Hyperdynamic circulation in cirrhosis: a role for nitric oxide?

776

TTP. For

example, one suggestion is that long-term ingestion of oestrogen-containing oral contraceptives decreases prostacyclin production ;27 however, raised concentrations of 6 keto PGF1, a major metabolite of prostacyclin, were found in washed human platelets incubated with ticlopidine.28 Others have suggested that bleomycin directly damages the vascular endothelial cell,16 and some studies have shown that ticlopidine retards adherence and growth of human endothelial cells and alters endothelial cell morphology.29 Although how ticlopidine causes

TTP remains

uncertain, we believe that TTP could

haematological side-effect of ticlopidine. Our findings certainly contrast with the report3° that ticlopidine be

a new

prevents TTP.

22.

Resegotti L, Pistone MA, Testa D, Charbonnier R, Toselli P, Vivalda S. Bone marrow culture in patients receiving ticlopidine treatment. Nouv

Rev Fr Hematol 1985; 27: 19-22. 23. Abou-Khalil WH, Lim LO, Yunnis AA, Abou-Khalil S. Effects of ticlopidine, a new platelet antiaggregating agent, and its analogues on mitochondrial metabolism. Oxidative phosphorylation, protein synthesis and DNA polymerase activity. Biochem Pharmacol 1984; 33: 3893-98. 24. Claas FHJ, de Fraiture WH, Meyboom RHB. Thrombocytopenia due to antibodies induced by ticlopidine. Now Rev Fr Hematol 1984; 26: 323-24. 25. Remuzzi G, Misiani R, Marchesi D, et al. Haemolytic uraemic syndrome: deficiency of plasma factor(s) regulating prostacyclin activity? Lancet 1978; ii: 871-72. 26. Lian ECY, Harkness DR, Byrnes JJ, Wallach H, Hunez R. Presence of a platelet aggregating factor in the plasma of patients with thrombotic thrombocytopenic purpura and its inhibition by normal plasma. Blood

1979; 53: 333-38. Caggiano V, Fernando LP, Schneider JM, Haesslein HC, WatsonWilliams EJ. Thrombotic thrombocytopenic purpura: report of fourteen cases-occurence during pregnancy and response to platelet exchange. J Clin Apheresis 1983; 1: 71-85. 28. Lagarde M, Ghazi I, Dechavanne M. Effects of ticlopidine on platelet prostaglandin metabolism: possible consequences for prostacyclin production. Prostaglandins Med 1979; 2: 433-39. 29. Piovella F, Ricetti MM, Almasioi P, et al. The effect of ticlopidine on 27.

We thank Prof M. Ollagnier for his cooperation and Mr J. technical and secretarial help.

Lugnier

for

REFERENCES 1. de Gramont A, Canuel

C, Krulik M,

et

al.

ticlopidine. Now Rev Fr Hematol 1982; 24: 2. Amorosi

Hematological toxicity of 35-37.

EL, Ultmann JE. Thrombotic thrombocytopenic

purpura.

of 16 cases and review of the literature. Medicine 1966; 45: 139-59. 3. Taft EG. Thrombotic thrombocytopenic purpura and dose of plasma exchange. Blood 1979; 54: 842-49. 4. Kwaan HC. The pathogenesis of thrombotic thrombocytopenic purpura. Semin Thromb Hemostas 1979; 5: 184-98. 5. Goodman A, Ramos R, Petrelli M, et al. Gingival biopsy in thrombotic thrombocytopenic purpura. Ann Intern Med 1978; 89: 501-04. 6. Kovacs MJ, Roddy J, Grégoire S, Cameron W, Eidus L, Drouin J. Thrombotic thrombocytopenic purpura following hemorrhagic colitis due to Escherichia coli O157:H7. Am J Med 1990; 88: 177-79. 7. Brown RC, Blecher TE, French EA, Toghill PJ. Thrombotic thrombocytopenic purpura after influenza vaccination. Br Med J 1973; 2: 303. 8. Mettler BE. Isolation of a microtatobiote from patients with haemolyticuraemic syndrome and thrombotic thrombocytopenic purpura and from mites in the United States. N Engl J Med 1969; 281: 1023-27. 9. Dekker A, O’Brien ME, Cammarata RJ. The association of thrombotic thrombocytopenic purpura with systemic lupus erythematosus. Am J Med Sci 1974; 267: 243-49. 10. Neame PB. Immunologic and other factors in thrombotic thrombocytopenic purpura. Semin Thromb Hemost 1980; 6: 416-22. 11. Sack GH Jr, Levin J, Bell WR. Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathologic, and therapeutic features. Medicine 1977; 56: 1-37. 12. Parker JC, Barret DA, Hill C. Microangiopathic hemolysis and thrombocytopenia related to penicillin drugs. Arch Intern Med 1971; 127: 474-77. 13. Ahmed F, Sumalnop V, Spain DM, Tobin MS. Thrombohemolytic thrombocytopenic purpura during penicillamine therapy. Arch Intern Med 1987; 138: 1292-93. 14. Vesconi S, Langer M, Rossi E, Mondonico P, Cambiaghi G, Donati MB. Thrombotic thrombocytopenic purpura during oral contraceptive treatment. Thromb Haemost 1978; 40: 563-64. 15. Tardy B, Page Y, Decousus H, et al. Heparin induced thrombocytopenia associated with thrombotic thrombocytopenic purpura. Eur J Intern

Report

Med 1989; 1: 145-48. 16. Jackson AM, Rose BD, Graff LG,

et al. Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Ann Intern Med 1984; 101: 41-44. 17. Catizone L, Santoro A, Scialfa G, Cagnoli L, Fabbri L. Thrombotic thrombocytopenic purpura probably induced by ibuprofen. Min Nefr 1974; 21: 439-44. 18. Zacharski LR, Lusted D, Glick JL. Thrombotic thrombocytopenic purpura in a previously splenectomized patient. Am J Med 1976; 60: 1061-63. 19. Bukowski RM. Thrombotic thrombocytopenic purpura. A review. Prog Hemostasis Thromb 1982; 6: 287-337. 20. Rose M, Eldor A. High incidence of relapse in thrombotic thrombocytopenic purpura. Am J Med 1987; 83: 437-44. 21. Quaglini D, Venturoni L, Cretara G, Riciotti M. Reversible bonemarrow suppression primarily involving granulopoiesis following the use of ticlopidine. Haematologica 1982; 67: 940-41.

human endothelial cells in culture. Thromb Res 1984; 33: 323-32. 30. Vianelli N, Catani L, Belmonte MM, et al. Ticlopidine in the treatment of thrombotic thrombocytopenic purpura: report of two cases. Haematologica 1990; 75: 274-77.

HYPOTHESIS Hyperdynamic circulation in cirrhosis:

a

role for nitric oxide?

Hypotension, low systemic vascular resistance, and a reduced sensitivity to vasoconstrictors are features of cirrhosis. These cardiovascular changes might be the result of increased synthesis of a vasodilator. Nitric oxide (NO), a potent vasodilator, is synthesised in and released from peripheral blood-vessels in man. Studies in animals indicate that bacterial endotoxin and cytokines induce NO synthase expression in vessel walls, with sustained NO release and consequent hypotension. Endotoxaemia is a common feature of cirrhosis; persistent induction of NO synthase may account for the associated haemodynamic changes. Lancet1991; 337: 776-78.

is Cirrhosis often complicated by systemic haemodynamic disturbances, with hyperdynamic circulation, high heart rate and cardiac output, and low blood pressure and systemic vascular resistance.’ As

cirrhosis progresses, vascular resistance continues to fall: such vasodilatation may help to ensure adequate tissue perfusion but, if it persists, the low arterial pressure may lead to secondary disturbances in renal and hepatic blood-flow ADDRESS: Wellcome Research Laboratories, Langley Court, Beckenham, Kent BR3 3BS, UK (P Vallance, MRCP, S. Moncada, FRS). Correspondence to Dr S. Moncada

777

and to ascites." Indeed, the degree of haemodynamic disturbance correlates with prognosis.3 The precise mechanisms that underlie these cardiovascular changes are not known, but resistance to vasoconstriction is indicated by the associated peripheral vasodilatation which persists despite increased sympathetic tone, high concentrations of circulating noradrenaline, and activation of the renin-angiotensin system.1.4 Excess production of a vasodilator seems likely;1-3 prostacyclin, bradykinin, substance P, and atrial natriuretic peptide (ANP) have all been implicated, but clear evidence of their involvement is lacking.’ Nitric oxide and endotoxin Nitric oxide

a vasodilator synthesised from for the biological activity of L-arginine, endothelium-derived relaxing factor.s,6 In animals, agonistinduced NO release from vascular endothelium leads to peripheral vasodilatation, a fall in blood pressure, and tachycardia 7,8 but these effects are short-lived and vascular tone returns to normal once agonist infusion is stopped. However, porcine aortic endothelial cells in culture express a second, distinct, inducible NO synthase in response to bacterial lipopolysaccharide endotoxin.9 Once induced, this enzyme releases NO over many hours without the need for further stimulation. This long-acting NO synthase is similar to the inducible enzyme found in activated macrophages. In-vitro incubation of vascular rings with endotoxin or cytokines leads to induction of NO synthase in both endothelium and smooth muscle and to progressive vascular with diminished relaxation responsiveness to vasoconstrictors.10,11 When induced by endotoxin these effects can be prevented by cycloheximide (an inhibitor of protein synthesis), polymyxin B (an antagonist of endotoxin), and N°-monomethyl-L-arginine (L-NMMA, an inhibitor of NO synthase).9,10 Once NO synthase is induced and the vascular rings are relaxed, however, only L-NMMA will reverse these changes.10,12 Glucocorticoids also inhibit induction of this NO synthase vascular relaxation and and the consequent hyporesponsiveness,9,lo,13 but have no effect once the enzyme has been expressed.1o Thus induction of an NO synthase may cause the vasodilatation observed in endotoxaemia, and NO appears to be an important mediator of the vascular actions of endotoxin and cytokines. These findings may also explain why glucocorticoids prevent septic shock in animals, but are ineffective once septic shock is established. The acute cardiovascular effects of endotoxin in man are similar to those described in animals: intravenous administration of endotoxin to healthy volunteers leads to a fall in systemic vascular resistance and blood pressure and an increased heart rate.’4 These effects occur after a lag phase of 1-2 hours; this delay is also seen in rats, where it corresponds to induction of NO synthase.

(NO),

accounts

Cyclic

guanosine

monophosphate

(cGMP)

concentrations have been used to indicate NO generation because NO dilates blood vessels through activation of guanylate cyclase, which leads to increased intracellular cGMP concentrations.19.20 cGMP leaks out of cells and urinary cGMP concentration increases as vascular NO synthesis increases:19.20 up to half the cGMP in urine may be attributable to NO release, with the remainder derived from ANP activity.19 Urinary cGMP is raised in patients with cirrhosis-an increase detectable before the development of ascites and not always associated with raised ANP concentrations.21 Glucocorticoids, which prevent expression of inducible NO synthase, increase diuresis22 and survival23 in some patients with cirrhosis, but their precise effects on peripheral haemodynamics remain unclear. Sterilisation of the intestine may reduce endotoxaemia and it will be interesting to see whether this diminishes cGMP production and alters the hyperdynamic state. The haemodynamic effects of the expression of inducible NO synthase in man would depend on where this induction occurred, because NO acts locally and is not a circulating hormone.24 Pharmacological studies in volunteers show that increased local synthesis of endothelium-derived NO leads to a large fall in vascular resistance in forearm arteries2s and increased capacitance of superficial veins.26 If other vascular beds behave in a similar way, widespread induction of NO synthase should lead to a hyperdynamic state with a fall in total peripheral resistance and a rise in total venous capacitance-changes which resemble those found in cirrhosis.

Hypothesis We propose that the endotoxaemia of cirrhosis induces NO synthase in peripheral blood-vessels directly, or indirectly via cytokines ’1127 and that this increased NO synthesis and release accounts for the associated hyperdynamic circulation. If this hypothesis is correct, inhibition of NO synthesis should restore sensitivity to vasoconstrictors and reverse these haemodynamic abnormalities. However, data from animal studies indicate a need for caution before this experimental approach is adopted in patients with cirrhosis, because available NO synthase inhibitors may increase mortality in endotoxaemia (unpublished observations). While greatly increased NO synthesis may lead to harmful hypotension, small increases in NO synthesis may have a protective role, perhaps by ensuring adequate tissue perfusion. Specific inhibitors of either the constitutive or the inducible NO synthase would enable more precise manipulation of NO synthesis and would help to establish the pathophysiological importance of NO in endotoxaemia and cirrhosis. REFERENCES RW, Caramelo C. Hemodynamic and hormonal alterations in hepatic cirrhosis. In: Epstein M, ed. The kidney in liver disease.

1. Schrier

Cirrhosis and endotoxin In cirrhosis, infection with gram-negative organisms is common;portasystemic shunts allow micro-organisms and endotoxin from the intestine to bypass liver macrophages and Kupffer cells and enter the systemic circulation.16 High concentrations of circulating endotoxin (10-100 pg/ml) are found even in cirrhotic patients with no clinical evidence of infection,17,18 and may cause several of the clinical manifestations of chronic liver disease.16

Baltimore: Williams and Wilkins, 1988: 265-85. Murray JF, Dawson AM, Sherlock S. Circulatory changes in chronic liver disease. Am J Med 1958; 32: 358-67. 3. Bosch J, Gines P, Arroyo V, Navasa M, Rodes J. Hepatic and systemic hemodynamics and the neurohumoral systems in cirrhosis. In: Epstein M, ed. The kidney in liver disease. Baltimore: Williams and Wilkins,

2.

1988: 286-305. 4. Bendtsen F, Henriksen JH, Sorensen TIA, Christensen NJ. Effect of oral propranolol on circulating catecholamines in cirrhosis: relationship of severity of liver disease and splanchnic haemodynamics. J Hepatol 1990; 10: 198-204.

778

5. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524-26. 6. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesise nitric oxide from L-arginine. Nature 1988; 333: 664-66. 7. Rees DD, Palmer RMJ, Moncada S. The role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 1989; 86: 3375-78. 8. Aisaka K, Gross SG, Griffith OW, Levi R. L-arginine availability determines the duration of acetylcholine-induced systemic vasodilation in vivo. Biochem Biophys Res Commun 1989; 163: 710-17. 9. Radlomski MW, Palmer RMJ, Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci USA 1990; 87: 10043-47. 10. Rees DD, Cellek S, Palmer RMJ, Moncada S. Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone. An insight into endotoxin shock. Biochem Biophys Res Commun 1990; 173: 541-47. 11. Busse R, Mulsch A. Induction of nitric oxide synthase by cytokines in vascular smooth muscle cells. FEBS Lett 1990; 275: 87-90. 12. Julou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, Stoclet J-C. Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway. Am J Physiol 1990; 259: H1038-43. 13. Knowles RG, Salter M, Brooks SL, Moncada S. Anti-inflammatory glucocorticoids inhibit the induction by endotoxin of nitric oxide synthase in the lung, liver and aorta of the rat. Biochem Biophys Res Commun 1990; 172: 1042-48. 14. Suffredini AF, Fromm RE, Parker MM, et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989; 321: 280-87. 15. Wyke RJ. Bacterial infections complicating liver disease. Ballière’s Clin Gastroenterol 1989; 3: 187-210.

16.

Bourgoignie JJ, Valle GA. Endotoxin and renal dysfunction in liver disease. In: Epstein M, ed. The kidney in liver disease. Baltimore:

Williams and Wilkins, 1988: 486-507. AB, Henderson JM, Kutner MH. Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral blood in patients with cirrhosis. Hepatology 1988; 8: 232-36. 18. Yomota M, Kambayashi J, Tanaka T, Tsujinaka T, Sakon M, Mori T. A simple turbidometric time assay of the endotoxin in plasma. J Biochem Biophys Meth 1989; 18: 97-104. 19. Burton GA, MacNeil S, de Jonge A, Haylor J. Cyclic GMP release and vasodilation induced by EDRF and atrial natriuretic factor in the isolated perfused kidney of the rat. Br J Pharmacol 1990; 99: 364-68. 20. Tolins J, Palmer RMJ, Moncada S, Raij L. Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses. Am J Physiol 1990; 258: H655-62. 21. Miyase S, Fujiyama S, Chikazawa H, Sato T. Atrial natriuretic peptide in liver cirrhosis with mild ascites. Gastroenterol Jpn 1990; 25: 356-62. 22. Lintrup J, Friis Th, Nissen NI. Comparative studies on the diuretic and biochemical effects of prednisolone and spironolactone in hepatic cirrhosis. Acta Med Scand 1966; 179: 13-21. 23. Shearman DJC, Finlayson NDC, eds. Diseases of the gastrointestinal tract and liver. Edinburgh: Churchill Livingstone, 1989: 795-808. 24. Moncada S, Palmer RMJ, Higgs EA. Biosynthesis of nitric oxide from L-arginine: a pathway for the regulation of cell function and communication. Biochem Pharmacol 1989; 38: 1709-15. 25. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989; ii: 997-1000. 26. Vallance P, Collier J, Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium-dependent dilatation in human veins in vivo. Cardiovasc Res 1989; 23: 1053-57. 27. Fong Y, Marano MA, Moldawer LL, et al. The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans. J Clin Invest 1990; 85: 1896-904.

17. Lumsden

VIEWPOINT Perestroika for Britain’s NHS DONALD W. LIGHT

Monday, April 1, marks the beginning of Britain’s radical effort to restructure health services for the entire nation around competitive market forces. Advocates talk of unshackling services from an insensitive and hierarchic bureaucracy that is often likened to those in former East Germany or the Soviet Union. Indeed, this observer was struck by the six-inch pile of memoranda and regulations on every conceivable detail, issued by the Department of Health to a district general manager over a five-week period in 1990. Equally striking was the flurry of preparations for implementing the changes, even before Parliament had finished debating the Bill and months before it became law. Despite near-universal opposition to the reform by clinicians and other service providers, one was assured that introducing an alternative bill was "pointless". That a Prime Minister has such power within a democracy surprised me. The ostensible purpose of introducing internal competitive markets is to ferret out the extensive inefficiencies in the NHS so that one gets "better value for money". The effects, in my view, will be both better and worse. But first to the "extensive inefficiencies" in what most experts consider the most efficient health care system in the industrialised world. Yet a few months of investigation uncovered a wide array of macro and micro inefficiencies.1.2 These include unnecessary bed-days, wasted theatre time, high turnover due to low wages and poor working conditions, fragmented purchasing of supplies, unnecessary referrals, and lack of accountability. Nonetheless the NHS delivers more services for less cost than any other, even aside from the services not delivered to

on waiting-lists for elective procedures. Does this that other health-care systems, especially those ’vhere imply market forces have some play, are even more inefficient? Odd as it may sound for an administration hell-bent on applying market forces to inefficiencies, Britain’s Conservative government did not assess either the extent and nature of the inefficiencies or the number of services and localities where markets might be possible. It still has not. As a result, many forms of waste will continue, and in many places not much competition will occur because the reforms do not fit the problems. Ironically, the creation of internal markets is less likely to produce more services for less money than they have very tight budgets over the past ten years. How can so many inefficiencies remain in such an efficient system? Quite simply that most "inefficiencies" in a health-care system are deeply embedded in custom, values, the "right" way to do things, the structure of budgets, power, and hierarchy. They have more to do with anthropology and sociology than with time-and-motion studies or economics. Mechanistic inefficiencies are easily addressed. The others involve such questions as, "How stable should patients be before discharge?" Or, "How much autonomy should a surgeon have in deciding when and how to operate, or whether to operate at all?" Physician autonomy, many say, is the real agenda behind the market reforms. Managers have few leverage points against consultants who do interesting work like fertility clinics rather than pregnancy terminations, or who waste resources through their clinical habits. Autonomy, despite its connotations, is not an island unto itself. Either the

those

ADDRESS

Division of Behavioral and Social Medicine, of Medicine and Dentistry, Camden, New Jersey 08103, USA (Prof D. W. Light, PhD).

University