J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from J Clin Pathol 1983;36:365-378 Review article Clinical pathology of alcohol

V'INCENT MARKS From the Department ofBiochemistry, (Division of Clinical Biochemistry), University ofSurrey, Guildford GU2 SXH

SUMMARY There is good though not conclusive evidence that a small to modest average daily intake of alcohol-that is, 20-30 g/day is associated with increased longevity due mainly to a reduction in death from cardiovascular disease. Larger average daily alcohol intakes-especially those in excess of 60 g/day for men and 40 g/day for women-are associated with gradually increasing morbidity and mortality rates from a variety of diseases. Alcohol may be unrecognised as the cause of somatic disease, which can occur without overt psychosocial evidence of alcohol abuse, unless the index of suspicion is high and a thorough drink history obtained. Laboratory tests for the detection and/or confirmation of alcohol abuse are useful but subject to serious limitations being neither as sensitive nor specific as sometimes believed. The value of random blood and/or breath alcohol measurements, in outpatients, as an aid to diagnosis of alcohol-induced organic disease is probably not sufficiently appreciated and,

though relatively insensitive, is highly specific. copyright.

Ethanol, more commonly referred to as alcohol, of alcohol and those of larger intoxicating doses. shares with caffeine and nicotine the distinction of Similarly, it is important to differentiate between the being amongst the three most widely used drugs in acute effects of alcohol in previously healthy sub- the world. Its ability to cause disease through a van- jects and those which result only from long con- ety of mechanisms has been recognised since early tinued alcohol abuse. The latter may itself produce times, but the full spectrum has only recently different effects depending on whether drinking is http://jcp.bmj.com/ become apparent and is probably still incomplete. It continuing (ie the drinking alcoholic), or whether it has displaced syphilis as the great mimic and should has been discontinued in the recent or remote past. be thought of as a potential aetiological factor in The former type of subject is referred to as the almost any differential diagnosis of somatic or "acutely withdrawn" and the latter as the "reco- psychopathology.' It has been estimated that in Bri- vered" alcoholic. Though many diseases are largely tain, at the present time, alcohol is a major con- or wholly attributable to chronic alcohol abuse the tributing factor in over a quarter of the illnesses factors that determine why so relatively few of those on September 29, 2021 by guest. Protected leading to admission to acute medical units.2 Despite at risk suffer from any particular adverse effect are the greater awareness of the role of alcohol in the largely unknown. Attempts to correlate susceptibil- pathogenesis of disease, almost nothing is known ity to alcohol liver disease with HLA types have about the molecular mechanisms involved. Some of been made,' without unanimity, and the possibility the systemic abnormalities that have been described of genetic factors determining which organ, if any, are explicable on the basis of the known consequ- will bear the brunt of alcohol assault, though attrac- ences of alcohol metabolism in the liver and others tive, must be considered unproven.8 are a consequence3-5 of associated nutritional During recent years many books devoted mainly deficiencies.6 In the majority of cases, however, no or entirely to the metabolic and clinical aspects of such simple explanations are possible and their alcohol9-'4 have appeared. In this review the major elucidation awaits further research. emphasis will be on the laboratory detection and It is important, in any discussion of the measurement of organ damage due to chronic pathophysiology of alcohol to distinguish between alcohol abuse but consideration will also be given to the acute effects of modest, subinebriating amounts those functional abnormalities induced by alcohol that are themselves largely, if not wholly, dependent Accepted for publication 16 November 1982 upon laboratory diagnosis. 365 J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from 366 Marks Alcohol in the community our) into the blood of experimental animals over prolonged periods.27 It is absorbed with great facility The use of alcohol is ubiquitous but its pattern of along the whole length of the gastrointestinal tract, usage is enormously varied; what constitutes but more rapidly from the small intestine than from abnormal or excessive alcohol use is, therefore, the stomach. More than twice as much alcohol can determined more by cultural than by clinical factors. be consumed with a meal as without one, yet pro- Not only are there large differences in the average duce a smaller rise in blood alcohol concentration.28 amount of alcohol consumed by individuals in dif- This is probably mainly as a result of delayed gastric ferent cultures, but also in the proportion of the emptying but also to changes in the pharmacokine- population who are total abstainers. In Britain as a tics of alcohol29 which are still poorly understood whole, for example, less than 10% of the adult despite more than 80 years of research. population are abstainers (in 1982) but there are Orthodox teaching, based upon the work of Mel- large regional differences which do not necessarily lanby,30 is that "the rate of oxidation (of alcohol) is correspond with average alcohol intake."' These are constant throughout the whole period (ie from the held to account for divergences from the general beginning of absorption to the end of oxidation and rule that the greater the consumption of alcohol by a elimination) and this is the case in spite of the fact community, the higher its incidence of alcohol- that the amount of alcohol in the body is getting induced disease. progressively less. The interpretation of the fact is, There is epidemiological evidence from several therefore, that whatever the amount of alcohol in sources that regular, modest alcohol consumption- the body the rate of oxidation is independent of the that is, 20-30 g/day, is associated with optimum amount drunk". This view of alcohol disposal, health and maximum longevity and that this is due espoused and developed by others-notably Wid- mainly to a reduction in coronary artery occlusion'6 mark32 who coined the term beta (J3) to describe the and the number of premature deaths from rate of fall in blood alcohol concentration with arteriovascular disease.'7-20 A causal relation with time-has not gone unchallenged29 32 and must now alcohol has not, however, been established nor has be considered too simplistic to warrant uncriticalcopyright. the association been universally observed2' and acceptance. It presupposed that alcohol is removed there is currently insufficient confidence in the be- from the body pool by a single metabolic pathway. neficial effects of small doses of alcohol to warrant This is now known to be incorrect and at least two advocating their use as a health measure. mechanisms capable of converting alcohol to carbon An average daily intake of alcohol greater than dioxide and water, in addition to that employing 40 g/day is associated with gradually increasing alcohol dehydrogenase, have been described; one morbidity and mortality rates. The Royal College of utilises catalase the other an NADP-dependent mic- http://jcp.bmj.com/ Psychiatrists' report22 recommends that the average rosomal oxidising system (MEOS). The quantitative daily intake of alcohol must be kept below 60 g/day importance of these two metabolic pathways in (eight drinks*) if the risks of suffering from its phys- alcohol metabolism is still controversial both in rela- ical or social consequences are to be kept to an tion to each other and to overall body metabolism acceptable figure. Doubtless some people acquire and current opinion inclines to the view that the alcohol-induced disease at lower average daily alcohol dehydrogenase pathway is responsible for intakes than this whilst many who exceed it do not. disposal of 70% or more of alcohol ingested, at least on September 29, 2021 by guest. Protected Nevertheless, this admittedly arbitrary figure does for as long as blood alcohol concentrations remain provide a useful dividing line between moderate and below 20 mmolI (92 mg/100 ml). At higher blood excessive alcohol use except in pregnancy23 24 where alcohol concentrations the MEOS, and possibly also it is undoubtedly too high (see below), and probably the catalase system, assumes greater relative and in women as a whole since they appear to be more absolute importance. This ability to involve addi- sensitive to the tissue damaging effects of alcohol tional metabolic pathways probably explains why than men.25 This, however, may be related more to alcoholic subjects can often dispose of up to 500 g their smaller size than their biology and certainly alcohol a day for weeks on end. This is roughly three warrants further investigation. times as much as would be expected on the basis of metabolic studies performed on countless subjects Absorption, disposition which indicate that, at more socially acceptable Though generally taken by mouth, alcohol can be *By an interesting quirk almost all drinks provide 7-9 g alcohol absorbed through any mucosal surface, including the when consumed in the conventional "public house measure,' ie skin;26 indeed the lungs provide one of the best 280 ml beer; 120 ml wine; 60 ml sherry, 24 ml whisky, gin, or routes for getting large quantities of alcohol (as vap- vodka. J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from Clinical pathology of alcohol 367 blood alcohol concentrations-for example, 2-22 thiol-containing compounds.39 In vivo it is normally mmol/l, the normal rate of alcohol oxidation is rapidly deactivated by acetaldehyde dehydrogenase, roughly 100 mg/kg/h, ie 7 g/h or 168 g/day for a an enzyme which, like ADH, exhibits polymorph- 70 kg person.5 ism.404' It, too, utilises NAD as cofactor with the Time of day is one of the important factors deter- production of NADH whose rate of reoxidation is mining the rate of alcohol metabolism33 as it is of one of the main determinants of alcohol metabolism other drugs, although it has received relatively scant in vivo. The role of acetaldehyde dehydrogenase attention from most investigators. What evidence itself in determining the rate of alcohol metabolism there is currently suggests that alcohol disappears is unknown. It might reasonably be expected to play from the blood faster in the morning than in the a central role since it is responsible for oxidation, to evening." If this is confirmed it could explain some acetate, of the acetaldehyde formed by all three of the discrepancies that dog the alcohol- alcohol oxidative pathways. This supposition is, metabolism literature. however, difficult to square with the observation The limiting factor determining the rate of alcohol that hepatic acetaldehyde dehydrogenase activity is metabolism at any time of the day is not known with reduced in alcoholics42 and as an inherited anomaly certainty. It is not, as was once thought, the amount in Japanese38 despite their normal or enhanced and availability of alcohol dehydrogenase in the capacity to metabolise alcohol. liver, but probably is something to do with the rate of reoxidation of the NADH which is formed whenever alcohol is oxidised to CO2 and water. MEASUREMENT Alcohol dehydrogenase exhibits marked The assay of acetaldehyde in biological fluids has polymorphism. Three autosomal gene loci (ADH, presented many difficulties in the past43 and only ADH2 ADH3) are thought to be concerned with very recently have meth'ods capable of accurately determining the structure of alcohol dehydrogenase measuring it in blood become available."445 Special in man-the first two manifesting themselves almost attention must be paid to the method of collecting exclusively during fetal life and the last during the sample if reliable results are to be obtained. copyright. infancy and adulthood.34 An "atypical" alcohol Data collected using such methods suggest that dehydrogenase (ADH2) has been distinguished from studies performed before 1980 grossly overesti- the typical enzyme (ADHI) by its optimum pH and mated the concentration of acetaldehyde in blood greater activity at physiological hydrogen ion con- after the ingestion of alcohol by normal and It is said to occur in of Euro- alcoholic subjects, and that many of the conclusions centrations. 5-20% based upon them may be wrong. It appears, peans and in 90% of Oriental populations and could http://jcp.bmj.com/ be responsible for the high incidence of alcohol- moreover, that much of the acetaldehyde present in induced flushing observed in the latter.35 This seems blood is protein-bound46 and might not, therefore, than and currently be available for measurement by widely used gas less likely formerly, however, chromatographic methods47-50 that depend upon comparatively little importance is attached by most analysis of head-space vapour. Older colorimetric,51 investigators to genetic variance of alcohol dehyd- spectrophotometric-" and enzymatic53 techniques, rogenase in the pathogenesis of alcohol-induced though capable of measuring protein-bound acetal-

or of itself.36 on September 29, 2021 by guest. Protected symptoms, organ damage, alcoholism dehyde are so unreliable on other counts as to be Acetaldehyde worthless for clinical investigation.

Acetaldehyde is the first metabolic product of SIGN IFICANCE alcohol metabolism regardless of whether oxidation Several studies, using gas chromatographic methods, is effected by alcohol dehydrogenase, catalase, or have revealed marked differences in blood acetal- MEOS. It has attracted considerable interest in the dehyde concentrations after alcohol ingestion bet- past few years and has been held responsible for ween normal and alcoholic subjects, being much many, if not most, of the tissue-damaging effects of higher in the latter.54 This differential acetaldehyde chronic alcohol abuse as well as for the unpleasant response to alcohol is said55 also to extend to the reaction experienced by people taking certain drugs healthy sons and other blood relatives of alcoholics or belonging to particular racial groups.3738 (who are at risk of becoming alcoholics themselves) Acetaldehyde is an extremely reactive compound and might be supposed to result from the inheri- capable, at very low concentrations, of interfering in tance of an abnormal (or atypical) acetaldehyde vitro with a number of vital processes including pro- dehydrogenase. It could also serve as a marker pre- tein synthesis and secretion by cells, mitochondrial dicting alcoholism in later life and would therefore ATP production and the inactivation of diverse be immensely useful clinically. Confirmatory or J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from 368 Marks negatory studies using reliable methodology are, compounds was first raised on theoretical grounds therefore, essential and are awaited with interest. by Davis and coworkers6" and developed by Sand- Certain drugs sensitise patients to alcohol. Two of ler68 who demonstrated the presence, after alcohol, them, disulfiram and citrated calcium carbimide are of significant amounts of salsolinol-a vaguely used therapeutically for the treatment of alcoholism morphine-like compound-in the urine of Parkin- because of the predictability of their effect whilst for sonian patients receiving L-dopa. most others-for example chlorpropamide, tol- Although there are many differences between butamide, metronidazole, pargyline, furazolidone, morphine and alcohol physical dependence, the griseofulvin and chloramphenicol, sensitisation is tetrahydroisoquinoline hypothesis-as it is now only a troublesome side effect that occurs in a vari- called-cannot be dismissed completely.69 There is able number of subjects. It has long been suspected evidence that salsolinol is present at 20 times greater that accumulation of acetaldehyde in the blood is concentrations in the urine of "drinking alcoholics" responsible for some of the unpleasant symptoms than of control subjects and that it falls to baseline that follow ingestion of alcohol. This has been concentrations within four days of alcohol with- confirmed in the case of disulfiram and citrated cal- drawal.70 Though it has not yet been established cium carbimide by direct measurements of acetal- whether salsolinol itself is addictive-that is, dehyde in the blood. Accumulation of acetaldehyde responsible for withdrawal symptoms, it is perhaps in these circumstances is due to inactivation of not without interest that the chlorpropamide- aldehyde dehydrogenase which, in the case of alcohol flush can be blocked by the specific opiate disulfiram, develops slowly over 12 hours;56 restora- antagonist, naloxone, and reproduced by an tion of aldehyde dehydrogenase activity depends enkephalin analogue with opiate-like activity.63 upon de novo synthesis which occurs over six days or more.57 Much less predictable than disulfiram Acute metabolic effects of alcohol induced alcohol sensitivity is that produced by chlorpropamide58 which occurs in a variable propor- In addition to its well known direct actions upon the tion of diabetic patients receiving treatment with the nervous system, alcohol has certain profound, acutecopyright. drug or who are given it experimentally. The prop- metabolic effects upon the body, the nature and ensity to develop chlorpropamide-alcohol flushing extent of which depend upon a variety of factors. [CPAF] is said to be inherited as a dominant trait59 These include the quantity of alcohol consumed, and to have a higher prevalance in patients with previous dietary history, the presence or absence of non-insulin dependent diabetes (type II) than in pre-existing organic and/or metabolic disease and

those with insulin-dependent diabetes (type I) and the genetic make-up of the individual. Many, though http://jcp.bmj.com/ control subjects, though others have not confirmed by no means all, of the effects on metabolic proces- this.6061 Patients with chlorpropamide-alcohol flush- ses are mediated through changes in the intrahepatic ing are said also to have a reduced risk of developing redox potential consequent upon the formation of "diabetic complications" but this too requires NADH, and the resultant depletion of intracellular confirmation. NAD, during oxidation of alcohol and acetaldehyde. The cause of the flushing is unknown but several Others are an indirect consequence of intoxication hypotheses have been put forward,62 one of the and its activation of sympathetic nervous activity most favoured being that it is due to the accumula- and other neurohumoral mechanisms. In some cases on September 29, 2021 by guest. Protected tion of acetaldehyde in the blood.5865 A certain the effects are the result of alcohol-drug interac- resemblance to disulfiram-induced alcohol tions,' 72 a small number of which have been used sensitivity-which is, however, generally much more therapeutically as in the case of disulfiram and severe66 and often accompanied by symptoms of citrated calcium carbimide.'3 intensive palpitations, dyspnoea, nausea, vomiting Metabolic consequences of the changes in and headache which are never observed in the intracellular redox potential include the accumula- chlorpropamide-induced variety-and to racial tion of lactate in the blood, a rise in hydrogen ion alcohol flushing supports this suggestion. In both of concentration-that is, fall in pH, and an increase in these latter conditions plasma acetaldehyde con- the plasma lactate:pyruvate ratio. A rise in plasma centrations rise higher after alcohol ingestion than in urate, due to impaired excretion of urate by the kid- non-affected controls,38 4 though seldom to the con- neys, and inhibition of gluconeogenesis, which mani- centrations encountered during severe disulfiram fests itself as hypoglycaemia and ketonaemia if reactions. alternative sources of glucose-for example, food The possibility that acetaldehyde formed from and/or liver glycogen, are not available, also occur. alcohol might condense chemically with dopamine Plasma fatty acid concentrations may rise or fall and other catecholamines to produce morphine-like depending upon dosage. J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from Clinical pathology of alcohol 369

Probably the most dramatic example of alcohol mechanism involved is still uncertain though precipitating a metabolic emergency in genetically hypotheses abound. predisposed individuals is acute intermittent por- phyria747 5 and in Glasgow it was the third common- Endocrine function est precipitating factor accounting for 13% of all the acute attacks observed during a three-year period. The profound effects of alcohol upon endocrine Alcohol is also one of the main aetiological agents in function, which can arise as a result of both acute the development of cutaneous hepatic porphyria76 and long-term ingestion, have only been fully through its effect upon haem synthesis, though in appreciated within the past 10 years or so.84-89 this instance the disturbance is subacute rather than Almost no part of the endocrine system is exempt acute in onset. though some glands and systems are more suscept- Alcohol-induced (fasting) hypoglycaemia is ible than others. Though interest has centred mainly equally dramatic77 as acute porphyria but can occur upon the hypothalamic-pituitary-adrenal axis and in anyone-providing the circumstances are right- latterly the gonads, disturbances of other endocrine as well as in the genetically or otherwise predis- functions have attracted attention, notably those of posed. It is, however, especially common in chil- the pancreas,90 adenohypophysis99 and thyroid.92 dren, the malnourished, and alcoholics. The blood The ability of alcohol to stimulate calcitonin release glucose concentration is invariably low and plasma in patients with medullary carcinoma of the lactate and /3-hydroxybutyrate high. Blood alcohol thyroid,9394 flushing in patients with carcinoidosis95 is more often below than above 25 mmolIl by the and adrenaline release in patients with time the hypoglycaemia develops. pheochromocytoma96 is sometimes used diagnosti- Large doses of alcohol can, though seemingly only cally. very rarely, precipitate acute hyperglycaemic (diabetic) ketoacidosis in diabetic subjects previ- HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ously stabilised on dietary treatment alone.78 More It has long been known that large intoxicating doses commonly79-82 it produces a type of ketoacidosis of alcohol given to animals activate adrenocortical copyright. which resembles diabetic ketoacidosis clinically but as well as adrenomedullary activity. More recently it in which hyperglycaemia plays no part. It is accom- has been reported9799, that the administration of panied by marked increases in plasma and urinary modest but intoxicating doses of alcohol stimulate lactate and ketone concentrations but, because of cortisol secretion in healthy volunteers although it the shift in the ratio of 83-hydroxybutyrate to now seems likely that the intoxication rather than

acetoacetate produced by the change in redox alcohol itself is the operative agent.'00 More clini- http://jcp.bmj.com/ potential the ketosis can easily be overlooked since cally relevant is the recognition that occasional conventional tests for urinary (and the semi- chronic alcohol users develop physical and biochem- quantitative tests for plasma) ketones are insensitive ical stigmata resembling those of Cushing's syn- to /8-hydroxybutyrate. drome from which they can often be distinguished Alcohol is one of the most important causes of only with great difficulty.'01-'06 The most telling hyperlipidaemia83 and its possible aetiological role point is that both the clinical and biochemical fea- should be suspected whenever this condition is tures of adrenocortical hyperactivity abate within on September 29, 2021 by guest. Protected encountered. Gross hypertriglyceridaemia some- 2-3 weeks of withdrawal from alcohol. Chronic times observed after comparatively mild alcohol use alcoholics without either clinical or biochemical evi- is partly due to increased triglyceride formation in dence of Cushing's syndrome often show impaired the liver and partly to impaired removal of suppression of adrenocortical activity in response to chylomicrons and VLDL from the circulation. This dexamethasone,'07 the most likely cause of which is may occur whenever alcohol and fatty food are defective hypothalamic function though accelerated ingested together and persist for up to 14 hours after metabolism of dexamethasone by alcohol-induced the meal. enzymes and its consequent failure to reach and Differentiation of alcohol-induced from geneti- maintain suppressive plasma concentrations, has not cally determined hypertriglyceridaemia may be been excluded. difficult without a detailed history since increases in More common than alcohol-induced Cushing's plasma gamma glutamyl transferase and urate are syndrome, but less clinically evident, is a reversible common in both. form of ACTH deficiency which can often only be Whether such well known somatic manifestations demonstrated by the failure of plasma ACTH and of alcohol ingestion as acute pancreatitis, alcoholic cortisol concentrations to rise in response to hepatitis, gastritis, myocarditis, and muscle disease insulin-induced hypoglycaemia.85 101 108 109 This are "metabolic" in origin is unknown. If so, the abnormality occurs in up to 25% of alcoholics and is J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from 370 Marks often accompanied by an impairment of growth- hypothalamic-pituitary involvement as well as a hormone secretion which can also occur as an iso- gonadal effect. lated, but reversible, abnormality."0 In a small Chronic alcohol ingestion may produce gonadal proportion of cases the abnormality in ACTH and/ atrophy, severe germ cell injury and a marked or growth hormone secretion is accompanied by a reduction in plasma steroid concentrations in propensity to develop symptomatic fasting hypo- experimental animals reminiscent of those seen in glycaemia especially in response to alcohol inges- chronic alcoholic men in whom spuriously high tion. plasma levels of 17,B-hydroxy androgens are some- There is no evidence that either primary or secon- times85 108 seen, possibly due to an increase in sex dary adrenocortical insufficiency predisposes to hormone binding globulin (SHBG) concentration.'22 alcoholism. There is, however, a cult-which origi- Evidence from a number of quarters suggests that nated, and is especially influential in the United the effects of alcohol on sexual function are exerted States, where it has many adherents both amongst through multiple mechanisms including indirectly registered medical practitioners and the laity- through the hypothalamus, by direct inhibition of which maintains that it does. Warnings have been testosterone synthesis in the testes and its increased issued in the medical press by the American Diabetes metabolism in peripheral tissue.87 122 Much less is Association, American Medical Association and known about the effect of alcohol on gonadal func- Endocrine Society"' 112 on two occasions in the past tion in women, though impaired fertility is a recog- 10 years against practitioners who, amongst other nised complication of chronic alcohol abuse.'23 As things, attribute many of the vague symptoms mentioned elsewhere the regular ingestion of even experienced by alcoholic and other patients to small amounts of alcohol-for example, 30 g alcohol "hypoglycaemia" for which there is invariably no per day, during pregnancy increases the incidence of diagnostic laboratory evidence apart from an fetal abnormalities.23 24 abnormal glucose tolerance test, the general worth- lessness of which in the diagnosis of genuine hypo- SY MPATHETICO-ADREN OMEDULLARY glycaemia is now well established." FUNCTION copyright. Chronic alcoholism is often associated with Experiments on animals, and experimental and clin- reduced urinary excretion of 17-oxosteroids (for- ical observations in man, have shown that intoxicat- merly thought to be a useful index of adrenocortical ing doses of alcohol activate sympathetico- function), due to alcohol-induced alterations in adrenomedullary activity.8499 Whether smaller non- steroid metabolism in the liver, as well as with an inebriating doses, or chronic alcohol abuse, have increased propensity to the development of both similar effects is unknown. Conclusions relating to fasting and (experimental) reactive hypoglycaemia. sympatheticoadrenomedullary function in alcoholics http://jcp.bmj.com/ These facts have been used by adherents of the cult based on urine analysis are complicated by the fact to support their "scientific arguments" that hypo- that alcohol alters the metabolism of catecholamines glycaemia predisposes to alcoholism and their habit through changes in redox potential in the liver. As a of prescribing inactive adrenocortical extracts for its result, urinary excretion of 3-methoxy-4-hydroxy treatment. mandelic acid (HMMA; VMA) the normal major product of adrenaline and noradrenaline HYPOTHALAMIC-PITUITARY-GONADAL catabolism-is decreased and there is a correspond- on September 29, 2021 by guest. Protected FUNCTION ing increase in 3-methoxy-4-hydroxy phenyl glycol The well known effects of alcohol upon sexual func- (MHPG) excretion.'24 125 tion in both men and women have long been attri- Few studies have been made of the effects of buted mainly to liver damage."3 "I Although this is modest amounts of alcohol on catecholamine still recognised to play a contributory role when it is release using modern analytical techniques with present, there is good evidence for a more direct sufficient sensitivity and specificity to detect small effect of alcohol upon the hypothalamic-pituitary- but significant changes in plasma adrenaline and gonadal axis'" 117 and gonads themselves. noradrenaline. An unpublished study in my own Ethanol administration to immature male rats laboratory, using an isotope derivatisation technique prevents the normal rise in plasma LH concentra- with chromatographic separation for the measure- tion that occurs with the onset of puberty"8 and ment of adrenaline and noradrenaline, showed that produces a fall in plasma testosterone concentra- alcohol given on an empty stomach to healthy volun- tions. In normal human subjects its administration teers in doses sufficient to raise blood alcohol con- leads to an acute fall in plasma testosterone'19-121 centrations to 10-21 mmolI (50-100 mg/100 ml) which may, paradoxically, lead to an acute rise in had no effect upon plasma adrenaline and only a plasma LH but usually does not, indicating a small, clinically unimportant stimulatory effect on J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from Clinical pathology ofalcohol 371 plasma noradrenaline concentrations unless symp- plasma insulin secretion is inhibited and plasma con- toms of alcohol intoxication intervened when centrations are low. Glucagon secretion, on the plasma concentrations of both catecholamines rose other hand, is stimulated but in the absence of hepa- dramatically. What role, if any, sympathetic nervous tic glycogen stores is ineffective in raising the blood activation plays in the aetiology of reversible hyper- glucose concentration. tension observed in some heavy alcohol users is unknown but would probably repay investigation. Diagnostic considerations Though catecholamine production is markedly increased during alcoholic inebriation, as well as by The ingestion of alcohol is associated with numerous alcohol withdrawal, a certain number of chronic changes in blood chemistry and morphology, the alcoholics-two out of 12 in the series reported by nature, magnitude and number of which are deter- Wright91-for example-show no sympathetico- mined by the amount and duration of alcohol con- adrenomedullary response to insulin-induced sumption and the interval since any was last con- hypoglycaemia, suggesting that the hypothalamic sumed. Hopes have long been expressed that it depression noted in respect of growth hormone and might be possible, by measuring one or more of the ACTH secretion extends to the autonomic nervous constituents of the blood, to determine the average system. Suppression of sympatheticoadrenomedul- daily dose of alcohol ingested and whether alcohol- lary activation by alcohol is not confined to chronic induced tissue damage was present. None of these alcohol users. Modest amounts of alcohol prevent hopes has been more than partially fulfilled and cur- the normal homeostatic restoration of blood glucose rent evidence suggests that even a battery of to normal following its experimental depression by laboratory tests is less sensitive or specific than a exogenous insulin, and a combination of alcohol and properly conducted interview.'30'-33 There is no exercise in the cold can lead to severe and poten- doubt, however, that laboratory tests are occasion- tially dangerous hypoglycaemia in healthy volun- ally helpful in detecting alcohol-induced disease teers, presumably due to impaired hypothalamic before it becomes clinically apparent, and for asses- function126 and impaired gluconeogenesis. sing the response to treatment.'34-'38 They have copyright. recently been reviewed.'39 140 ENTEROINSULAR AXIS The effect of alcohol upon the enteroinsular axis, ALCOHOL IN THE BLOOD like that of other endocrine systems, is profoundly Alcohol is not normally present in blood in more affected by dose and duration.90 In modest doses it than trace amounts unless it has been imbibed enhances the insulinotropic effects of various recently; even then it seldom exceeds a concentra- http://jcp.bmj.com/ secretagogues-for example, glucose and glucagon, tion of 15 mmolI except in the presence of clear through an unknown mechanism which involves evidence of intoxication. The presence of such high increased cAMP production in the pancreatic B concentrations without cerebral dysfunction is evi- cells. One effect of enhancement is that ingestion of dence of habituation and consequently, indirectly, of an appropriate mixture of alcohol and sugar-for chronic alcohol abuse. The signs of cerebral dysfunc- example, gin and tonic, may, if taken on an empty tion need not necessarily be distressing to the sub- stomach, predispose to development of (symptoma- ject himself, and may only be apparent if actively on September 29, 2021 by guest. Protected tic) reactive hypoglycaemia one and a half to three sought. They consist mainly of mild euphoria, hours later.'27 128 Small carbohydrate-yielding snacks increased self-confidence, decreased inhibitions, may exacerbate rather than diminish the tendency reduced attention and loss of efficiency in fine per- which can have important implications for those formance tests. Amongst the criteria proposed by who drink and drive.'29 the American National Council on Alcoholism'4' for Larger doses of alcohol-that is, those leading to the diagnosis of alcoholism, is the presence of a blood alcohol concentrations greater than 25 mmolI blood alcohol concentration greater than 65 mmolI do not enhance and may even inhibit glucose- (300 mg/100 ml) at any time, or of over 33 mmol/l induced insulin secretion. This, together with the (150 mg/100 ml) without symptoms. The finding of activation of sympathetic nervous activity that fol- a blood alcohol concentration of 22 mmolI (100 lows heavy drinking, may explain the well known mg/100 ml) during a routine clinical examination ability of alcohol abuse to depress rather than to provides strong presumptive evidence of the diag- improve glucose tolerance.90 nosis. Blood alcohol concentrations seldom rise Alcohol consumed whilst the subject is fasting or above 35 mmolI even after quite heavy social drink- on a low carbohydrate intake may cause fasting ing though it is still possible, in the latter circums- hypoglycaemia by inhibition of gluconeogenesis." tances, for blood alcohol concentrations to exceed In this condition, which is extremely dangerous, 10 mmol/I the following morning.'42 J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from 372 Marks In view of the ease'43 with which blood alcohol animotransferase (AST), alanine aminotransferase measurements can now be carried out-on breath as (ALT) glutamate dehydrogenase (GDH), and well as on blood itself-it is suprising how rarely alkaline phosphatase (ALP), of which the first is by they are included in routine health screening prog- far the most important.'49 150 rammes or, despite their proven usefulness," 145 employed by clinicians confronted with alcohol Gamma glutamyl transferase (GT) abuse as a differential diagnosis. In a study of 1476 The measurement of plasma GT activity as a patients, carried out in Switzerland, 2% of patients biochemical index of alcohol consumption was attending the medical outpatient clinic, 9% of all introduced and popularised by Rosalki.'49 It has new admissions to the medical emergency ward and subsequently come to enjoy a unique place in the no less than 12% of those admitted to the surgical detection of alcohol abuse in patients with a variety emergency ward had blood alcohol concentrations of somatic and psychosocial diseases. Early reports on arrival at the hospital in excess of 22 mmoIl.'46 In indicated that between 75% and 85% of chronic another study from America, blood alcohol meas- alcoholics had moderately to markedly raised urements were made on 76 patients attending the plasma GT activities'50- 153 but subsequently lower emergency room of a large hospital in Pennsylvania figures of between 30-50% were reported.'33 154 The over a period of two years, who admitted drinking latter figure corresponds well with the sensitivity- alcohol within the past six hours but were deemed that is, the percentage correctly identified, of plasma sober or "non-intoxicated" by the examining physi- GT measurements in detecting excessive alcohol use cian.'47 Patients who were drunk or otherwise consi- (an average intake of more than 65 g alcohol per dered incapable of being released from the day) amongst 8000 attendees at a Medicheck Centre emergency room on their own recognisance, were in Sydney,'35 and in healthy manual workers and excluded from the study. No alcohol was detected in company directors'55 who volunteered to participate the blood of 11 of the subjects but in the remaining in an extensive investigation of drinking habits in 65, its average concentration was a staggering 58*2 Edinburgh. In the latter study plasma GT measure- + 2.2 mmol/l (range 26-117 mmolIl; 120-540 mg/ ments yielded false-positive results in 11% of thecopyright. 100 ml). Concentrations such as these are generally manual workers and 22% of the company directors associated with stupor or coma from acute alcoholic if their accounts of their own alcohol intakes are to poisoning and serve to illustrate how unreliable clin- be believed. Thus, GT is not only a relatively insen- ical impressions can be in assessing the extent of sitive test (despite being the best there is) but also a alcohol use by habitual users. non-specific one for the detection of alcohol abuse

Blood alcohol measurements, though already very even in a high risk population. http://jcp.bmj.com/ simple to carry out in a clinical laboratory setting, would undoubtedly be used more frequently if, as is Aspartate aminotransferase (AST) now technically possible, simple quantitative stick Of the other plasma enzymes perturbed by chronic tests-analogous to those used for glucose and other alcohol abuse, aspartate aminotransferase is the blood and urine constituents-were readily avail- most sensitive, being pathologically raised in 25- able for use in clinics and outpatient departments. 30% of chronic alcoholics'50 154 and in 10-15% of

Laboratory reagent manufacturers may have been those who drink more than 65-80 g of alcohol a day on September 29, 2021 by guest. Protected inhibited from making them from fear of litigation without overt evidence of liver damage.'33 135 138 arising from their (mis)use for forensic rather than for clinical purposes. Hopefully, this and other obs- Glutamate dehydrogenase (GDH) tacles to the introduction of these potentially useful Plasma GDH, like the two enzymes already men- diagnostic aids will soon be overcome. tioned, correlate positively with alcohol consump- tion but is an even less sensitive index of alcohol PLASMA ENZYMES abuse than either'56 being abnormally raised in only Chronic excessive alcohol ingestion is associated 15-25% of all heavy alcohol users.'33 It is, however, with increased activity of many of the enzymes nor- remarkably specific (98%) for alcohol abuse when mally found in the plasma. Most of those that have used in an apparently healthy population and being been studied extensively derive mainly, if not exclu- a mitochondrial enzyme probably identifies latent or sively, from the liver,'48 and their presence in occult hepatocellular damage.156 157 increased amounts in the plasma has been construed as evidence of potential or real liver damage though Other enzymes this interpretation is not necessarily correct. Various other serum enzyme activities-for exam- Enzymes that have attracted most attention include ple, isocitrate dehydrogenase, alanine aminotrans- gamma glutamyl transferase (GT), aspartate ferase, lactate dehydrogenase, alkaline phosphatase, J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from Clinical pathology of alcohol 373 ornithine carbamoyltransferase, are raised in ciency. The authors warned against too ready accep- alcoholics and heavy alcohol users but none has tance of macrocytosis as evidence of alcohol abuse sufficient sensitivity and/or specificity to make it use- without further investigation.'63 164 ful either for screening or diagnosis.'54 One of the most promising of the enzymes to have been investi- URIC ACID gated for the diagnosis of alcohol abuse is red-cell Serum uric acid concentrations correlate positively A-amino-laevulinic dehydrase'58-'60 which is said to with alcohol intake'33-135 165 even though the aver- be depressed in 90% of heavy alcohol users.'58 It is, age value in heavy users is only 15% higher than in however, an unstable enzyme whose measurement is abstainers. It is not surprising, therefore, that serum difficult and it has not been introduced into the clini- urate is both non-specific'35 and insensitive as an cal laboratory repertoire. indicator of alcoholism (a sensitivity of 20%) or excessive drinking (a sensitivity of 18%) in an MEAN RED CELL VOLUME (MCV) unselected population'33 though higher percentage In unselected populations, mean red cell volume figures for sensitivity have been quoted,'65 especially (MCV) correlates positively with average daily in men. Nevertheless, serum urate may occasionally alcohol intake.'33 13' The average difference in red provide a clue to an unsuspected alcoholic aetiology cell size between abstainers and heavy users is, how- of a patient's disease'65 or add weight to a presump- ever, less than 4.5 fl (approximately 5%) and tive diagnosis of alcoholism. although abnormally large red cells are said to be comparatively common in alcoholics and chronic PLASMA LIPIDS alcohol abusers, the exact proportion depends heav- ily upon the upper reference limit (of normality) set Triglycerides by the investigator. Clearly, with such small percen- Although plasma triglyceride concentrations'34 135 tage differences in MCV between abstainers and correlate positively with average daily alcohol intake heavy alcohol users (whether considered in absolute in fasting subjects, unlike those of total plasma terms or in relation to the variation between healthy cholesterol'33 which show neither positive nor nega- copyright. individuals) there is a premium on both accuracy tive correlation, neither its sensitivity (20%) nor and precision of measurement. Wu et al,'6' for specificity (6%) makes it suitable as a diagnostic test example, reported that 89% of 63 patients consum- of alcohol abuse. Nevertheless, because of its high ing more than 80 g ethanol daily had a macrocytosis prevalence, chronic alcohol abuse is one of the compared with healthy controls with an upper refer- commonest causes of (fasting) hypertriglycer- ence limit of 92 fl. In a subsequent larger study'62 no idaemia. It should, therefore, always be suspected as http://jcp.bmj.com/ less than 94% of women and 71 % of men who were an aetiological factor in the pathogenesis of fasting, drinking excessively (over 80 g alcohol per day) had or indeed random, lipaemia since alcohol not only a macrocytosis by these criteria. Whitfield et al,'35 increases triglyceride synthesis in the liver, but also using a similar upper reference limit of 90 fl for men prolongs the hypertriglyceridaemia produced by and 92 fl for women, reported an incidence of mac- ingestion of fatty meal. The mechanism of this rocytosis in 35% of subjects drinking more than 65 g hypertriglyceridaemia is incompletely understood alcohol per day against 6% in abstainers or infre- but is probably due more to the delayed clearance of on September 29, 2021 by guest. Protected quent alcohol users. Using the more realistic figure chylomicrons from the plasma than to accelerated of 96 fl as the upper reference limit for MCV Ber- absorption from the gut. nadt et al'33 found no macrocytosis amongst 42 excessive drinkers (over 120 g alcohol per day) and Cholesterol only one case amongst 49 alcoholics attending a Contrary to earlier suggestions'66 167 there is no cor- psychiatric clinic for the first time. Between these relation between average daily alcohol intake and two extremes are the results reported by Chick et plasma total cholesterol concentration'33 in the gen- al'"5 who, having set the upper reference limit for eral population. It has, however, been established MCV at 98 fl, observed macrocytosis in 10 out of 47 that in healthy volunteers addition of moderate manual workers (a sensitivity of 23%) and in 10 out amounts of alcohol to the diet produces a temporary of 30 company directors admitting to a daily alcohol rise in plasma a-lipoprotein cholesterol (HDL), intake of more than 65 g. Employing identical which returns to baseline values when drinking criteria, macrocytosis was observed by Stockdill and ceases'68 169 and that actively drinking alcoholics (but Allan'63 in 386 out of 9474 consecutive blood not dried-out ones) have higher plasma HDL con- specimens (4-1%) submitted for analysis by General centrations than abstainers and modest alcohol Practitioners in Edinburgh, of which 20% could be drinkers.'40 It has been suggested'70 that this could accounted for by vitamin B12 and/or folate defi- provide the basis of a test for chronic alcohol abuse, J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from 374 Marks but its low sensitivity, especially in patients with inducing drugs. Lack of specificity reduces its clinical alcohol-liver disease, makes it more suitable as an usefulness as a screening procedure. The same con- adjunct to diagnosis-especially in hyperlipidaemic straints probably also apply to urinary patients with raised plasma GT and urate concentra- 6-/3-hydroxycortisol measurements which have been tions"' who deny excessive or indeed any alcohol used in other contexts as an indicator of enzyme consumption-than as a screening procedure. induction. It is still unsettled as to whether the changes in plasma HDL produced by alcohol contributes to the Conclusions reduction in deaths from myocardial infarction observed in moderate social drinkers compared with Alcohol is an important cause of illness in man when abstainers, a reduction incidentally which does not consumed in excess and sometimes even in socially carry over into immoderate drinking which is itself a acceptable amounts over prolonged periods. The risk factor for acute, fatal myocardial infarction.'72 psychosocial features of chronic alcohol abuse are often inconspicuous and the alcoholic aetiology of a TRAN SFERRIN patient's illness may be unsuspected unless An unusual transferrin band can be found, by specifically sought since patients often underesti- isoelectric focusing followed by immunofixation, in mate their average daily alcohol intake. Laboratory the serum of 80% of chronic alcoholics admitting to tests-notably measurements of blood alcohol, an average daily consumption of 60g alcohol during plasma GT, aspartate transferase, alkaline phos- the week prior to testing, compared with only 8% of 14 phatase activities, urate and triglycerides, and the those who claim to have been abstinent.'"73 The MCV-often provide the first clue to an alcoholic same anomalous transferrin can be found in the aetiology in a patient with symptoms, or point to the serum of only 1 % of control subjects. The protein, possibility of alcohol abuse in an otherwise seem- therefore, appears to provide a specific and a mod- ingly fit person undergoing a "routine" medical erately sensitive test for the detection of excessive check-up. Although none of the tests yet devised is alcohol use which is independent of hepatocellular as reliable, alone or in combination, as a well con- copyright. disease since it is absent from the serum of patients ducted interview, discriminant function analysis of with non-alcohol induced liver disease. Confirmat- only three of them-namely, GT, ALP and MCV- ory reports of its value for diagnostic purposes are is said'77 to identify correctly 80% of subjects awaited with interest for although the methodology whose alcohol intake is "excessive". of its detection and measurement are at present too There is little doubt that alcohol is no exception to complicated for regular clinical use, they could

the rule that pharmacodynamic and toxicological http://jcp.bmj.com/ undoubtedly be simplified if the need existed. responses to drugs are highly individualist and often OTHER PLASMA CONSTITUENIT S bear little or no relation to dose or duration of use, Over the years many other constituents of the except in a statistical or epidemiological sense. My plasma have been reported to be qualitatively or own practice is, therefore, to use laboratory abnor- quantitatively altered by chronic alcohol abuse; malities as an aid to convincing patients in whom some, such as the ratio of a-amino-n-butyric acid to they are demonstrably due to alcohol that, regard- less of how little alcohol they are drinking, or admit

leucine, were thought originally to be more or less on September 29, 2021 by guest. Protected specific'75 but turned out not to be So,"76 whilst to, it is clearly too much for them as an individual. others were considered inconsequential because of It must, however, be admitted here, though not their non-specificity from the very beginning. Refer- necessarily in the clinic, that clear proof is still lack- ences to these substances can be found in the litera- ing that the presence of biochemical (and ture.'2 haematological) abnormalities demonstrable only in the laboratory portends the appearance of clinical Urine disease at a later date. Likewise, it would be mis- guided to believe that a diagnosis of alcoholism Chronic alcohol abuse is accompanied in approxi- made on psychosocial or clinical grounds is rendered mately 50% of cases by an increased excretion of untenable by failure to detect evidence of it in the glucaric acid.'52 Generally looked upon as a non- laboratory, though prudent re-examination of the invasive marker of microsomal enzyme induction, evidence upon which the diagnosis was originally glucaric acid excretion is increased by the long-term made may be indicated. use of many drugs and is consequently not specific for alcohol. It can, however, provide valuable References confirmatory evidence of heavy alcohol use in sub- 'Robb SA, Bramble MG, Hamilton PJ. Alcohol abuse in dis- jects who are not regularly taking known enzyme- guise. Lancet 1980;i:804. (letter). J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from Clinical pathology of alcohol 375

2 Jarewalla AF, Adams PH, Hore BD. Alcohol and acute general ism: Clinical and Experimental Research 1980;4:6-21. medical admissions to hospital. Health Trends 1979;11:95-7. 3 Mellanby E. Alcohol: its absorption into and disappearance 3Badawy AA-B. The metabolism of alcohol. Clin Endocrinol from the blood under different conditions. Medical Research Metab 1978;7:247-71. Council Special Report Series No 31. London: HMSO, 1919. 4Peters TJ. Ethanol metabolism. Br Med Bull 1982;38: 17-20. 31 Widmark EMP. Der Einfluss der Nahrungsbedstandteile auf der 5 Khanna JM, Israel I. Ethanol metabolism In: Javitt NB, ed. Alkolgehalt des Blutes. Biochemische Zeitschrift Liver and biliary tract physiology Vol 21. Baltimore: Univer- 1933;267:135-42. sity Park Press; 1980:275-315. 32 Lundquist F, Wolthers H. The kinetics of alcohol elimination in Morgan MY. Alcohol and Nutrition. Br Med Bull 1982;38:21- man. Acta Pharmacol Toxicol 1958;14:265-89. 9. 33 Sturtevant FM, Sturtevant RP. Chronopharmacokinetics of 7Saunders JB, Haines A, Portman B, Wodak AD, Powell- ethanol In: Majchrowicz E, Noble EP, eds. Biochemistry and Jackson PR, Williams R. Accelerated development of pharmacology of ethanol. New York: Plenum, 1979:27-40. alcoholic liver cirrhosis in patients with H2A-B8. Lancet 34 Smith M, Hopkinson DA, Harris H. Developmental changes 1981 ;i: 1381-4. and polymorphism in human alcohol dehydrogenase. Ann Eddleston ALWF, Davis M. Histocompatibility antigens in Hum Genet 1971;34:251-71. alcoholic liver disease. Br Med Bull 1982;38:13-6. 3S Stamatoyannopoulos S, Chen S-H, Fukui M. Liver alcohol 9 Seixas FA. Currents in alcoholism; biological, biochemical and dehydrogenase in Japanese: high population frequency of a clinical studies. New York: Grune and Stratton, 1977. typical form and its possible role in alcohol sensitivity. Ann J '° Lieber CS. Metabolic aspects of alcoholism. Lancaster: MTP Hum Genet 1975;27:789-96. Press, 1977. 36 Propping P. Pharmacogenetics. Pharmacol Rev Physiol Biochem "Majchrowicz E, Noble EP. Biochemistry and pharmacology of 1978;83:123-73. ethanol Vol I and II. New York: Plenum, 1979. 37 Ewing JA. Alcohol sensitivity and ethnic background. Am J 12 Kricka U, Clark PMS. Biochemistry ofalcohol and alcoholism. Psychiatr 1974;131:206-10. Chichester: Ellis Horwood, 1979. 3' Harada S, Agarwal DP, Goedde HW. Alcohol dehydrogenase 13 Clark PMS, Kricka U. Medical consequences of alcohol abuse. deficiency as a cause of facial flushing reaction to alcohol in Chichester: Ellis Horwood, 1980. Japanese. Lancet 1981;u:982 (letter). "Sherlock S, ed. Alcohol and disease. Edinburgh: Churchill- 3 Lieber CS. Alcohol, protein metabolism, and liver injury. Gas- Livingstone, 1982. troenterology 1980;79:373-90. 15 Smith R. Alcohol and Alcoholism: the relation between con- Greenfield NJ, Pietruszko R. Two aldehyde dehydrogenases sumption and damage. Br Med J 1981;283:895-8. from human liver. Isolation via affinity chromatography and 36 Barboriak JJ, Rimm AA, Anderson AJ, Schmidhoffer M, Tris- characterisation of the isoenzymes. Biochim Biophys Acta tani FE. Coronary artery occlusion and alcohol intake. Br 1977;483:33-45. copyright. Heart J 1977;39:289-93. 4' Harada S, Misawa S, Agarwal DP, Goedde HW. Liver alcohol 71 Blackwelder WC, Yano K, Rhoads GG, Kagan A, Gordon T, dehydrogenase and aldehyde dehydrogenase in the Japanese: Palesch Y. Alcohol and mortality: the Honolulu heart study. isoenzyme variation and its possible role in alcohol intoxica- Am J Med 1980;68:164-9. tion. Am J Hum Genet 1980;32:8-15. 1Kozararevic DJ, McGee D, Vojvodic N, Racic Z, Dawber T, 42 Jenkins WJ, Peters TJ. Selectively reduced hepatic acetaldehyde Gordon T, Zukel W. Frequency of alcohol consumption and dehydrogenase in alcoholics. Lancet 1980;i:628-9. morbidity and mortality: the Yugoslavia cardiovascular dis- 43 Eriksson CJJ. Problems and pitfalls in acetaldehyde determina-

ease study. Lancet 1980;i:613-6. tions. Alcohol: Clinical and Experimental Research 1980;4: http://jcp.bmj.com/ 9 Klatsky AL, Friedman MD, Siegelamb MS. Alcohol and mortal- 22-9. ity: a 10-year Kaiser-Permanente experience. Ann Intern Med " Knop J, Angelo H, Christensen JM. Is role of acetaldehyde in 1981;95: 139-45. alcoholism based on an analytical artefact? Lancet 1981 ;u: 102 2U Marmot MG, Rose G, Shipley MJ, Thomas BJ. Alcohol and (letter). mortality: a U-shaped curve. Lancet 1981;i:580-3. 4 Thomas MC, Chan JYY, Mansell F, Lim CK, Peters TJ. Plasma 21 Dyer AR, Stamler J, Paul D, Lepper M, Shekelle RB, McKean acetaldehyde: a new assay technique for protein-bound H, Garside D. Alcohol consumption and 17-year mortality in acetaldehyde. Clin Sci 1981;61:24P. the Chicago Western Electric Company study. Prev Med 4Thomas M, Lim C-K, Peters TJ. Assaying acetaldehyde in

1980;9:78-90. biological fluids. Lancet 1981;ii:530-1. on September 29, 2021 by guest. Protected 22 Royal College of Psychiatrists. Alcohol and alcoholism. Report 47 Duritz G, Truitt EB. A rapid method for the simultaneous of the Special Committee. London: Tavistock Publications, determination of acetaldehyde and ethanol in blood using gas 1979. chromatography. Quaterly Journal of the Study of Alcohol 23 Bostrom H. Fetopathy caused by alcohol - a critical review In: 1964;25:498-510. Avogaro P, Sirtori CR, Tremoli E, eds. Metabolic effects of 4' Eriksson CJ, Sippel HW, Forsander OA. The determination of alcohol. Amsterdam: Elsevier/North Holland, 1979:49-54. acetaldehyde in biological samples by head-space gas 24 Pratt OE. Alcohol and the developing fetus. Br Med Bull chromatography. Anal Biochem 1977;80: 116-24. 1982;38:48-52. 49 Medenhali CL, Macbee J, Green SE. Simple, rapid and sensitive 25 Saunders JB, Davis M, Williams R. Do women develop method for the simultaneous quantitation of ethanol and alcoholic liver disease more readily than men? Br Med J acetaldehyde in biological materials using head space gas 1981 ;282: 1140-3. chromatography. J Chromatogr 1980;190:197-200. 26 Moss MH. Alcohol induced hypoglycemia and coma caused by 56 Von Wartburg JP, Ris MM. Determination of acetaldehyde in alcohol sponging. Pediatrics 1970;46:445-7. human blood. Experientia 1979;35: 1682-3. 27 Grieve SJ, Littleton JM. The rapid development of functional 5, Stotz E. A colorimetric determination of acetaldehyde in blood. tolerance to ethanol by mice. J Pharm Pharmacol J Biol Chem 1943;148:589-91. 1979;31:605-10. B2Rurbridge T, Hine CH, Schlick AF. A simple spec- 28 Lolli G, Meschieri L. Mental and physical efficiency after wine trophotometric method for the determination of acetaldehyde and ethanol solutions ingested on an empty and on a full in blood. J Lab Clin Med 1950;35:983-7. stomach. Quarterly Journal of Studies on Alcohol Lundquist F. Enzymatic determination of acetaldehyde in 1964;25:535-46. blood. Biochem J 1958;68:172-7. 29 Wilkinson PK. Pharmacokinetics of ethanol: a review. Alcohol- 54 Korsten MA, Matsuzaki S, Feinman L, Lieber CS. Blood J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from 376 Marks

acetaldehyde levels after ethanol administration: difference 78 Phillips GB, Safrit HF. Alcoholic diabetes: induction of glucose between alcoholic and non-alcoholic subjects. N Engl J Med intolerance with alcohol. JAMA 1971;217:1513-9. 1975;292:386-9. 79 Jenkins DW, Eckel RE, Craig JW. Alcohol ketoacidosis. JA MA 5 Schukit MA, Rayes V. Ethanol ingestion differences in blood 1971;217:177-80. acetaldehyde concentration in relatives of alcoholics and con- Levy LJ, Duga J, Girgio M, Gordon EE. Ketoacidosis associ- trols. Science 1979;203:54-5. ated with alcoholism in non-diabetic subjects. Ann Itntertn Med 56 Marchner H, Tottmar 0. A comparative study on the effects of 1973;78:213-9. disulfiram, cyanamide and I-aminocyclopropanol on the 8I Miller PD, Heinig RE, Waterhouse C. Treatment of alcohol acetaldehyde metabolism in rats. Acta Pharmacol Toxicol acidosis: the role of dextrose and phosphorus. Arch Intertn Med (Kbh) 1978;43:219-32. 1978;138:67-72. 57 Deitrich RA, Erwin VG. Mechanism of the inhibition of 8' Podratz KC. Alcoholic ketoacidosis in pregnancy. Obstet aldehyde dehydrogenase in vivo by disulfiram and diethyl- Gynecol 1978;52:54-7S. thiocarbamade. Mol Pharmacol 1971;7:301- 17. 83 Janus ED, Lewis B. Alcohol and abnormalities of lipid metabol- 58 FitzGerald MG, Gaddi R, Mallins JM, O'Sullivan DT. Alcohol ism. Cliti Endocrinol Metab 1978;7:321-32. sensitivity in diabetics receiving chlorpropamide. Diabetes 84 Marks V, Chakraborty J. The clinical endocrinology of alcohol- 1962;11:40-3. ism. British Journal on Alcohol and Alcoholism 1973;8:94- 59 Leslie RDG, Pyke DA. Chlorpropamide alcohol flushing; a 103. dominantly inherited trait associated with diabetics. Br Med J 85 Marks V, Wright JW. Endocrinological and metabolic effects of 1978;ii: 1519-21. alcohol. Proc Roy Soc Med 1977;70:337-44. 61 De Silva NE, Tunbridge WMG, Alberti KGMM. Low incidence 86 Marks V, Wright J, eds. Metabolic effects of alcohol. Clinics ini of chlorpropamide-alcohol flushing in diet-treated, non-insulin Endocrininology and Metabolismn Vol 7, No 2. London: WB dependent diabetes. Lancet 1981 ;i: 128-31. Saunders, 1978. hl Kobberling J, Bengsch N, Bruggeboes B, Schwarck H, Tillil H, 87 Van Thiel DH. Alcohol and its effect on endocrine function. Weber M. The chlorpropamide alcohol flush. Lack of Alcoholism: Clinical and Experimental Research 1980;4:44-9. specificity for familial non-insulin dependent diabetes. 88 Avogaro P, Sirtori CR, Tremoli E, eds. Metabolic effects of Diabetologia 1980;19:359-63. alcohol. Amsterdam: Elsevier/North-Holland, 1979. 62 Medbak S, Wass JAH, Clement-Jones V, Cooke ED, Bowcock Zeiner AR. Endocrinological aspects of alcoholism In: Progress SA, Cudworth AG, Rees LH. Chlorpropamide alcohol flush in biochemical pharmacology Vol 18. Berlin: Karger, 1982. and circulating met-enkephalin: a positive link. Br Med J 96 Marks V. Alcohol and carbohydrate metabolism. Clini Endoc- 1980;283:937-9. rinol Metab 1978;7:333-49. 63 Leslie RDG, Pyke DA, Stubbs WA. Sensitivity to enkephalin as 91 Wright J. Endocrine effects of alcohol CliOt Enidocriniol Metab

a cause of non-insulin dependent diabetes. Lancet 1978;7:351-67. copyright. 1979;i:341-3. 92 Morgan MY. Alcohol and the endocrine system. Br Med Bull 4 Barnett AH, Spiliopoulos AJ, Pyke DA. Blockade of 1982;38:35-42. chlorpropamide-alcohol flushing by indomethacin suggests an 13 Wells SA, Cooper CW, Ontjes DA. Stimulation of thyrocalcito- association between prostaglandin and diabetic vascular com- nin by ethanol in patients with medullary thyroid carcinoma- plications. Lancet 1980;ii: 164-6. an effect apparently not mediated by gastrin. Metabolisms h Barnett AH, Gonzales-Auvert C, Pyke DA, Saunders JB, Wil- 1975;24: 1215-9. liams R, Dickenson CJ, Rawlings MD. Blood concentrations Dymling JF, Ljungberg D, Hilyard C, Greenberg PB, Evanis

of acetaldehyde during chlorpropamide-alcohol flushing. Br IMA, Maclntyre I. Whisky; a new provocative test for calcito- http://jcp.bmj.com/ Med J 1981;283:939-41. nin secretion. Acta Endocrinol 1976;82:500-9. Peachey JE, Brien JF, Roach CA, Loomis CA. A comparative 9 Grahame-Smith D. Natural history and diagnosis of the car- review of the pharmacology and toxicology of disulfiram and cinoid syndrome. Clit7 Gastroenterol 1974;3:575-94. calcium carbimide. J Clin Psychopharmacol 1981;i:21-6. 96 Manager WW, Gifford RW. Pheochromocytoma. Berlin: 67 Davis VE, Walsh MJ. Alcohol, amines and alkaloids: a possible Springer-Verlag, 1977. basis for alcohol addiction. Science 1970;167:1005-7. 9 Jenkins JS, Connolly J. Adrenocortical response to ethanol in 8 Sandler M, Carter SB, Hunter KR, Stern GM. Tetrahydroiso- man. Br Med J 1968;2:804-4. quinoline alkaloids: in vivo metabolism of L-DOPA in man. 98 Merry J, Marks V. Plasma hydrocortisone response to ethanlol ill

Nature 1973;241:439-43. chronic alcoholics. Lancet 1969;i:921-3. on September 29, 2021 by guest. Protected 69 Davis VE, Cashaw JL, McMurtrey KD. Catecholamine-derived 99 Sturtevant FM, Sturtevant RP. Ethanol and blood corticosteroid alkaloids in dependence In: Richter D, ed. Addiction and brain levels in chromobiology. Intern J CliOt Pharmacol Iherap Iox- damage. London: Croom Helm, 1980:17-45. icol 1981;19:427-31. 7'\ Collins MA, Nijm WP, Borge GF, Teas G, Goldfarb C. ""' Jeffcoate WJ. Personal communication, 1982 Dopamine-related tetrahydroisoquinoline; significant urinary Merry J, Marks V. Hypothalamic-pituitary adrenal function i18 excretion by alcoholics after alcohol consumption. Science chronic alcoholics In: Gross MM, ed. Alcoholic initoxicationi 1979;206: 1184-6. and withdrawal: experimental studies. New York: Plenum, 71 Seixas FA. Alcohol and its drug interactions. Ann Intern Med 1973:167-79. 1975;83:86-92. 112 Smals AGH, Njo KT, Knober JM, Ruland CM, Kloffenburg 7 Chakraborty J. Alcohol and its metabolic interrelations with PWE. Alcohol-induced Cushingoid syndrome. J R Coll Ph.s other drugs. Clin Endocrinol Metab 1978;7:273-96. 1977;12: 36-41. 7 Sellers EM, Naranjo CA, Peachey JE. Drugs to decrease alcohol 03 Rees LH, Besser GM, Jeffcoate WJ, Goldie DJ, Marks V. consumption. N Engl J Med 1981;305:1255-62. Alcohol-induced pseudo-Cushing' s syndrome. Latncet 7 Golberg A, McColl KEL, Moore MR. Alcohol and porphyria. 1977;i:726-8. Lancet 1981;ii:925 (letter). 94 Lamberts SWJ, Klijn GM, De Jong FH, Bukinhager JC. Hor- Doss M, Baumann H, Sixel F. Alcohol in acute porphyria. Lan- mone secretion in alcohol-induced pseudo-Cushing's syn- cet 1982;i:1307. drome. JA MA 1979;242:1640-8. Moore MR. International review of drugs in acute porphyria. Int 15 Jordan RM, Jacobson JM, Young RL. Alcohol-induced Cush- J Biochem 1980;12:1()89-97. ingoid syndrome. South Med J 1979;72:1347-8. " Marks V, Rose FC. Hypoglycaemia. Oxford: Blackwell Sci- 116Jenkins RM, Page MMB. A typical case of alcohol-induced entific, 1981. Cushingoid syndrome. Br Med J 1981;282:1117-8. J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from Clinical pathology of alcohol 377

'v Fink RS, Short F, Marjot DH, James VHT. Abnormal suppres- 132 Hurt RD, Morse RM, Swenson WM. Diagnosis of alcoholism sion of plasma cortisol during the intravenous infusion of with a self-administered alcoholism screening test; results with desamethasone to alcoholic patients. Clin Endocrinol 1002 consecutive patients receiving general examinations. 1981 ;15:97-102. Mayo Clin Proc 1980;55:365-70. 108 Marks V. Alcohol and changes in body constituents; glucose and 33 Benadt MW, Taylor C, Mumford J, Smith B, Murray RM. hormones. Proc R Soc Med 1975;68:377-80. Comparison of questionnaire and laboratory tests in the detec- 109 Chalmers RJ, Bennie EH, Johnson RH, Masterton G. Growth tion of excessive drinking and alcoholism. Lancet hormone, prolactin and corticosteroid responses to insulin 1982;i:325-8. hypoglycaemia in alcoholics. Br Med J 1978;i:745-8. 34 Whitehead TP, Clark CA, Whitfield AGW. Biochemical and "0 Andreani D, Tamburrano G, Javicoli M. Alcohol hypoglycemia: haematological markers of alcohol intake. Laoicet hormonal changes In: Andreani D, Lefebvre PJ, Marks V, eds. 1978;i:978-81. Hypoglycemia: Proceedings of the European Symposium, 135 Whitfield JB, Hensley WJ, Bryden D, Gallagher H. Some Rome. Stuttgart: Georg Thieme, 1976:95-105. laboratory correlates of drinking habits. Ann Clin Biochem Special Report. Statement on hypoglycemia. Diabetes 1978;15:297-303. 1973;22: 137. 3 Eschwege E, Papoy L, Lellouch J, Claude JR, Cubeau J, 112 American Diabetes Association. Special report: Statement on Pequignot G, Richard JL, Schwartz D. Blood cells and alcohol Hypoglycemia. Diabetes Care 1982;5:72-3. consumption with special reference to smoking habits. J Clin 13 Adlercreutz H. Hepatic metabolism of estrogens in health and Pathol 1978;31:654-8. disease. N Engl J Med 1974;290:1081-3. 137 Bagrel A, d'Houtaud A, Gueguen R, Siest G. Relations bet- 114 Green JRB. Mechanism of hypogonadism in cirrhotic males. ween reported alcohol consumption and certain biological var- Gut 1977;18:843-53. iables in an "unselected population. Clin Chein 115 Van Thiel DH, Lester R. Alcoholism: its effect on hypothalamic 1979;25:521-5. pituitary function. Gastroenterology 1976;71:318-27. 138 Baxter S, Fink R, Leader AR, Rosalki SB. Laboratory tests for 16 Cobb CF, Gavaler JS, Van Thiel DH. Is ethanol a testicular excessive alcohol consumption evaluated in general practice. toxin? Clin Toxicol 1981;18:149-54. British Journal on Alcohol and Alcoholism 1980;15:164-6. "' Fry JR, English J, Lowing RK, Chakraborty J, Symons AM, 139 Clark PMS, Kricka LJ. Biochemical tests for alcohol abuse. Brit- Marks V. Effect of chronic alcohol ingestion on the structure ish Journal on Alcohol and Alcoholism 1981;16:11-28. and function of liver, adrenals and testes of male rats. Br J 140 Holt S, Skinner HA, Israel Y. Early identification of alcohol Alcohol 1977;12:177-84. abuse. (2) Clinical and laboratory indicators. CMA Jourtnal 118 Symons AM, Marks V. The effects of alcohol on weight gain and 1981;124:1279-99. the hypothalamic-pituitary adrenal axis in the maturing rat. 141 National Council on Alcoholism: Criteria Committee. Criteria Biochem Pharmacol 1975;24:955-8. for the diagnosis of alcoholism. Ann Intern Med copyright. 119 Ylikakri R, Huttenen M, Harkonen MJ, Adlercreutz H. Hang- 1972;77:249-58. over and testosterone. Br Med J 1974;ii:445 (letter). 142 Flanagan NG, Lochridge GK, Henry JG, Hadlow AJ, Hamer 120 Gordon GC, Southren AL. Metabolic effects of alcohol on the PA. Blood alcohol and social drinking. Med Sci Law endocrine system In: Lieber CS, ed. Metabolic aspects of 1979;19: 180-5. alcoholism. Lancaster: MTP Press, 1977:249-302. 143 Dubowski KM. Alcohol determinations in the clinical laborat- 121 Mendelson JH, Mello NK, Ellingboe J. Effects of acute alcohol ory. Clin Chem 1980;74:747-50. intake on pituitary-gonadal hormones in normal human males. 144 Hamlyn AN, Brown AJ, Sherlock S, Baron DN. Casual blood J Pharmacol Exp Ther 1977;202:676-82. ethanol estimations in patients with chronic liver disease. Lan- http://jcp.bmj.com/ 122 Morgan MY. Sex and alcohol. Br Med Bull 1982;38:43-52. cet 1975;ii:345-7. 123 Hugues JN, Coste T, Perret G, Jayle MF, Sebaoun J, Modigliani 45 Orrego H, Blendis LM, Blake JE, Kapier BM, Israel Y. Reliabil- E. Hypothalamicopituitary ovarian function in thirty-one ity of assessment of alcohol based on personal interviews in a women with chronic alcoholism. Clin Endocrinol live clinic. Lancet 1979;i: 1354-6. 1980;12:543-51. 146 Schneider J. Vorkommen und Haufigkeit von erhohtrem 124 Ogata M, Mendelson JH, Mello NK, Majchrowicz E. Adrenal Blutalkokol bei ambulanten Patienten. Schweiz Rundschau function in alcoholism II. Catecholamines. Psychosomatic Med Med Proxis 1980;69:762-6. 1971 ;33: 159-63. 47 Urso T, Gavaler JS, Van Thiel DH. Blood ethanol levels in 125 Akhter MI, Clark PMS, Kricka LJ, Nicholson G. Urinary sober alcohol users seen in an emergency room. Life Sciences on September 29, 2021 by guest. Protected metabolites of tryptophan, serotonin and norepinephrine in 1981 ;28: 1053-6. alcoholics. Journal of Studies on Alcohol 1978;39:833-41. 148 Kay WW, Murfitt KC, Glatt MM. Liver damage in addictive 126 Haight JSJ, Keatinge WR. Failure of thermoregulation in the alcoholics. J Ment Sci 1959;105:748-54. cold during hypoglycemia induced by exercise and alcohol. J 149 Rosalki SB. Gamma glutamyl transpeptidase. Adv Clin Chim Physiol 1973;229:87-93. 1975;17:53-107. 127 O'Keefe SJD, Marks V. Lunchtime gin and tonic; a cause of '50 Rosalki SB, Rau D. Serum y-glutamyl transpeptidase activity in reactive hypoglycaemia. Lancet 1977;i: 1286-8. alcoholism. Clin Chim Acta 1972;39:41-7. 128 Joffe BI, Roach L, Baker S, Shires R, Sandler M, Seftel HC. Rosalki SB. Enzyme tests for alcoholism. Rev Epidemiol Sante Failure to induce reactive hypoglycaemia by drinking a Publique 1977;25: 147--58. starch-based alcohol beverage (sorghum beer). Ann Clin 15' Spencer-Peet J, Wood DCF, Glatt MM, Wiseman SM. Urinary Biochem 1981;18:22-4. D-glucaric acid excretion and serum gamma-glutamyl- 129 Marks V, Wright J. Alcohol provoked reactive hypoglycaemia transpeptidase activity in alcoholism. Br J Addict In: Andreani D, Lefebvre PJ, Marks V, eds. Current views on 1975;70:359-64. hypoglycaemia and glucagon. London: Academic Press, 153 Skude G, Waldstein J. Amylase, hepatic enzymes and bilirubin 1980:283-95. in serum of chronic alcoholics. Acta Med Scand 130 Selzer ML. The Michigan Alcoholism Screening Test: the quest 1977;201:53-8. for a new diagnostic instrument. Am J Psychiatry 154 Patel S, O'Gorman P. Serum enzyme levels in alcoholism and 1971;127:1653-8. drug dependency. J Clin Pathol 1975;28:414-7. 131 Moore RA. The diagnosis of alcoholism in a psychiatric hospi- 55 Chick J, Kreitman N, Plant M. Mean cell volume and gamma tal: a trial of the Michigan Alcoholism Screening Test glutamyl-transpeptidase as markers of drinking in working (MAST). Am J Psychiatry 1972;128:1565-9. men. Lancet 198 1i: 1249-5 1. J Clin Pathol: first published as 10.1136/jcp.36.4.365 on 1 April 1983. Downloaded from 378 Marks lS Jenkins WJ, Rosalki SB, Foo Y, Scheuer PJ, Nemesanszky E, Ih9 Belfrage P, Berg B, Hagerstrand I, Nilsson-Ehle P, Tomqvist H, Sherlock S. Serum glutamate dehydrogenase is not a reliable Wiebe T. Alterations of lipid metabolism in healthy volunteers marker of liver cell necrosis in alcoholics. J Clin Pathol during long-term ethanol intake. Eur J Clin Invest 1982;35:207-10. 1977;7:127-31. '7 Van Waes L, Leiber CS. Glutamate dehydrogenase: a reliable Danielsson B, Ekman R, Fex G, Johansson BG, Kristensson H, marker of liver cell necrosis in the alcoholic. Br Med J Nillson-Ehle P, Wadstein J. Changes in plasma high density 1977;ii: 1508-10. lipoproteins in chronic male alcoholics during and after abuse. 158 Moore MR, Golberg A. Some biochemical responses to ethanol Scand J Clin Lab Invest 1978;38:113-9. in man. InsermIMRC Symposium. Franco-Brittanique sur '7' Martin PJ, Martin JW, Goldberg DM. y-glutamyl transpeptid- l'Alcoolisme 1975;54:101-16. ase, triglycerides, and enzymes induction. Br Med J 59 Moore MR, Beattie AD, Thompson GG, Goldberg A. Depres- 1975;1:17-20. sion of delta aminolaevulinic acid dehydrase activity by 72 Tibbin G, Wilhelmsen L, Werko L. Risk factors for myocardial ethanol in man and rat. Clin Sci 1977;40:81-88. infarction and death due to ischaemic heart disease and other Hamlyn AN, Hopper JC, Skillen AW. Assessment of delta causes. Am J Cardiol 1975;35:514-22. anino-laevulinate dehydratase for outpatient detection of '73Stibler H, Borg S, Allgulander C. Clinical significance of abnor- alcoholic liver disease: comparison with gamma- mal heterogeneity of transferrin in relation to alcohol con- glutamyltransferase and casual blood ethanol. Clin Chim Acta sumption. Acta Med Scand 1979;206:275-82. 1979;95:453-9. Stibler H, Sydow 0, Borg S. Quantitation of qualitative change Wu A, Chanarin I, Levy AJ. Macrocytosis of chronic alcohol- of transferrin heterogeneity in alcoholics. Drug Alcohol ism. Lancet 1974;i:829-30. Depend 1980;6: 11-12. 162 Chalmers DM, Chanarin I, MacDermott S, Levi AJ. Sex related Shaw S, Stimmel B, Lieber CS. Plasma alpha amino-n-butyric differences in the haematological effects of excessive alcohol acid to leucine ratio: an empirical biochemical marker of consumption. J Clin Pathol 1979;33:3-7. alcoholism. Science 1976;194: 1057-8. Ih Stockdill G, Allan NC. Red-blood-cell volume as an index of 76 Morgan MY, Milson MP, Sherlock S. Ratio of plasma alpha alcoholism. Lancet 1978;i:1160 (letter). amino-n-butyric acid to leucine as an empirical marker of '^ Colman N, Herbert V. Hematologic complications of alcohol- alcoholism: diagnostic value. Science 1977;197: 1183-5. ism: overview. Semin Hematol 1980;17:164-76. 177 Chalmers DM, Rinsler MG, MacDermott, S, Spicer CC, Levi ,65 Drum DE, Goldman PA, Jankowski CB. Elevation of serum AJ. Biochemical and haematological indicators of excessive uric acid as a clue to alcohol abuse. Arch Intern Med alcohol consumption. Gut 1981;22:992-6. 1981;141:477-9. 166 Stakelin HB, Sommer P, Widmer LK. Alcohol consumption and serum lipids in normolipidemic and hyperlipidemic men. Nutr copyright. Metab 1977;21(Suppl 1): 135-8. 17 Castelli WP, Doyle JT, Gordon T, Hames CG, Hjorltand MC, Hulley SB, Kagan A, Zukel WJ. Alcohol and blood lipids. Lancet 1977;ii:153-5. 68 Johansson BG, Medus A. Increase in plasma a-lipoproteins in Request for reprints to: Professor Vincent Marks, chronic alcoholics after acute abuse. Acta Med Scand Department of Biochemistry, University of Surrey, Guil- 1974;195:273-7. ford, Surrey GU2 5XH, England. http://jcp.bmj.com/ on September 29, 2021 by guest. Protected