROID 3.38 0.27 13.6 131 690 0.19

HYPER + ETHO 3.06 0.26 13 .6 120 771 0.15 ~; r

-20-

( A L C 0 H 0 L I C K E T 0 A C I D 0 S I S

I. HISTORICAL REVIEH In 1940 Drs. Dillon, Dyer and Smelo from the Metabolic Division of the Phildelphia General Hospital reported 11 episodes of ketone ac idosis in seven non-diabetic patients. In this report they clearly defined the clinical characteristics and appropriate treatment of this syndrome . They stressed the fact that the blood glucose was either norma l or at hyoo­ glycemic levels (range 20-137 mg/100 ml). In three of the eleven episodes \ hypoglycemia was present. All patients were acidotic and had urine \ examinations strongly positive for ketones. In one patient they confirmed the presence of 9 mM/L of BOH in the plasma. They concluded that glucose ( administration and physiologic saline were essential in the treatment and that insulin was not necessary. They also pointed out that the apparent

rarity of the syndrome was most likely the result of the fact that ~ost physicians were not aware of its existence (46) .

For 31 years no further articles on this syndrome were reported in the literature until an article by Jenkins, Echels and Craig on Alcoholic Ketoacidosis appeared in the JAMA describing 24 episodes in 3 patients (47). Apparently, since 1941 the syndrome was well-known at Philadelphia General Hospital where it was recognized as an not uncommon di so rder but )! no further reports to bring it to the attention of phys icians appeared from this institution (48).

Since the article of Jenkins et al in 1971, nine other reports have appeared describing an additional 70 episodes of alcoholic ketoacidosis (

-21- .,

( in 56 patients (48-57). Cooperman et al (1974) also pointed out that the syndrome is not uncommon si nce they diagnosed one case of alcoholic ketoaci d- osis for every four cases of diabetic ketoacidosis.

In 1975, Fulop and Hoberman expanded the syndrome of alcoholic ketoac ido si s by studying all alcoholics with significant ketonemia an d ketonuria . AlthJugh many of their patients had severe acidosis, in ll patients with increased BOll (mean 8.7 mM/L; range 5.2-13.0 mM/L) the blood pH 1vas normai or elevated (mean 7.48; range 7.33-7 . 61) as a consequence of the associatEd metabolic alkalosis resulting from prolonged vomiting (56).

II. REPORTS OF ALC OHOLIC KETOACIDOSIS

EPISODES YEAR AUTHOR NO. CASES H0~1Etl t1EN rw . Dillon 7 5 2 11 l 'HO 24 ( 1971 Jenkins 3 3 0 Weisberger l l 0 l Jacob l 0 l l l 1973 Edwards l 0 l Le vy 5 3 2 6 197 4 Klock l 0 l l Territo 9 6 3 11 Cooperman 6 6 0 7 1975 Fulop 24 7 17 24 Heinig 9 5 4 w TOTAL 67 36 31 105

* Note all reports from USA

I I I. CLINICAL SETTING IN HH!CH ALCOHOLIC KETOACIDOSIS OCCURS l. Chronic alcoholics- with recent debauc h but patient may not have had alcohol in past 24.48 hours. 2. Starvation- poor diet for months to weeks with more recent complete or almost comp l ete starvation of at least l-2 days, J I

-22- .,

3. Vo~iting - usually for 12 hours to several days. In some cases this ( led to cessation of alcohol intake . 4. Abdominal pain - (90% cases) frequently associated wi th pancreatitis.

~\ 5. ~- median 40 years; range 25-76 years. I 6. Associated-Conditions - hepatic dysfunction, delerium tremens, GI bleeding.

>[ IV. ACIDOSIS IN ALCOHOLICS (ref 1, 46-71) I 1. Ethano 1 2. Poi soning s A) Methanol D) Para 1de hyde B) Ethylene Glycol E) Isopropyl A1 coho 1 (severe ketosis C) Sal icylates without acidosis) 3. Thiamine Deficiency 4. Lactic Acidosis secondary to vascular collapse ECF Volume Depletion GI Bleeding ( Pancreatitis V. PANCREATITIS IN ALCOHOLIC KEOTACIDOSIS ,,. Author Episodes Pancreatitis

Weisberger 1 0 Jacobs 1 1 Levy 6 4 Klock 1 1 Territo 11 4 Cooperman 7 4 Fulop 24 6 Heinig* 18 14 TOTAL 6g 34 = 49% cases * tested for specifically (78% of the cases had pancreatitis)

VI. CHARACTERIZATIO;~ OF TI-lE ACIDOSIS Iii PATIENTS WITH ALCOHOLIC KETOI\C IDOSI S In 28 cases ketones and lactate were measured simultaneously while some cases had predominately ketoacidosis and some predominantely lactic -23- .,

( acidosis, the majority had a combination of keto- and lactic acidosis.

MEAN BOH- 7.8 mM/L (2.4-22.5) MEAN LACTATE- 5.4 mM/L (0.7-20.6)

BOH LEVELS IN ALCOHOLIC KETOACIDOSIS 60% Greater than 6 mM/L 43% Greater than 7 mM /L 32 % Greater than 10 mM/L 756 Greater than 15 m~1/L

LACTATE LEVELS IN ALCOHOLIC KETOACID OSIS 40% Greater than 5 mM/L 36% Greater than 6 mM/L 25% Greater than 7 mM/L 18% Greater than 9 mM/L ll % Greater than 14 mM/L

IN 32% CASES BOH WAS 10 mM/L OR GREATER ( ~1EAN BOH - 15 mM/L (10-22.5) MEAN LACTATE- 5.1 mM/L (1.0-20.6)

IN 36% CASES LACTATE WAS 6 mM/L OR GREATER

MEAN LACTATE 10.7 (6.0-2~.6) · MEAN BOH 5.5 (2.4-16.5)

., OTHER ORGANIC ACIDS CONTRIBUTING TO THE ACIDOSIS

l. Acetate - 2 m~1 (if alcohol still present in blood) 2. Free Fatty Acids (FFA) - only 9 measurements Mean 2900 mEq/L Range 1808 - 3350 mEq/L 5 of 9 greater than 3000 mEq/L ,.

SERUM ANn URINE ACETEST RESULTS Serum and urine "ketones" are frequentl y underestimated in the presence of lactic acidosis, since BOH does not cause a positive test and in · ~ I

-24- .,

( alcoholic ketoacidosis the BOH/AcAc ratio is high. When alcoholic keto- acidosis is suspected, a freshly opened bottle of Ketostix should be useo

'~ since Ketostix is more likely to pick up the associated acetonemia and ( acetonuria. Also, re-check plasma. ketones after saline has been ad min- istered. Fulop and Hoberman reported a patient with a plasma BOH of 12.9 mt1/ L and a negative serum Acetest (56).

VII. PLASMA GLUCOSE IN ALCOHOLIC KETOACIDOSIS (62 obs ervations) RANGE 5-288 mg/100 ml* Distribution 10% less than 30 mg/100 ml 16% less than 50 mg/100 ml 51)% less than 100 mg/100 ml I 60% less than 130 mg/100 ml 75% less than 150 mg/100 ml 86% less than 190 mg/1 00 ml ( * In only one series·was blood alcohol measured, hypoglycemia was noted

~ in patients with positive blood alcohol levels and ~patients I with alcohol present in the blood were hypoglycemic (57).

VIII. SERUM PHOSPHATE IN ALCOHOLIC KETOACIDOSIS MEAN 6.3 mg/100 ml RMGE 2.8 - 13 .0 mg/100 ml Although in series unselected for hypophosphatemia, the mea n serum phosphate was 6.8 mg/100 ml, in other reports selected for hypophosphatemia (54, 55) 12 patients had initial hypophosphatemia (mean 0.8 mg/100 ml; range 0.3- 1. 3 mg/100 ml). Even when the initial phosphate level is high, treatment with glucose and saline results in severe hypophosphatemia unless phosphate is administered . l -25-

( IX. SERUM POTASSIUM IN ALCOHOLIC KETOACIDOSIS

Author No. of Observations f1ean Cooperman (51) 7 4.6 mEq/L (3 .4-6.2) Levy (49) 6 4.9 mEq/L (2. 8-6.0) Mixed 8 4. 8 r.: Eq/L (3 . 5-5.7)

As in diabetic -ketoacidosis, initial potassium may be high, normal or low and can be expected to fall during treatment.

X. TREATMENT OF ALCOHOLIC KETOACIDOSIS AND RESPONSE TO THE RAPY l. GLUCOSE infusion at rate of about 200 mg/min. If hypoglycemia is present initially, IV glucose should be given rapidly to fill glucose pool. 2. SALINE- to combat ECF volume depletion and collapse . The incidence of associated pancreatitis is high (49-78%). About 3 to 4 liters in first 12 hours unless greater amounts are indicated from associated c conditions. 3. INSULIN shoul_d not be routinely used. However, in at least the 14% of patients who have initial blood sugars in excess of 190 mg % or in those patients whose blood glucose rises to levels over 200 mg/100 ml during glucose infusion, small amounts of IV insulin seem indicated. 4. IV THIAMINE- as in all chronic alcoholics who receive IV glucose. 5. PHOSPHATE - if initial phosphate is high wait 2-3 hours until ECF volume is repleted and urine flow is adequate. By this time potassium will also be required. Administer 60-SQ m~1 potassium-phosphate at rate of 20 mM/hour. Follow serum phosphate and po t assium values. Salutary response to this therapy can be expected in most patients. Acidosis is corrected within 12-15 hours in most cases.

XI. MORTALITY RATE IN ALCOHOLIC KETOACIDOSIS 8 deaths in 105 episodes= 7.6%

r~st of the deaths were associated with complicating condition, i.e . severe GI bleeding, pancreatitis, alcoholic hepatitis, etc . l -26- .,

PATHOGENESIS OF ALCOHOLIC KETOACIDOSIS 1I I. EFFECT OF ALCOHOL ON KETOGE~ESIS The reported effects of ethanol on hepatic ketogenesis are contradictory. Severa l investigators (72-75) have reported a decreased rate of ketogenes is . On the other hand there are many reports (76-82) of increased ketogenesis.

These ~ vitro. and ~vivo studies were performed under a variety of experimental and clinical conditions. Very few experimentsv1ere concerned with the effect of chronic alcohol intake in fasted, starving, protein depleted subjects. There is evide.nce suggesting that ethanol is ketogeni c, at least in metabolic situations where the rate of ketone body production is already increased (80).

Ethanol has several effects on fat metabolism, some producing changes C. which would be expected to increase ketogenesis and others to decrease ketogenesis. A. SHOULD DECREASE KE TOGENE SIS 1. Decrease in s-oxidation

B. SHOULD !~CREASE KETOG ENESIS 1. Increase in acetyl-CoA 2. Possible activations of acetate, the end product of ethanol metabolism to acetyl-CoA. Althou gh 80% of the acetate produced 1 during oxidation of ethanol leaves the liver, 20% remains. In a chronic alcoholic who oxidizes alcoho l at a rate of 10 .5 gms/hr, 20% of this caul d account for the production of 10 ml1 of ketones/ hour or 240 mM/day. (_ 3. Decrease in Citric Acid Cycle activity. ', -27- '•

( It i s also importa nt to remember that in most repo rted cases , ethanol inta ke was chronically high, increased even more for 2-4 weeks but in .,. many instances non e was taken for l-2 days prior to hos pitalization for alcoholic ketoac idosis . Where blood ethanol was measured in all such patients, 78% had no alcohol in the blood at the t i me of hospitalization. In thi s group accelerated ketogenesis wo uld be expected as a consequence of severe and-p rolonged starvation. f:ere one onl y ha s to account for the greater degree of ketosis compared to non-a lcoho lic starvi ng patients. In the rema ining 22 % of the cases alcohol was stil l present at t he time of ketoacidosis and it is pertinent therefore to examine the effect of alcohol on ketogenesis.

II. PREREQUISITE S FOR AUGMENTED KETOGENE SIS The recent stud ies of McGarry and Fo ster have shown evidence supporti ng r C. a two- si te, bihormonal concept in the co ntrol of hepatic ketone bo dy production (85). l. INSULIN DEPEND ENT- Inc reased lipolys is resulting in increased plasma FFA and increased FFA del i very to the liver. 2. GLUCAGON DEPENDENT - Change in the "me t abo lic set" in the liver res u1 ti ng in an enhancement of the liver's capacity to convert FFA to ketone bodies. Thi s i s assoc iated with (83): a. decrease in glycogen b. in crease in carnitine con tent c. activation of carnitine acyltransferase

III. EFFECT OF ALCOHOL ON THE SE TWO PREREQUISITES

A. CHANGES I~ PLASMA FREE FATTY ACIDS l . In acute studies ethanol causes a sup pression of li polys i s and a decrease in plasma FFA. Thi s effect i s the consequence of increased plasma acetate (87). Ho wever, ca reful examination of the data reveals that after a initial suppress ion of plasma FFA there is a later escape and ri se of FFA abo ve control values . ,..

-28- .,

( ., f· r

ANTILIPOLYTIC EFFECTS OF ETHYL ALCO:iOL Duration of Fast 3 11 22 (Doyal Fasting FFA 1099 1<29 1259 (jiEq/Ll 120 w 3 100 ~ 80 · I · ;·I 0 \ . \ \ I I= 60 '/ ...... ,J z

8 40 t------1 1-----~1 1-----l ;f. 0 30 60 0 30 60 0 30 60 I MINUTES Effect of alcohol on the FFA levels during fasting. Fasts of 3, II, and 22 days. J (

Bouchier and Dawson in another study in human subjects with more prolonged administration of ethanol showed that the initial fall in plasma FFA was followed by a subsequent over-shooting of the baseline (83).

Bagdade, Gale and Porte (44) showed that infusion of alcohol to 3-day fasted subjects over a 6-hour period led initially, within the first 30 minutes, to a fall in FFA from about 1600 to 1400 mEq/L followed by a sustained rise after one hour to about 3000 mEq/L. While this was associated with hypoglycemia, the rise was out of proportion to the usual levels in hypoglycemia, suggesting a hyper-sensitivity to catecholamines. I..

r

-29- .,

(

n (

ALCOHOL HYPOGLYCEMIA

~~ -- -~ ETHANOL 236mg / lOOm !

-.

MINUTES SIX MALE SUBJECTS DURING ALCOHOL HYPOGLYCEMIA

( i

HYPERSENSITIVITY TO CATECHOLAMINES IN CHRONIC ALCOHOLISM Isreal, Videla and Bernstein (20) have reported that chronic r ethanol treatment results in adrenergic super-sensitivity. I 3, CATECHOLAMINE SECRETION IN CHRONIC ALCOHOLISM I Mendelson (90) showed that in chronic alcoholics during free- J choice alcohol consumption there was a significant and progressive I rise in catecholamines, especially epinephrine, which persi sted during withdrawal even though alcohol had disappeared from the I blood. It is worth noting that in Fulop's series of 24 cases of l l alcoholic ketoacidosis, five had Oelerium Tremens (20%). L I I I -30- ( .,

(

II r

(

4. ADDITIONAL CAUSES OF EPINEPHRINE SECRETION IN ALCOHOLIC KETOACIDOSIS

A. ~poglycemia - about 26% of patients with alcoholic ketoacidosis have concomitant alcohol-induced hypoglyc em ia. In Heinig's series (57) 22% of the patients were hypogl yc emic. More

important is the fact that ~patients who had any alcohol remaining in their blood were hypoglyc emic . Since most patients with alcoholic ketoacidosis have abs tained from alcohol for at least 1-2 days due to abdominal pain, nausea and vomiting, it is possibl e that they went through a phase of alcohol hypoglycemia and thereby stimulated epinephrine secretion. I

r

I -31- r ., ( B. Pancreatitis - the stress and ECF volume depletion associat ed l ~) with pancreatitis elevates catecholamines. Where pancreati:is \ was specifically looked for, it was found in 78% of the cases (57). This stress would also increase pl asma glucagon. rI 5. LOW PLASMA INSULIN LEVELS - these low levels are compatible wi tn prolonged fasting. However, they rise only very little despite elevated blood glucose values following glucose infusion .

SUMMARY - whatever different combination of mechanisms are operati ve J I concurrently, FFA levels are inordinately high during alcoholic ketJ-

acidosis. ~1ean FFA equaled 2900 mEq/L. Fifty-five per cent of t he f. \ cases where FFA were measured were in excess of 3000 mEq/L.

B. CHANGES IN THE METABOLIC SET OF THE LIVER SECONDAR Y TO ALCOHOL INGE S7ION

( 1. Increased Plasma Glucagon

Precise measurements of glucagon levels in alcoholic ketoacidos ~ s have not been reported. The not infrequent occurrence of hypo gly- I cemia (26%) and the frequent presence of pancreatitis (49% to 751 of the cases) would be expected to raise plasma glucagon. Pal mer r and Ensinck (91) reported a dramatic two-to-threefold increase in plasma glucagon levels during ethanol administration to two day I fasted subjects even though blood glucose fell only 18 mg/100 ml . ' Moreover, starvation alone should elevate glucagon to levels 1-1hi ch l alter the "metabolic set" of the liver. I 2. "Functional Uncoupling" of Oxidation from Phos phorylation in Chronic Alcoholism (20) I Chronic ethanol treatment has been shown to decrease the levels of ATP as well as the phosphorylation potential (ATP/ADP x Pi). ...

-32- .,

( This is associated with a 50-60% increase in the rate of oxygen consumption in liver tissue (20 ). This increase occurred even in the absence of ethanol provided the an i ma l s previously 1vere exposed chronically to ethanol.

In this hypermetabolic state, mitochondrial uncouplers do not further enhance the respiratory rate.

The state appears to be produced by increased utilization of ATP by the sodium pump of the cell membrane. So dium pump ' activity and carrier (Na+K)-ATPase i ncreased by 70 and 190% in the livers of animals chronically treated with alcohol. In hibi ­ tion of the (Na+K )-ATPase by ouabain returned t he rate of oxygen utilization to control values. Such "functional uncou pling" ( should increase the rate of FFA s-oxidation and augment ketogene- sis.

PHOSPHORYLATION POTENTIAL IN CJIRONIC ALCOIIOLICS (20)

500 P

l Effect of chronic ethanol treatme nt on the phosphorylation potential of rat liver. -33- .,

EFFECT OF CHRONIC ALC OH OL TREATM ENT ON THE RATE OF OXYGEN ( CONSUMPTION BY LIVER - EFFECT OF OUABAIN AND DNP (20) --- --

OU~a• ONP c OUAB T 1.4 0 Controls . ~ D Chronic Alcohot ONP NONE ~ ~ 1.2 I ONP IONP 1:

3. Effect of Ethanol on Hepatic Ketogenesis in the Presence of FFA Wil liamson et al (32) showed in the perfused liver that ethanol alone decreased the rate of ketone production. However, when FFA (oleate)were administered before ethanol administration, a marked increase in ketogenesis (from 80 to 125 ~M/100 gms body wt/hrl ( occurred, EFFECT OF OLEATE PLUS ETHANOL ON KETOGENESIS

140 r···l···· ...J . o••.••• 120 : l Elhanal ~ 100 : i< ~ 80 I l Oleate 0"' Q 60 'v~ l 40~ 20 ~-,_....__F-'-l'=rr- Control ~--l--· · Ethanol 0 0 30 60 90 Minutes of Perfusion 1 331 3u moles /m1n Oleate I tOmM Ethanol ·.t -34- ., c 4. Effect of Ethanol on Ketogenesis in Protein Depleted Animals In view of the fact that alcoholic ketoacidosi s occurs in mal- nourished, starved and protein-depleted chronic ai coholics \44 - 54) the study of Bode et al is especially pertinent to this problem (81).

P-HYDROXYBUTYRATE(P-HOB)ond 0 .7 ACETOACETATE (Ac Ac) (RAT LIVER)

0.6 C=CONTROL E= ETHANOL

0 .5 D ,8-HOB D AcAc ,." 0.4 ...."' ( .,~ 0.3 0 E ~ 0.2

c E c E O.t l-r- ~ 1-z.. ~ HOB /AcAc 2 .3 6.9 6.6 [}11 DIET STANDARD 0 .5% PROTEIN

Marked elevation of ketone body concent ration and the ratio {.3- hydroxybutyrate I acetoacetate in the liver of pro te in deficient rots 2 hours after on oral dose of ethanol. -35-

( SUMMARY In the 78% of patients with alcoholic ketoacidosis (post-alcoholic ketoacidosis ) who do not have alcohol present in the blood, the development of ma rked keto­

acidos is i s not puzzling. T~e starvation alone would raise plasma glucagon and alter the ''metabolic set" of the liver in favor of enhanced ketogenesis . The studies of McGarry and Foster have shown that maximal rates of ketogenesis are possible in such starved livers and the rate is modulated only by the magnitude of FFA delivery to the liver. Since FFA in starve d chronic alcoholics is much higher than in starved non-alcoholics, the rates of ketogenesis' sho uld be greater resulting in levels of plasma ketones greater than that found i n the starving non-alcoholic. The precise reason for the unusual elevation of FFA has not been defined but certainly may be related to either the reported hype r­ ( sensitivity to catecholamines, to the increased catecholamine secretion re po rted in chronic alcoholics, and to the increase associated with pancreatitis.

In~e other 22% of the starving chronic alcoholics with alcoholic ke toacidosis who have ethanol present in their blood, the accelerated ketogenic rate may be related to the hypoglycemia which appears to occur in all of these patients. This increases both plasma glucagon and epinephrine, and prov ides a high plasma FFA to a liver already set for hi gh ketogenesis by starvation. Moreover, in chron ic starvation and protein depletion, ethanol may not depress 3-oxidation since ketogenic rates are higher in such livers.

l -36 - . R'' E F E R E N C E S r ( I I. CLINICAL PICTURE OF ALCO HOL - INDUCED HYPOG LYCEmA I A. General Review 1. Madi so n, L. L. : Ethanol-induced hypogl ycemia. in Advances in t~etabolic Disorders. Vol . III. Levine, R., and Luft, R., Eds. London, Academic Press, 1968, pp 85 -109. Review ~f world ' s litera t ure, ·101 cases (89 adults, 12 children) -clinical picture and mechanism of production of hypoglycemia Pertinent reference to 1965. B. Additional -case Reports 2. Seltzer, H.S. 1975. Drug-induced hypoglycemia - A review of 473 cases. Diabetes 29:955-966 . Tabulates additional cases of alcohol­ induced hypoglycemia bringing the total to 174 ca ses. 3. Neame, P. B. Post-alcohol it hypogl ycemia. A clinical and pathological study. Thesis - University of Capetown, South Africa, 1965 . Fi fty­ two patients personally studied by Dr. Neame . 4. Bogdanski, K. and H.J . Lindenauer. 1966. Post-alcoholic hypog lycemia. Med. Ser. J . Canada . 22:614-617. Three cases reported by Americans in parap l egic patients at a meeting in Canada . ( 5. Depario, M., G. Manigand, P. Auzepy, R. Levil lain, and A. Chelloul. 1966. L 'hypog lycemie alcool ique. Rev. Internat. d'Hepatologie . 16:1111-1120. 6. Gerscovich, J., L. Dragun and J . Divinski. Coma hipoglucemico por ingestion de alcohol. 1965. Arch. Argentin. de Ped. 63:465-469 . 7. Dettwyler, B. L'alcool ethylique: Cause dechenchante d' une hypo­ glycemie. 1967. Rev. Med . de la Suisse Rom. 67:60-70. 8. lied. R. and A. Nygren. 1968. Alcohol-induced hypog lycem i a in chronic alcoholics with l iver di sease. Acta Med. Scan. 183 :507 -510. ··' '3 . t~ac L aren, tLK., H. B. Valman and B. Levin. 1970. Acute al coho l ic hypoglycemia in two 4-year-ol ds . Br. Med. Jr. 1:280 . 10. Moss, M.H. 1970. Alcoho l -induced hypog lycemia and coma caused by alcohol sponging Pediat. 46:445. Case of a 6 month-o ld infant in whom alcohol-sponging resu l ted in a bl ood ethanol ·of 220 mg % ,, and a blood glucose of 22 mg %. 11. Golding, D.N. 1970. Al cohol-induced hypoglycemia in childhood. Br . t~ed. Jr. 1:273-280 . l -37- .,

12. Morano, J., H. Rios, H. Morano and E. Resches. 1970. Coma hipo­ ( glucemico y convulsiones poringestion de alcohol etilico. Arch. Argent. de Ped . 68:204.

13. Dorf, G., M. Tutin, B. Guy-Grand and H. Bour. 1967. L'h ypoglyc~ m ie post-alcoolique: A propos de 12 observations. Excerpta. Me~ . 140: ~I 169.

14. Ohara, H., Y. Hosoka~1a, II. Ho sokawa, S. t•1aeda and T. vlada. 1973. Two cases of ethanol-induced hypoglycemia in siblings. Jr. Jap. Soc. Int. Med. 62:58-64. 15. Gillam; D.t1. and J.R. Harper. 1973. Hypog lycem ia after alcohol ingestion. The Lancet. 1: 829 -830.

16. Baruh, S., L. Sherman, H.D. Kolodny and A.J. Singh. 1973 . Fasting hy poglycemia. Med. Clin. N. Am. 57:1441-1462.

II. METABOLISM OF ALCOHOL 17. Hawkin s, R.D. and H. Kalant. 1972. The metabolism of ethanol and its metabolic effects. Pharm. Rev. 24:67-157. ·18. Thurman, R.G., W.R. McKenna, J. Brentzel, Jr., and S. Hesse. 1975. Significant pathways of hepatic ethanol metaboli sm . Federation Proc. ( 34:2075-2081. 19 . Lieber, C.S., R. Teschke, Y. Hasumura and L. Decarli. 1975. Differences in hepatic and metabolic changes after acute and chronic alco hol consump­ tion. Federation Proc. 34:2060-2074 .

20. Isreal, Y., L. Videla and J. Bernstein. 1975. Liver hypermetabolic state after chronic ethanol consumption: Hormonal interrelations and pathogenic implications. Federation Proc. 34:2052 -2058. 21. Haight, J.S.J. and W.R. Keatinge. 1973. Failure of thermoregulation in the cold during hypoglycemia induced by exercise and ethanol. J. Physiol. 229:87-97. 22. Martini, G.A. and Ch. Bode, eds. 1971. Metabolic changes induced by ethanol. Springer-Verlag, New. York. 23. Kissim and Beg leiter, eds. 1971. The Biology of Alcoholism. Plenum Press, New York.

I I I. t1ECHAN ISt·1S OF ETHAIIOL- INDUCED HYPOGLYCEMIA

24. ~ladison, L.L. 1968. Ethanol-induced hypoglycemia. in Advances in Metabolic Disorders. Levine, R and Luft, R., eds. London, Academic Press. pp. 85 -109. -38-

25. Lochner, A., ~Julff, J. and ~1adison, L.L. 1967. Ethano l-induced ( hypoglycemia. I. The acute effect of ethanol on hepatic glucose output and peripheral glucose utilization in fasted dogs. Metabolis ~ 16: l-18. 26. Madison, L.L., Lochner, A. and Wulff, H. 1967. Ethanol-induced hypoglycemia. II. Mechanism of suppression of he patic gluconeo­ genesis. Diabetes 16:252. 27. Field, J.B., Williams, H. E., and Mortimore, G. E. 1963. Studies on the mechanism of ethanol induced hypoglycemia. J. Clin. Invest. 42: 497.

28. Freinkel, tl., Singer, D.L., Arky, R.A., Bleicher, S.J., Anderson,.J.B. and Silbert, C.K. 1963. Alcohol hypoglycemia. I. Carbohydrate metabolism of patients with clinical alcohol hypoglycemia and the experimental reproduction of the syndrome with pure ethanol. J . Clin. Invest. 42:1112. 29. Freinkel, N., Cohen, A.K., Arky, R.A., and Foster, A.D . Alcohol hypoglycemia II. A postulated mechanism of action based on exper­ iments with rat liver slices. J. Clin. Endocr. and Metabl. 25:76. 30. Freinkel, et al. 1965. Alcohol hypoglycemia. IV. Current concepts of its pathogenesis. Diabetes 41:350. ( 31. Lundquist, F., Tygstrup, tl., Hinkler, K., and Birger Jensen, K. 1965. Glycerol metabolism in human liver: Inhibition by ethanol. Science 150:616. 32. Hilliamson, J.R., R. Scholz, E.T. Browning, R. Thu rman and N.H. Fuka mi. 1969. Metabolic effects of ethanol in perfused rat liver. J. Biol. Chern. 244:5Q44-5054. 33. Arky, R.A. 1971. The effect of alcohol on carbohydrate metabolism in alcoholics. in The Biology of Alcoholism, Vol. I. Kissim and negleiter, eds. -plenum Press, New York, pp. 197-227. 34. Lumeng, L. and E.J. Davis. 1970. Mechanism of ethanol suppression of gluconeogenesis. Inhibition of phosphoenolpyruvate synthesis from glutamate and a-ketoglutarate. J. Biol. Chern. 245:3179 -31 85. 35. Krebs, H.A. 1968. The effects of ethanol on the metabolic activities of the liver. Adv . Enzyme. Reg. 6:467-480. 36. Krebs, H.A., R.A. Freedland, R. Hems and M. Stubbs . 1969. Inhibition of hepatic gluconeogenesis by ethanol. Biochem. J. 112:117-124. 37. Krebs, !LA., R. ·Hems and P. Lund. 1973. Accumulation of amino acids by the perfused rat liver in the presence of ethanol . Biochem. J. 13 :: :697-705. l -39-

38. Lundquist, F. Influence of ethanol on carbohydrate metabolism: A ( review. 1971. Quart. J. Stud. Ale. 32:1-12. 39. Kreisberg, R.A., A.M. Siegal and W.C. Owen. 1971. Glucose-lactate interrelationships: Effects of ethanol. J. Clin. Invest. 50:175- 185.

40. Kreisberg, R.A., A.~1. Siegal and ~l.C. 011en. 1972 . Alanine and gl uconeo­ genesis in man: Effects of ethanol. J. Clin. Endo. and Metab. 34: 876-883. 41. Ylikahri, R.H. 1970. Ethanol-induced hypoglycemia in thyroxine­ treated ~ats. Metab. 19:51 8-528. 42. Lindros, K.O., and M.E. Hillbom. 1971. Hepatic redox state and ketone body metabolism during oxidation of ethanol and fructose in normal, hyper- and hypothyroid rats. Ann . Med. Exper. et Biol. Fenn. 49:162-169. 43. \·Jilliamson, J.R. 1965. Glycolytic control mechanisms. Inhibition of glycolysis by acetate and pyruvate in the isolated perfused rat heart. J. Biol, Chern. 240:2308- 2321. 44. Bagdade, J.D., C.C. Gale and D. Porte, Jr. 1972. Hormone fuel interrelationships during alcohol hypoglycemia in man. Proc . Soc. Exp. Biol. Med. 141:540-542. · C. 45. Kre isberg, R.A. 1973. in Alcoholism-Medical Grand Rounds. South. Med. J. 66:1415-1420.

IV. ALCOHOLIC KETOACIDOSIS-CASE REPORTS

46. Dillon, E. S., ~J.W. Dyer, L. S. Smelo. 1940. Ketone acidosis in non­ diabetic adults. · Med. Clin. N. Am. 24:1813-1822.

47. Jenkins, D.\~., R.E. Eckel and J.W . Craig. 1971. Alcoholic ketoacidosis. J.A .~1.A. 217:177-183. 48. Weisberger, C.L. 1971. Alcoholic ketoacidosis. JAMA 217:1865-1 866 . 49. Jacob, II.S. and T. Amsden . 1971. Acute hemolytic anemia with rigid red cel ls in hypophosphatemia . N.E.J.M. 285:1446-1450.

50. Edwards, ~U1 . and R. Hoyt. 1973 . Alcoholic ketoacidosis. South. i•! ed . J. 66:281-282. 51. Levy, L.J . , J. Duga, M. Girgis and E.E. Gorden. 1973. Ketoacidosis associated with alcoholism in non-diabetic subjects. Ann. Int. Med. 78:213-219. 52. Petersen, G. 1973. Alcoholism and ketoacidosis. Ann . Int. Med. 78: 933. (No case reports in detail but states he saw 13 cases in 3 years­ these were not added into total since Territo (ref 55) reported some of the same cases.) -40-

53. Cooperman, M.T., F. Davidoff, R. Spark and J. Pallotta. 1974. ( Clinical studies of alcoholic ketoacidosis. Diabetes. 23:433-439.

54. Klock, J.C., H. E. Williams and vJ.C. Mentzer. 1974. Hemotytic ane e1 ia and somatic cell dysfunction in severe hypophosphatemia. Arch. Int. Med. 134:360-364.

55. Territo, N.C. and K.R. Tanaka. 1974~ Hypophosphatemia in chronic alcohol ism. Arch. Int. ~1ed. 134:445-447. 56. Fulop, M. and H.D . Hoberman, 1975. Alcoholic ketosis. Diabetes. 26:785-790. 57. Heinig, R.E., P.O. Miller and C. Waterhouse. 197 6. Metabolic aspects of alcoholic ketoacidosis. Clin . Res . 24:362A. V. METABOLIC ACIDOSIS IN ALCOHOLICS A. Ethanol l. Madison, L.L 1968. Ethanol-induced hypoglycemia. in Advanc es in t1etabolic Disorders. Vol. III Levine, R., and Luft, R., eds. London, Academic Press. pp. 85- 109 .

( B. Other Causes 58. Kahn, H. S. and Brotchner, R. J. l g5o. A recovery from ethylene glycol intoxication: A case of survival and two fatalities from ethylene glycol including autopsy findings. Arch. Int. Med. 34: 284. 59. Freedman, E.A., Greenberg, J.B., Merrill, J.P. and Dammin, G.J. 1962. Consequences of ethylene glycol poisoning : Report of four cases and review of the literature . Am . J. Med. 32:891. 60 . Leonard, S., Norgaard, D., Foster, D., Carter, N., Rector, F. , Madison, L., Baum, J., and Eigenbrodt, E. 1967. Clinicopathologic Conference. Texas Med. 63:76. 61. Bennett, I.L., Cary, F.H., t·1ichell, G.L., Jr. , and Cooper, M.iL 1953. Acute methyl alcohol poisoning: A rev iew based on experiences in an outbreak of 323 cases. Medicine 32:431. 62. Bennett, J.L. 1953. Poisoning due to substances commonly substituted for ethyl alcohol . V.A. Tech. Bul l . TB 10-89. 63 . Hadden, J. W. and R. J. t1etzner. 1969. Pseudoketos is and hyperaceta 1- dehydemia in paraldehyde acidosis. Am. J. Med. 47:642-647. 64. Ha yward, N.J . and Boshell, B. R. 1957. Paraldehyde intoxication l with metabolic acidosis. Am. J. Med. 23:965. 65. Elkinton, J.R., Huth, E.J., Clark, J.K., Barker, E.S. and Seligson, D. 1957 . Renal tubular acidosis with orga nic aciduria during paraldehyde ingestion. Am. J. Med. 23:977. -41-

( 66. Waterhou se, C. and Stern, E.A. 1957. Metabolic acidosis occ u rri ~ ~ during administration of paraldehyde. Am. J. Med. 23 :987. -

67. Beier, L.S., Pitts, \·I.H. and Gonick, H.C. 1963. r~etabolic acidosis occurring during paraldehyde intoxication. Ann. Int. ~1ed. 5&:155. 68. Gutman, R.A. and Burnell, J.M . 1967. Paraldehyde acidosis. Am . J. Med. 42:435. 69. Askar, F.S. and R. Miller. 1971. Hospital ketosis in the alcoholic diabetic. A syndrome due to i so propyl alcohol intoxi cation. So uth. ~1ed , J . 64: 1409- 1411. 70. fkCord, W.H . , Switzer, P.K., Brill, H. H. 1948. Isopropyl alcoh ol intoxication. South Med. J. 41:639-642. 71. Freireich, A.\·1., Cinque, T.J, Xanthaky, G., et al. 1967. He r::o ­ dialysis for isopropanol poisoning. N.E.J.M. 277:699-700.

VI. EFFECTS OF ALCOHOL ON KETOGENESIS A. DECREA SE IN KtTOGENESIS 72. Kreisberg, R.A. 1967. Effect of alcohol on glucose production and ( lactate, pyruvate and ketone body metabolism by the isolated ~ erfused rat liver. Diabetes. 16:784-790. 73. McGarry, J.D . and D.W. Foster. 1971. The regulation of ketog enesis from oleic acid and the influence of antiketogenic ag ents. J. Biol. Chem. 246:6247-6253 74. Wolfe, B.t·1., J.R. Havel, E.B. Marliss, J.P. Kane, J. Seymour end S.P. Ahuja. 1976. Effects of a 3-day fast and of ethanol on splanchnic metabolism of FFA, amino acids and carbohydrates in healthy young men. J. Clin . Invest. 57:329-340. 75. Arky, R,A, and N. Freinkel . 1964. Alcohol hypoglycemia. Effects of ethanol on plasma; III glucose, ketones and FFA in "juvenile diabetes! A model for "non-ketotic diabetic acidosis"? Arch. Int . Med. ll4: 501-507.

B. INCREASE IN KETOGENESIS 76 . Forsander, O.A,, N. Raiha, M. Sa laspuro, and P. Maenpaa . 1963, Influence of ethanol on the liver metabolism of fed and starved rats. Biochem. J. 94:259-265. 77 . . Williamson, J,R,, R. Scholz, E.T. Browning, R.G. Thurma n, and M,H. Fukami. 1969 . Metabolic effects of ethanol in perfused (_ rat liver, J. Biol. Chern, 244:5044-5054. -42-

( 78. Rawat, A,K . 1968. Effects of ethanol infusion on the redox sta te and metabolite levels in rat liver ---in vivo. Eur. J. Biochem. 6: 585-592. 79. Lindros, K.O. 1970. Interference of ethanol and sorbitol 1·tith hepatic ketone body metabolism in normal , hyper- and hypothyroid rats. Eur. J. Biochem . 13:111-116 . 80. Lindros, K.O. and M.E. Hillbom. 1971. Hepatic redox state and ketone body metabolism during oxidation of ethanol and fructose in normal, hyper- and hypothyroid rats. Ann. Med. Exper. et Biol. Fenn. 49:162-169. 81. Ch. Bode, C. Bode, H. Goebell, H. Kono and G.A. Mat·tini. 1971. On the independence of ethanol-induced triglyceride accumulati on in the liver from metabolic changes due to the oxidation of ethanol in the liver. in Metabolic Changes Induced by Ethano l. G.A. Martini and Ch. Bode, eds. Springer-Verlag, Ne1~ York. pp . 133-141. 82. Lefevre, A., H. Adler, and C.S . Lieber. 1970. Effect of ethanol on ketone metabolism. J. Clin. Invest. 49:1775-1782.

C. NO CHANGE IN KETOGENESIS 83. Ontko, J.A. 1973. Effects of ethanol on the metabolism of FFA in isolated liver cells. J. Lipid . Res. 14:78-86 .

D. GENERAL REVIEW OF KETOGENESIS/AND EFFECTS OF ETHANOL 84. r'1cGarry, J.D. and D.W. Foster. 1972. Regulation of ketogenesis and clinical aspects of the ketotic state. Metab. 21:471-489. 85 . McGarry, J.D. and D.VJ. Foster. 197 6. Ketogenesis and its regula­ tion. Am. J. Med. 61:9-13.

86 . Ha~tkins, R.D. and H. Kalant. 1972. The metabolism of ethanol and its metabolic effects. Pharm. Rev. 24:67 -15 7. (see pp. 11 2-121) E. EFFECTS OF ALCOHOL ON LIPOLYSIS AND FFA LEVELS 87. Abramson, E.A. and R.A. Arky. 19 68 . Acute antilipolytic effects of ethyl alcohol and acetate in man. J . Lab. Clin. Med. 72:105 - 117. 88. Bouchier, !.A.D. and A.M. Dawson. 1964. Effects of infusions of ethanol on pl asma FFA in man. Clin . Sci. 26:47-54 . 89. See reference 44. l ' } -43-

( 90. Mendelson, J ,H. 1971. Biochemical mechanisms of alcohol addiction. in The Biology of Alcoholi sm, Vol. I. Kissim and Begleiter, edS. Plenum Press, New York. pp. 513-544.

F. EFFECTS OF ALCOHOL ON CONDITIONS WHICH ALTER THE t'1£T.A.BOLIC SET OF T'i E LIVER 91. Palmer, J.P. and J.W. Ensinck . 1975. Stimulation of glucagon secretion by ethanol-induced hypoglycemia in man. Diabetes . 24:295-300. 92. See references 20 and 81.

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