- Email: [email protected]
NUTRITIONAL OEDEMA, ALBUMIN, AND VANADATE
646
staining is also seen, however,29 and this may represent hepatotoxic copper metallothionein monomer or free copper. Furthermore, if the presence of easily demonstrated CAP indicates normal metallothionein synthesis and function, this is further evidence that Indian childhood cirrhosis is an environmental rather than a genetic disease, similar to chronic copper poisoning in infancy.3D These theoretical considerations are eminently susceptible to experimental study, and the time is ripe for a more detailed examination of metallothionein in health and disease. NUTRITIONAL OEDEMA, ALBUMIN, AND VANADATE DESPITE the fact that nutritional oedema has been recognised for several thousand years (Deuteronomy 8 v.4) no adequate pathophysiological explanation of its development has beenI offered. In the current issue of the British Medical Bulletin W. A. Coward and P. G. Lunn discuss the respective roles of altered albumin metabolism and altered sodium transport whilst M. and B. Golden look into the possible role of vanadate. Coward and Lunn describe with admirable clarity the concept of adaptation to limited supplies of energy and protein. They rehearse the evidence that in kwashiorkor the early changes seen before children reach medical care are different from those usually seen in hospital. They propose that marasmus is the response to energy deficit with a reasonable proportion of protein in the diet. Adipose tissue and muscle are reduced in a graduated fashion under the influence ofcortisol and growth hormone. Concentrations of insulin are low. Kwashiorkor, they postulate, is the result of a diet in which there is a relative protein deficit or alternatively a relative energy excess, even though absolute energy requirements may not be met. Man responds to such a diet with insulin secretion and with deposition of fat and muscle-a process which would also reduce extracellular concentrations of elements such as potassium, zinc, and possibly vanadate.2-4 Essential aminoacids for the synthesis of export proteins, such as albumin, which are important for the control of body fluid volumes will also be consequently reduced. That oft used substitute for man, the rat, is quite different and simply burns off the energy "excess" without any insulin-induced disturbances of protein metabolism and consequently does not easily retain fluid and become oedematous. Once fluid retention develops, anorexia and hypoglycaemia reduce the plasma insulin so that, by the time the patient reaches medical care, the hormonal picture is similar to that found in energy deficiency-i.e., low insulin, high cortisol, and high growth hormone. Oedema is seen as a direct result of a reduction in albumin mass. In malnutrition, albumin is redistributed from the 29.
Popper H, Goldfischer S, Sternleib I, Nayak NC, Madhavan TV. Cytoplasmic copper and its toxic effects Studies in Indian childhood cirrhosis. Lancet 1979; i: 1205-08. B, Walker-Smith JA, Tanner MS Wilson’s disease, chronic copper poisoning, or Indian childhood cirrhosis? Arch Dis Childh 1980; 55: 163-64.
30. Portmann
1. Nutrition of man. Edited by J C. Waterlow. British Medical Bulletin 1981; 37, no.1: 1-100. The Bulletin is now published for the British Council by Churchill Livingstone, Robert Stevenson House, 1-3 Baxter’s Place, Leith Walk, Edinburgh EH1 3AF, annual subscription £19 U.K., $53 U.S.A., £23 elsewhere (three issues). Single copies will be supplied in book form (soft covers), at £9.50 2. Muntwyler E, Griffin GE. Tissue electrolyte content of potassium and proteindeficient rats Proc Soc Exp Biol Med 1955; 89: 349-52. 3. Golden BE, Golden MHN. Am J Clin Nutr (in press). 4. Rudman D, Millikan WS, Richardson TS, Bikler TS, Stackhouse WJ, McGarrity WC. Element balances during intravenous hyperalimentation of underweight adult subjects. J Clin Invest 1975; 55: 94-106.
the vascular space,and Fiorotto and Coward6 proposed that, when this system reaches its limit of adaptation, the fall in plasma volume that ensues leads to renal salt and water retention. How the salt retention is achieved is unknown. The renal responses to experimental alterations in plasma albumin and oncotic pressure are entirely inappropriate to this scheme. There are three major steps in renal sodium reabsorption. The first step is entry of sodium into the cell down its electrochemical gradient. The second is extrusion by the sodium pump into the basolateral spaces. The third is removal of sodium into the vascular space under the influence of hydrostatic and oncotic pressures. The first and last are generally accepted as potentially rate-limiting. The second now seems to be controlled potentially by vanadate.a Entry of sodium into the cell is via carrier-mediated diffu. sion but whether there is one or several carriers and how this system links with other transport systems has not been delineated. The permeability of the luminal membrane can be altered by manoeuvres such as exposure to amphotericin B,9 and possibly by protein and energy deprivation. (In leucocytes and red cells from malnourished children, membrane permeability to sodium is greater in kwashiorkor than in marasmus. 10,11) There is, however, a mass of somewhat contradictory published work on the effects of alterations in albumin concentration on tubular function. Increases in the concentration of albumin perfusing the proximal tubule have generally led to increased rates of sodium reabsorption12,13 and in the isolated perfused kidney a similar effect has been observed. 14,15This implies that, in the absence of a profound change in filtration fraction, hypoalbuminaemia should be associated with salt wasting rather than salt retention. Clearly in kwashiorkor, the nephrotic syndrome, and cirrhotic oedema this is not so. Furthermore, the child with kwashiorkor may lose his oedema without alterations in serum albumin and whilst consuming only maintenance amounts of energy and protein. 11,16 In 1979 it was suggested that vanadate might be the factor required to make sense of this otherwise confusing story." Although, as Golden and Golden state, vanadium is known to be essential for growth of rats, its effects on sodium transport were entirely unexpected. The physiology and biochemistry of vanadium have lately been reviewed. 17,18 Briefly the story
interstitial
to
James WPT, Hay AM. Albumin metabolism: Effect of nutritional state and the dietary protein intake. J Clin Invest 1968; 47: 1958-72. 6 Fiorotto M, Coward WA. Pathogenesis of oedema in protein-energy malnutrition: The significance of plasma colloid oncotic pressure. Br J Nutr 1979; 42: 21-31. 7 Maack T, Windhager EH. In: Black D, Jones NF, eds. Electrolyte transport in the nephron in renal disease. Oxford: Blackwell, 1979: 107-38. 8. Day H, Middendorf D, Lukert B, Heinz A, Grantham J. The renal response to intravenous vanadate in rats. J Lab Clin Med 1980; 96: 382-95. 9. Stroup RF, Weinman E, Hayslett JP, Kashgarian M. Effect of luminal permeability on net transport across the amphibian proximal tubule. Am J Physiol 1974, 214: 5.
1096-1103. 10.
Kaplay SS.Erythrocyte membrane Na++ and K+activated adenosine triphosphatase in
protein-caloric malnutrition. Am J Clin Nutr 1979; 31: 579-84 11. Patrick J. Oedema in protein energy malnutrition: the role of the sodium pump Proc Nutr Soc 1979; 38: 61-68. 12. Falchuk KH, Brenner BM, Tadokoro M, Berliner RW. Oncotic and hydrostatic pressures in peritubular capillaries and fluid reabsorption by proximal tubule Am J Physiol 1971; 220: 1427-33. 13. Remeck HJ, Stein JH. Renal regulation of extracellular fluid volume. In: Bremer BM, Stein JH, eds. Sodium and water homeostasis. Edinburgh: Churchill Livingstone, 1979: 24-50. 14. Bowman RH, Maack T. Effect of albumin concentration and ADH on H2O and electrolyte transport in perfused rat kidney. Am J Physiol 1974; 226: 426-30 15 Little JR, Cohen JJ. Effect of albumin concentration on function of isolated perfused rat kidney. Am J Physiol 1974; 226: 512-17. 16. Golden MH, Golden BE, Jackson AA. Albumin and nutritional oedema Lancet 1980, i: 114-16. 17. Macara IG. Vanadium-an element in search of a role. TIBS 1980; 5: 92-94. 18. Grantham JJ. The renal sodium pump and vanadate. Am J Physiol 1980; 239: F97-F106.
647
is that, in 1975, the presence of an inhibitor of sodium transport was reported in some batches of ATP supplied by the Sigma Company. 19 SigmaATP is unusual because it is extracted from muscle rather than synthesised. Cant.ley20 pursued the idea that there was an important trace constituent and showed that it was vanadium. Unfortunately the chemistry of vanadium is exceedingly complex, since it has several oxidation states which are subject to redox control. 21 Only one of these, vanadate (Vv), is a potent inhibitor of sodium transport. The physiology of vanadate and the sodium pump has been investigated most extensively in red cells.22 The features of immediate relevance to nutritional oedema are that vanadate enters the cell rapidly where it inhibits the Na, K ATPase at concentrations in the nmol/1 range. This effect is large only at high external potassium concentrations which may be linked to the observation that plasma potassium is usually lower in kwashiorkor than in marasmus and that a diuresis often begins when the hypokalaemia is corrected. The diuretic capacity of vanadate in the volume-expanded rat is prodigious. With infusions of 20 nmol/kg per hour, half of the sodium filtered at the glomerulus appears in the urine. 8,23 However, it is by no means certain that this mechanism operates in vivo because under normal circumstances glutathione could be expected to reduce all the vanadate to vanadyl, which has only a fraction of the inhibitory potency of vanadate. Moreover, vanadium inhibits other enzymes including myosin ATPase, Ca ATPase, adenylate kinase, and phosphofructokinase and it also surprisingly stimulates adenyl cyclase. Vanadate has different actions on heart, kidney, and adipocyte. Thus there is clearly a lot to learn about this element. In the course of the investigations someone may even explain how and why the sea squirt concentrates vanadium to 1 mol/1 and stores it dissolved in
sulphuric acid at pH 2.
ROSACEA IN HOT WATER THE pathogenesis of rosacea-of which a cardinal diagnostic feature is excessive redness of the nose, cheeks, and forehead-remains an enigma. We know that patients with rosacea flush more often and more easily than controls, especially when eating or drinking,’ but this change is not usually accompanied by increased facial sweating. These clinical observations have now been extended in an investigation by Wilkin,2 who studied 19 women and 5 men with rosacea. Both malar skin temperature and the malar thermal circulation index, which is directly related to malar blood flow, were measured before and after the subjects had been given caffeine, coffee at 22OC, coffee at 60°C, water at 60oC, or alcohol. The factor causing flushing in coffee at 60°C was clearly shown to be heat and not caffeine and the time-course 19. Charney AN, Silva P, Epstein FH. An in vitro inhibitor of Na/K ATPase present in an adenosine tnphosphate preparation.J Appl Physiol 1975; 39: 156-58. 20. Cantley LC, Josephson L, Warner R, Yanagisawa M, Lechene C, Guidotti G. Vanadate is a potent ATPase inhibitor found in ATP derived from muscleJ Biol Chem 1977; 252: 7421-23. 21 Grantham JJ, Glynn IM. Renal Na, K-ATPase: Determinants of inhibition by vanadium. AmJ Physiol 1979; 236: F530-F535. 22 Beaugé LA, Cavières JJ, Glynn IM, Grantham JJ The effects of vanadate on the fluxes of sodium and potassium ions through the sodium pump. J Physiol 1979; 301: 7-23. 23 Balfour WE, Grantham JJ, Glynn IM. Vanadate-stimulated natriuresis. Nature 1978; 275 768. 1. Marks R, Beard RJ, Clark ML, Kwok M, Roberts WB. Gastrointestinal observations in rosacea. Lancet 1967; i: 739-42. 2 Wilkin JK. Oral thermal-induced flushing in erythematotelangiectatic rosacea. J Invest
(Na+ +K+)
Dermatol 1981; 76: 15-18.
of the flush after a hot drink suggested that the phenomenon neurally mediated. Thus the thermal regulatory reflex, stimulated by increased heat in blood draining from the mouth via the countercurrent heat exchange between the internal jugular vein and the common carotid artery, could be important in rosacea. This work is not, however, easy to interpret, partly because no control subjects were studied. The general view is that neurally mediated flushing is accompanied by sweating, whilst flushing resulting fromvasoactive agents acting directly on vascular smooth muscle is not.3 Therefore it would have been interesting to know whether the malarblood-flow changes were accompanied by increased sweating and also whether there were changes in skin blood-flow at other sites commonly affected in rosacea, such as the nose and forehead. Furthermore, is it possible to reduce facial bloodflow by sucking, for instance, ice, and if so, could this be useful in treatment of rosacea? Since even in very florid rosacea the face does not sweat excessively the erythema seems more likely to be mediated by locally acting vasoactive substances than by a neural mechanism. The flushing induced by alcohol in some non-insulindependent diabetics taking chlorpropamidé-6 could therefore be more relevant to the pathogenesis of rosacea. This facial flush can be blocked by both indomethacin’ and aspiring which are prostaglandin inhibitors. For many years dermatologists have used topical salicylic acid for rosacea and it is tempting to speculate that they have thereby been inhibitwas
ing prostaglandin synthesis.
INTRACTABLE DIARRHOEA OF INFANCY MOST of the chronic diarrhoeas in infancy can now be diagnosed with precision and managed effectively, but intractable diarrhoea as defined by Avery’ in 1968 remains troublesome in both respects. This syndrome begins in the first 3 months of life, and the definition requires more than two weeks’ diarrhoea and 3 or more stools negative for bacterial pathogens. Some of the children prove to have cow’s milk protein intolerance, coeliac disease, or Hirschsprung’s disease, but most have no obvious cause. Candy et al. give the name lethal familial protracted diarrhoea to a particularly severe form of this syndrome which they have seen in 24 infants. The diarrhoea is cholera-like, and in 2 infants who had perfusion of small intestine, it was shown to result from small intestinal secretion which overwhelmed the reabsorptive capacity ofanormally functioning colon. The cause remained a mystery and 21 of the infants died despite treatment including prolonged intravenous feeding and various pharmacological agents. Although this was probably not a single disease entity, the familial pattern in some cases suggested
3. 4.
Coil Physicians 1978; 12: 359-64. Mulley RP. Flushing. Roy J Fitzgerald MG, Gaddie R, Malins JM, O’Sullivan DJ. Alcohol sensitivity in diabetics receiving chlorpropamide. Diabetes 1962; 11: 40-43. 5. Leslie RDG, Pyke DA. Chlorpropamide-alcohol flushing: a dominantly inherited trait associated with diabetes. Br Med J 1978; ii: 1519-21. 6. Pyke DA, Leslie RDG. Chlorpropamide-alcohol flushing: a definition of its relation to non-insulin dependent diabetes. Br Med J 1978; ii: 1521-22. 7. Barnett AH, Spihopoulos AJ, Pyke DA. Blockade of chlorpropamide-alcohol flushing by indomethacin suggests an association between prostaglandins and diabetic vascular complications. Lancet 1980; ii: 164-66. 8. Strakosch CR, Jefferis DB, Keen H. Blockade of chlorpropamide-alcohol flushing by aspirin. Lancet 1980; i: 394-96. 1. Avery GB, Villavicencio D, Lilly JR, Randolph JG. Intractable diarrhea in early 2.
infancy. Pediatrics 1968; 41: 712-22. Candy DCA, Larcher VF, Cameron DJS, Norman AP, Tripp JH, Milla P, Pincott JR, Harries JT. Lethal familial protracted diarrhoea. Arch Dis Childh 1981; 56: 15-23.
staining is also seen, however,29 and this may represent hepatotoxic copper metallothionein monomer or free copper. Furthermore, if the presence of easily demonstrated CAP indicates normal metallothionein synthesis and function, this is further evidence that Indian childhood cirrhosis is an environmental rather than a genetic disease, similar to chronic copper poisoning in infancy.3D These theoretical considerations are eminently susceptible to experimental study, and the time is ripe for a more detailed examination of metallothionein in health and disease. NUTRITIONAL OEDEMA, ALBUMIN, AND VANADATE DESPITE the fact that nutritional oedema has been recognised for several thousand years (Deuteronomy 8 v.4) no adequate pathophysiological explanation of its development has beenI offered. In the current issue of the British Medical Bulletin W. A. Coward and P. G. Lunn discuss the respective roles of altered albumin metabolism and altered sodium transport whilst M. and B. Golden look into the possible role of vanadate. Coward and Lunn describe with admirable clarity the concept of adaptation to limited supplies of energy and protein. They rehearse the evidence that in kwashiorkor the early changes seen before children reach medical care are different from those usually seen in hospital. They propose that marasmus is the response to energy deficit with a reasonable proportion of protein in the diet. Adipose tissue and muscle are reduced in a graduated fashion under the influence ofcortisol and growth hormone. Concentrations of insulin are low. Kwashiorkor, they postulate, is the result of a diet in which there is a relative protein deficit or alternatively a relative energy excess, even though absolute energy requirements may not be met. Man responds to such a diet with insulin secretion and with deposition of fat and muscle-a process which would also reduce extracellular concentrations of elements such as potassium, zinc, and possibly vanadate.2-4 Essential aminoacids for the synthesis of export proteins, such as albumin, which are important for the control of body fluid volumes will also be consequently reduced. That oft used substitute for man, the rat, is quite different and simply burns off the energy "excess" without any insulin-induced disturbances of protein metabolism and consequently does not easily retain fluid and become oedematous. Once fluid retention develops, anorexia and hypoglycaemia reduce the plasma insulin so that, by the time the patient reaches medical care, the hormonal picture is similar to that found in energy deficiency-i.e., low insulin, high cortisol, and high growth hormone. Oedema is seen as a direct result of a reduction in albumin mass. In malnutrition, albumin is redistributed from the 29.
Popper H, Goldfischer S, Sternleib I, Nayak NC, Madhavan TV. Cytoplasmic copper and its toxic effects Studies in Indian childhood cirrhosis. Lancet 1979; i: 1205-08. B, Walker-Smith JA, Tanner MS Wilson’s disease, chronic copper poisoning, or Indian childhood cirrhosis? Arch Dis Childh 1980; 55: 163-64.
30. Portmann
1. Nutrition of man. Edited by J C. Waterlow. British Medical Bulletin 1981; 37, no.1: 1-100. The Bulletin is now published for the British Council by Churchill Livingstone, Robert Stevenson House, 1-3 Baxter’s Place, Leith Walk, Edinburgh EH1 3AF, annual subscription £19 U.K., $53 U.S.A., £23 elsewhere (three issues). Single copies will be supplied in book form (soft covers), at £9.50 2. Muntwyler E, Griffin GE. Tissue electrolyte content of potassium and proteindeficient rats Proc Soc Exp Biol Med 1955; 89: 349-52. 3. Golden BE, Golden MHN. Am J Clin Nutr (in press). 4. Rudman D, Millikan WS, Richardson TS, Bikler TS, Stackhouse WJ, McGarrity WC. Element balances during intravenous hyperalimentation of underweight adult subjects. J Clin Invest 1975; 55: 94-106.
the vascular space,and Fiorotto and Coward6 proposed that, when this system reaches its limit of adaptation, the fall in plasma volume that ensues leads to renal salt and water retention. How the salt retention is achieved is unknown. The renal responses to experimental alterations in plasma albumin and oncotic pressure are entirely inappropriate to this scheme. There are three major steps in renal sodium reabsorption. The first step is entry of sodium into the cell down its electrochemical gradient. The second is extrusion by the sodium pump into the basolateral spaces. The third is removal of sodium into the vascular space under the influence of hydrostatic and oncotic pressures. The first and last are generally accepted as potentially rate-limiting. The second now seems to be controlled potentially by vanadate.a Entry of sodium into the cell is via carrier-mediated diffu. sion but whether there is one or several carriers and how this system links with other transport systems has not been delineated. The permeability of the luminal membrane can be altered by manoeuvres such as exposure to amphotericin B,9 and possibly by protein and energy deprivation. (In leucocytes and red cells from malnourished children, membrane permeability to sodium is greater in kwashiorkor than in marasmus. 10,11) There is, however, a mass of somewhat contradictory published work on the effects of alterations in albumin concentration on tubular function. Increases in the concentration of albumin perfusing the proximal tubule have generally led to increased rates of sodium reabsorption12,13 and in the isolated perfused kidney a similar effect has been observed. 14,15This implies that, in the absence of a profound change in filtration fraction, hypoalbuminaemia should be associated with salt wasting rather than salt retention. Clearly in kwashiorkor, the nephrotic syndrome, and cirrhotic oedema this is not so. Furthermore, the child with kwashiorkor may lose his oedema without alterations in serum albumin and whilst consuming only maintenance amounts of energy and protein. 11,16 In 1979 it was suggested that vanadate might be the factor required to make sense of this otherwise confusing story." Although, as Golden and Golden state, vanadium is known to be essential for growth of rats, its effects on sodium transport were entirely unexpected. The physiology and biochemistry of vanadium have lately been reviewed. 17,18 Briefly the story
interstitial
to
James WPT, Hay AM. Albumin metabolism: Effect of nutritional state and the dietary protein intake. J Clin Invest 1968; 47: 1958-72. 6 Fiorotto M, Coward WA. Pathogenesis of oedema in protein-energy malnutrition: The significance of plasma colloid oncotic pressure. Br J Nutr 1979; 42: 21-31. 7 Maack T, Windhager EH. In: Black D, Jones NF, eds. Electrolyte transport in the nephron in renal disease. Oxford: Blackwell, 1979: 107-38. 8. Day H, Middendorf D, Lukert B, Heinz A, Grantham J. The renal response to intravenous vanadate in rats. J Lab Clin Med 1980; 96: 382-95. 9. Stroup RF, Weinman E, Hayslett JP, Kashgarian M. Effect of luminal permeability on net transport across the amphibian proximal tubule. Am J Physiol 1974, 214: 5.
1096-1103. 10.
Kaplay SS.Erythrocyte membrane Na++ and K+activated adenosine triphosphatase in
protein-caloric malnutrition. Am J Clin Nutr 1979; 31: 579-84 11. Patrick J. Oedema in protein energy malnutrition: the role of the sodium pump Proc Nutr Soc 1979; 38: 61-68. 12. Falchuk KH, Brenner BM, Tadokoro M, Berliner RW. Oncotic and hydrostatic pressures in peritubular capillaries and fluid reabsorption by proximal tubule Am J Physiol 1971; 220: 1427-33. 13. Remeck HJ, Stein JH. Renal regulation of extracellular fluid volume. In: Bremer BM, Stein JH, eds. Sodium and water homeostasis. Edinburgh: Churchill Livingstone, 1979: 24-50. 14. Bowman RH, Maack T. Effect of albumin concentration and ADH on H2O and electrolyte transport in perfused rat kidney. Am J Physiol 1974; 226: 426-30 15 Little JR, Cohen JJ. Effect of albumin concentration on function of isolated perfused rat kidney. Am J Physiol 1974; 226: 512-17. 16. Golden MH, Golden BE, Jackson AA. Albumin and nutritional oedema Lancet 1980, i: 114-16. 17. Macara IG. Vanadium-an element in search of a role. TIBS 1980; 5: 92-94. 18. Grantham JJ. The renal sodium pump and vanadate. Am J Physiol 1980; 239: F97-F106.
647
is that, in 1975, the presence of an inhibitor of sodium transport was reported in some batches of ATP supplied by the Sigma Company. 19 SigmaATP is unusual because it is extracted from muscle rather than synthesised. Cant.ley20 pursued the idea that there was an important trace constituent and showed that it was vanadium. Unfortunately the chemistry of vanadium is exceedingly complex, since it has several oxidation states which are subject to redox control. 21 Only one of these, vanadate (Vv), is a potent inhibitor of sodium transport. The physiology of vanadate and the sodium pump has been investigated most extensively in red cells.22 The features of immediate relevance to nutritional oedema are that vanadate enters the cell rapidly where it inhibits the Na, K ATPase at concentrations in the nmol/1 range. This effect is large only at high external potassium concentrations which may be linked to the observation that plasma potassium is usually lower in kwashiorkor than in marasmus and that a diuresis often begins when the hypokalaemia is corrected. The diuretic capacity of vanadate in the volume-expanded rat is prodigious. With infusions of 20 nmol/kg per hour, half of the sodium filtered at the glomerulus appears in the urine. 8,23 However, it is by no means certain that this mechanism operates in vivo because under normal circumstances glutathione could be expected to reduce all the vanadate to vanadyl, which has only a fraction of the inhibitory potency of vanadate. Moreover, vanadium inhibits other enzymes including myosin ATPase, Ca ATPase, adenylate kinase, and phosphofructokinase and it also surprisingly stimulates adenyl cyclase. Vanadate has different actions on heart, kidney, and adipocyte. Thus there is clearly a lot to learn about this element. In the course of the investigations someone may even explain how and why the sea squirt concentrates vanadium to 1 mol/1 and stores it dissolved in
sulphuric acid at pH 2.
ROSACEA IN HOT WATER THE pathogenesis of rosacea-of which a cardinal diagnostic feature is excessive redness of the nose, cheeks, and forehead-remains an enigma. We know that patients with rosacea flush more often and more easily than controls, especially when eating or drinking,’ but this change is not usually accompanied by increased facial sweating. These clinical observations have now been extended in an investigation by Wilkin,2 who studied 19 women and 5 men with rosacea. Both malar skin temperature and the malar thermal circulation index, which is directly related to malar blood flow, were measured before and after the subjects had been given caffeine, coffee at 22OC, coffee at 60°C, water at 60oC, or alcohol. The factor causing flushing in coffee at 60°C was clearly shown to be heat and not caffeine and the time-course 19. Charney AN, Silva P, Epstein FH. An in vitro inhibitor of Na/K ATPase present in an adenosine tnphosphate preparation.J Appl Physiol 1975; 39: 156-58. 20. Cantley LC, Josephson L, Warner R, Yanagisawa M, Lechene C, Guidotti G. Vanadate is a potent ATPase inhibitor found in ATP derived from muscleJ Biol Chem 1977; 252: 7421-23. 21 Grantham JJ, Glynn IM. Renal Na, K-ATPase: Determinants of inhibition by vanadium. AmJ Physiol 1979; 236: F530-F535. 22 Beaugé LA, Cavières JJ, Glynn IM, Grantham JJ The effects of vanadate on the fluxes of sodium and potassium ions through the sodium pump. J Physiol 1979; 301: 7-23. 23 Balfour WE, Grantham JJ, Glynn IM. Vanadate-stimulated natriuresis. Nature 1978; 275 768. 1. Marks R, Beard RJ, Clark ML, Kwok M, Roberts WB. Gastrointestinal observations in rosacea. Lancet 1967; i: 739-42. 2 Wilkin JK. Oral thermal-induced flushing in erythematotelangiectatic rosacea. J Invest
(Na+ +K+)
Dermatol 1981; 76: 15-18.
of the flush after a hot drink suggested that the phenomenon neurally mediated. Thus the thermal regulatory reflex, stimulated by increased heat in blood draining from the mouth via the countercurrent heat exchange between the internal jugular vein and the common carotid artery, could be important in rosacea. This work is not, however, easy to interpret, partly because no control subjects were studied. The general view is that neurally mediated flushing is accompanied by sweating, whilst flushing resulting fromvasoactive agents acting directly on vascular smooth muscle is not.3 Therefore it would have been interesting to know whether the malarblood-flow changes were accompanied by increased sweating and also whether there were changes in skin blood-flow at other sites commonly affected in rosacea, such as the nose and forehead. Furthermore, is it possible to reduce facial bloodflow by sucking, for instance, ice, and if so, could this be useful in treatment of rosacea? Since even in very florid rosacea the face does not sweat excessively the erythema seems more likely to be mediated by locally acting vasoactive substances than by a neural mechanism. The flushing induced by alcohol in some non-insulindependent diabetics taking chlorpropamidé-6 could therefore be more relevant to the pathogenesis of rosacea. This facial flush can be blocked by both indomethacin’ and aspiring which are prostaglandin inhibitors. For many years dermatologists have used topical salicylic acid for rosacea and it is tempting to speculate that they have thereby been inhibitwas
ing prostaglandin synthesis.
INTRACTABLE DIARRHOEA OF INFANCY MOST of the chronic diarrhoeas in infancy can now be diagnosed with precision and managed effectively, but intractable diarrhoea as defined by Avery’ in 1968 remains troublesome in both respects. This syndrome begins in the first 3 months of life, and the definition requires more than two weeks’ diarrhoea and 3 or more stools negative for bacterial pathogens. Some of the children prove to have cow’s milk protein intolerance, coeliac disease, or Hirschsprung’s disease, but most have no obvious cause. Candy et al. give the name lethal familial protracted diarrhoea to a particularly severe form of this syndrome which they have seen in 24 infants. The diarrhoea is cholera-like, and in 2 infants who had perfusion of small intestine, it was shown to result from small intestinal secretion which overwhelmed the reabsorptive capacity ofanormally functioning colon. The cause remained a mystery and 21 of the infants died despite treatment including prolonged intravenous feeding and various pharmacological agents. Although this was probably not a single disease entity, the familial pattern in some cases suggested
3. 4.
Coil Physicians 1978; 12: 359-64. Mulley RP. Flushing. Roy J Fitzgerald MG, Gaddie R, Malins JM, O’Sullivan DJ. Alcohol sensitivity in diabetics receiving chlorpropamide. Diabetes 1962; 11: 40-43. 5. Leslie RDG, Pyke DA. Chlorpropamide-alcohol flushing: a dominantly inherited trait associated with diabetes. Br Med J 1978; ii: 1519-21. 6. Pyke DA, Leslie RDG. Chlorpropamide-alcohol flushing: a definition of its relation to non-insulin dependent diabetes. Br Med J 1978; ii: 1521-22. 7. Barnett AH, Spihopoulos AJ, Pyke DA. Blockade of chlorpropamide-alcohol flushing by indomethacin suggests an association between prostaglandins and diabetic vascular complications. Lancet 1980; ii: 164-66. 8. Strakosch CR, Jefferis DB, Keen H. Blockade of chlorpropamide-alcohol flushing by aspirin. Lancet 1980; i: 394-96. 1. Avery GB, Villavicencio D, Lilly JR, Randolph JG. Intractable diarrhea in early 2.
infancy. Pediatrics 1968; 41: 712-22. Candy DCA, Larcher VF, Cameron DJS, Norman AP, Tripp JH, Milla P, Pincott JR, Harries JT. Lethal familial protracted diarrhoea. Arch Dis Childh 1981; 56: 15-23.