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like muscle cells. These ambivalent cells are now betterunderstood and they are labelled myofibroblasts.The myofibroblast was named in 1971 by Majno,

Ryan, and Gabbiani,’ whose group showed that it pos-sessed the apparatus and many of the functional proper-ties of both fibroblast and smooth-muscle cell. Tran-

siently present in young granulation tissue,myofibroblasts shrink the wound and lose their myofi-brils as it matures into a scar.2 The plastic surgeon triesto avoid excessive wound contraction by limiting the for-mation of granulation tissue with skin grafts, cortico-steroids, and X rays, but now the hunt is on for pharma-cological means of control. 3

Myofibroblasts have been demonstrated in variousreactive proliferations of connective tissue, includinghypertrophic scars,4 ischsemic contractures of intrinsichand muscles,s stenosing tenosynovitis, and carpal-tun-nel syndrome.6 They may also be responsible for someof the progressive, disabling distortion of normal archi-tecture in cirrhosis of the liver and sarcoidosis of thelung.8

.

Pluripotent cells in the aorta have been identified asmyofibroblasts capable of synthesising elastin as well ascollagen and matrix,9 and may phagocytose lipid too inatheroma.10 Their importance in elastogenesis is not yetestablished, though suggested by the fact that as elasticfibres wax in a wound, the myofibrils wane, and that thefamiliar but unexplained ganglia of the wrist consist ofmyofibroblasts capable of elastogenesis.11However, it is not only in reactive proliferations but

also in pseudotumorous and even a few frankly neo-plastic conditions that myofibroblasts are being found.Gabbiani and Majno themselves described them in

Dupuytren’s contracture,12 and the cells have also beenfound in the musculoaponeurotic fibromatoses (desmoidtumours),13 nodular fasciitis, 14 and Peyronie’s disease,15They may simply reflect a phase of normal maturationof fibroblastic tissue in the spontaneous regression ofmultiple congenital mesenchymal hamartomas16 or bepart of a change in a neoplasm analogous to the trans-formation of neuroblastoma into ganglioneuroma. In asmall series of truly malignant tumours, 75% of thespindle cells in both fibrosarcomas and malignantfibrous histiocytomas proved to be myofibroblasts,17 andsimilar claims have been made for single examples ofbenign neoplasms such as uterine plexiform tumour,18dermatofibroma, 19 and giant-cell fibroma of oral

1. Gabbiani, G., Ryan, G. B., Majno, G. Experientia, 1971, 27, 549.2. Guber, S., Rudolph, R. Surgery Gynec. Obstet. 1978, 146, 641.3. Madden, J. W., Morton, D., Peacock, E. E. Surgery, 1974, 76, 8.4. Baur, P. S., Larson, D. L., Stacey, T. R. Surgery Gynec. Obstet. 1975, 141,

22.5. Madden, J. W., Carlson, E. C., Hines, J. ibid. 1975, 140, 509.6. Madden, J. W. Plast. reconstr. Surg., 1973, 52, 291.7. Bhatal, P. S. Pathology, 1972, 4, 139.8. Judd, P. A., Finnegan, P., Curran, R.C.J. Path. 1975, 115, 191.9. Wissler, R. W. Circulation, 1967, 36, 1.

10. Moss, N. S., Benditt, E. P. Lab. Invest. 1970, 23, 521.11. Ghadially, F. N., Mehta, P. N. Ann. rheumat. Dis. 1971, 30, 31.12. Gabbiani, G, Majno, G. Am. J. Path. 1972, 66, 131.13. Stiller, D., Katenkamp, D. Virchows Arch. path. Anat. 1975, 369, 155.14. Wirman, J. A., Cancer, 1976, 38, 2378.15. Ariyan, S., Enriquez, R., Krizek, T.J. Archs Surg. 1978, 113, 1034.16. Benjamin, S. P., Mercer, R. D., Hawk, W. A. Cancer, 1977, 40, 2343.17. Churg, A. M., Kahn, L. B. Hum. Path. 1977, 8, 205.18. Fisher, E. R., Paulson, J. D., Gregorio, R. M. Archs Path. 1978, 102, 477.19. Hashimoto, K., Brownstein, M. H., Jakobiec, F. A. Archs Dermat., 1974,

110, 874.

mucosa.20 For a moment it seems that hope was mis-placed in electron microscopy as the means of classifyingmore accurately the notoriously difficult and debatablesoft-tissue tumours. Yet further work may show that

myofibrils are a feature of immaturity, and one wonderswhether radiotherapy will diminish them just as it"matures" other tumours, and whether their presence ina spindle-cell tumour will indicate a poorer prognosisthan their absence.The dynamic plasticity of mesenchyme has been un-

derlined by the description of the myofibroblast. Its orig-ins are so far unknown and may lie in immigrant cells,blood-vessels, or transformed local fibroblasts, but tis-sue-culture experiments show that smooth muscle cansecrete collagen and elastin. 21

HIGH-DENSITY LIPOPROTEIN AND ATHEROMA

VERY-LOW-DENSITY lipoproteins (V.L.D.L.) are secretedmainly by the liver, for transport of triglycerides to peri-pheral tissues such as muscle and heart. In the peripherythey are broken down to low-density lipoproteins(L.D.L..) by catabolic enzymes such as lipoprotein lipase(L.P.L.) and possibly lecithin:cholesterol acyltransferase(L.C.A.T.). L.D.L. delivers cholesterol to peripheral tissuesfor the renewal of cell membranes and also inhibits thecellular synthesis of cholesterol. Circulating L.D.L. cho-lesterol thus regulates, by feedback inhibition of choles-terol synthesis, the cellular content of cholesterol.The lipids of the atheromatous plaque (mainly choles-

terol, cholesteryl ester, and phospholipids) are derivedfrom the plasma lipoproteins. Arterial cells can degradelipoproteins; V.L.D.L. is metabolised in endothelial cellsby the enzyme L.P.L., and the product particle, L.D.L.,can filter through the endothelial barrier to be taken upby smooth-muscle cells in the subintimal space. Epide-miological and experimental evidence suggests, thatraised plasma levels of V.L.D.L. and L.D.L. can predisposeto atheroma, 1 although it is still disputed whetherv.L.D.L. acts as an independent variable for the develop7.ment of arterial disease. The fact that V.L.D.L. is con-verted into L.D.L. perhaps makes this argument specious.The current focus of attention in the development of

atheroma is H.D.L. There is good epidemiological evi-dence to support the view that reduced levels of H.D.L.

may retard the development of atheroma. For example,in 1953 Nikkila3 showed that patients with ischsemicheart-disease and normal total plasma-cholesterol con-centrations had significantly reduced levels of H.D.L.cholesterol. This observation was largely neglected until1975 when further evidence was assembled by Millerand Miller4 to suggest that a reduction in plasma-H.D.L.may impair the normal clearance of cholesterol from thearterial wall and thereby accelerate the development ofatherosclerosis. Further weight was given to this idea bythe Framingham epidemiological study: among 2815

20. Weathers, D. R., Campbell, W. G. Oral Surg. 1974, 38, 550.21. Ross, R., Klebanoff, S. J. J. Cell Biol. 1971, 50, 159.1. Carlson, L. A., Bottiger, L. E. Lancet, 1972, i, 865.2. Kannel, W. B., Castelli, W. P., Gordon, T., McNamara, P. M. Ann. intern.

Med. 1971, 74, 1.3. Nikkilä, E. Scand. J. clin. Lab. Invest. 1953, 5, suppl. 8.4. Miller, G. J., Miller, N. E. Lancet, 1975, i, 16.

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men and women followed up for four years, there wasa strong inverse association of H.D.L.-cholesterol withischaemic heart-disease while a statistically weaker posi-tive association was observed for L.D.L. cholesterol.5 Onp. 1271, a Birmingham group report similar findings inperipheral vascular disease; in 100 patients, H.D.L. apoli-poproteins were significantly lower than in controls.However, not all studies have demonstrated such a

strong inverse association with H.D.L. For example, indiabetics the statistical significance of the positive associ-ation between the prevalence of vascular disease andL.D.L.-cholesterol was greater than that of the negativeassociation with H.D.L.-cholesterol.6The clinical evidence for the role of H.D.L. as a pri-

mary determinant of arterial disease is not so compel-ling. Patients homozygous for familial hypercholester-olaemia have increased plasma-L.D.L. values, and arterialdisease develops early and extensively; such patientsoften die in their mid-twenties with myocardial infarc-tion. Patients homozygous for Tangier disease who havehardly any H.D.L. in plasma ought also to be at risk ofearly and extensive arterial disease with prematuredeath from myocardial infarction. But this does not hap-pen : these patients accumulate cholesteryl esters inreticuloendothelial cells and histiocytes, but the arterialtree is spared. They frequently survive to middle-agewithout manifestation of large-vessel disease.7 Such pa-tients usually have low circulating levels of L.D.L.-cho-

- lesterol, so the endothelial filtrations of L.D.L. may bereduced. However, cholesterol accumulates in thereticuloendothelial cells and not in arterial cells, suggest-ing that in the absence of H.D.L. other mechanisms mayprevent accumulation of cholesterol in the arterial wall.This argues against a primary role for H.D.L. in the de-velopment of atheroma.

If H.D.L. does protect against arterial disease whatmight be the mechanisms? The function of H.D.L. inlipid metabolism-and even its tissue of origin-is lessclearly understood than that of the other lipoproteins.Amongst many possibilities, H.D.L. may act as a reser-voir for the C-apoproteins of V.L.D.L.;8 one fraction ofH.D.L., H.D.L.2, may be a preferred substrate for theenzyme L.C.A.T. ;9 and the particle may function in theremoval of surplus cholesterol from peripheral cells fortransport back to the liver.10 It is also possible that thearginine-rich peptide of H.D.L. can bind to the L.D.L.receptor of mesenchymal cells and displace L.D.L. fromcellular uptake." The role of H.D.L. in the "reverse"transport of cholesterol has come under scrutiny in rela-tion to arterial disease. Most peripheral tissues can syn-thesise cholesterol but cannot metabolise it (adrenalglands and gonads excepted). Cholesterol can be used inthe formation or renewal of cell membrane but anyexcess cholesterol must be transported back to the liverif it is not to accumulate in the periphery. H.D.L. may act

5. Gordon, T., Castelli, W. P., Hjortland, M. C., Kannel, W. B., Dawber,T. R. Am. J. Med. 1977, 62, 707.

6. Reckless, J. P. D., Betteridge, D. J., Wu, P., Payne, B., Galton, D. J. Br.med. J., 1978, i, 883.

7. Herbert, P. N., Gotto, A. M., Frederickson D. S. in The Metabolic Basis ofInherited Disease (edited by J. S. Stanbury, J. B. Wyngaarden, and D. S.Frederickson). New York, 1978.

8. Havel, R. J., Kane, J. P., Kashyap, M. L. J. clin. Invest. 1973, 52, 32.9. Glomset, J. A. Am. J. clin. Nutr. 1970, 23, 1129.

10. Glomset, J. A. J. Lipid Res. 1968, 9, 15.11. Mahley, R. W., Innerarity, T. L. J. biol. Chem. 1977, 252, 3980.

as the transport particle and by removing cholesterolfrom arterial walls may retard the development of ather-oma. H.D.L. is a preferred substrate for the enzymeL.C.A.T., which converts some free cholesterol on the sur-face of H.D.L. to cholesteryl ester which then moves intothe apolar core of the particle. The altered H.D.L. cannow accept more free cholesterol following interactionwith peripheral cells. Studies in tissue culture haveshown that H.D.L. can indeed promote the release ofcellular cholesterol.12 An alternative is that H.D.L. com-

petes with L.D.L. for cellular binding sites, thus reducingthe uptake and degradation of L.D.L. by arterial cellswhen H.D.L. is present in excess.13 Both hypothesesrequire much further work.

Although it is now firmly established that a negativeassociation exists between plasma levels of H.D.L. andarterial disease, the importance of this association andthe possible mechanisms underlying it are still in dis-

pute. In practical terms, if the association is direct, thentherapy designed to raise H.D.L. levels in plasma shouldreduce the prevalence of arterial disease-in the sameway that factors decreasing L.D.L.-cholesterol levels tendto reduce the occurrence of arterial disease. 14 Thisremains to be demonstrated for H.D.L.

SUGAR MALABSORPTION IN CHILDHOOD

SUGAR malabsorption is important in childhood, par-ticularly early infancy. It results in watery diarrhoeawith variable abdominal pain and, when severe and per-sistent, in failure to thrive. It is usually diagnosed by de-monstration of excess reducing substances in the stooland by the response to an elimination diet. But the relia-bility of the stool test is controversial and other methodshave been tried: Harrison and Walker-Smith showedthat small-intestinal morphology and disaccharidase

activity correlated poorly with lactose tolerance tests. Inadults, Newcomer et awl. have identified lactose defi-

ciency by measurement of breath hydrogen. The hydro-gen arises from bacterial fermentation, in the colon, ofcarbohydrate which has not been absorbed in the smallintestine. This technique has now been adapted forchildren by Maffei et awl. 3 4 for lactose and by Perman etal. for sucrose. An oral load of sugar is given and thechild’s breath is sampled via a small plastic tube in thenostril..When there is carbohydrate malabsorption,breath hydrogen peaks 1-3 hours after the sugar load.The test has not been fully evaluated in routine practicebut some children in whom the only evidence of lactosemalabsorption was an abnormal breath test have re-

sponded well to a lactose-free diet.4 Samples can bestored, which means that epidemiological studies can bedone through a central laboratory. Breath hydrogenmay prove the most useful measure of sugar malabsorp-tion.

12. Stein, O., Vanderhock, J., Stein, Y. Biochim. biophys. Acta, 1976, 431, 347.13. Carew, T. E., Koschinsky, T., Hayes, S. B., Steinberg, D. Lancet, 1976, i,

1315.

14. Miettinen, M., Turpeinen, O., Karvonen, M. J. ibid. 1972, ii, 835.1. Harrison, M., Walker-Smith, J. A. Gut, 1977, 18, 48.2. Newcomer, A. D., McGill, D. B., Thomas, P. J. New Engl. J. Med. 1975,

293, 1232.3. Maffei, H. V. L., Metz, G. L., Jenkins, D. J. A. Lancet, 1976, i, 1110.4. Maffei, H. V. L., Metz, G., Bampoe, V., Shiner, M., Herman, S., Brook,

C. G. D. Arch. Dis. Childh. 1977, 52, 766.5. Perman, J. A., Barr, R. G., Watkins, J. B.J. Pediat. 1978, 93, 17.