82

tionship between hydrocarbon exposure and glomeru-lonephritis is that chemical damage to alveolar and glo-merular capillary basement membrane gives rise to

anti-G.B.M. antibodies and so initiates glomeruloneph-ritis58 59This hypothesis is to some extent supported bythe high frequency of anti-G.B.M. antibodies, of lineardeposition of IgG in glomerular basement membrane,and of clinical presentation as Goodpasture’s syndrome(in two of the reported series)58 59In view of the knownsusceptibility of the renal tubules to toxic injury by hy-drocarbons, Zimmerman et al.59 raised the possibilitythat antibody formation against altered tubular antigensmay account for other kinds of proliferative glomeru-lonephritis. A third possibility is that, through toxicaction on the glomeruli, hydrocarbons induce a prolifer-ative response directly, without any immunemechanism.

Cardiac arrhythmias, marrow depression, neuropsy-chiatric disorders, and hepatorenal failure have all beenreported after solvent sniffing.61 Originally uncommon inBritain, this habit has now reached almost epidemic pro-portions among the youth of some regions62 (see p. 84).Physicians in those parts should be on the look-out forfurther evidence of a relationship between glomerulo-pathy and hydrocarbon exposure.

CHILDHOOD LIVER DISEASE WITHALPHA-1-ANTITRYPSIN DEFICIENCY

SERious liver disease in infancy and childhood is com-monly associated with genetic deficiency of the serumprotein alpha-1-antitrypsin,63-66 a glycoprotein synthe-sised in the liver and accounting for about 90% of thealpha-1-globulin in serum.67 It is found in much lowerconcentration in other tissues.68 Its genetic control isthought to be by a single autosomal gene responsible forat least twenty-four different alleles which may be dis-tinguished by acid/starch-gel electrophoresis and anti-gen/antibody crossed immunoelectrophoresis. The var-iants so recognised are labelled alphabetically in theprotease-inhibitor (Pi) phenotyping system. PiM is thepredominant type, such individuals having a serum

alpha-1-antitiypsin of 200-400 mg/dl in health, in-

creasing with infection, pregnancy, oral contraceptives,perinatal diseases, and in many acute liver disorders. In-dividuals with genetic deficiency have serum concen-trations of 20-160 mg/dl which increase little with thesestresses and are of phenotypes PiZ or PiNul (in whichlittle or no antitrypsin is found in serum). 50-60% of in-dividuals with these phenotypes acquire emphysema inearly adult life, and 10-20% have serious liver diseasein childhood.The pattern of liver disease is becoming clearer. In the

great majority of children it is first identified as jaundicewith conjugated hyperbilirubinaemia, often followingdirectly from neonatal physiological jaundice but some-times starting as late as four months. These infants have

60. Lagrue, G. ibid. 1976, i, 1191.61. Wyse, D. G. Can. med. Ass. J. 1973, 108, 71.62. Watson, J. M. Hlth Bull., Edinb. 1975, 33, 153.63. Aagenaes, O., Matlery, A., Elgio, K., Munthe, E., Fagerhol, M. Acta pædiat.

scand. 1972, 61, 632.64. Cottrall, K., Cook, P. J. L., Mowat, A. P. Postgrad. med. J. 1974, 50, 3376.65. McPhie, J. L., Binnie, S., Brunt, P. Archs Dis. Childh. 1976, 51, 584.66. Odievre, M., Martin, J-P., Hadchouel, M., Alagille, D. Pediatrics, 1976, 57,

226.67. Talamo, R. C. ibid. 1975, 56, 91.68. Talamo, R. C., Langley, C. E., Barker, J. C. Pediat. Res. 1972, 6, 119.

the clinical and biochemical features of hepatitis, withdark urine, pale or acholic stools, hepatosplenomegaly,and raised serum transaminases and alkaline phospha-tase. The clinical severity of the hepatitis varies. Someinfants seem well apart from jaundice and slow weight-gain ; others fail to thrive, with vomiting, hypotension,purpura, and septicaemia. Jaundice usually persists fortwo to three months, but the duration varies from as littleas a week to more than thirteen months. Althoughthe serum bilirubin returns to normal, the aspartateaminotransferase tends to be intermittently raised whilepersistent increases of alkaline phosphatase and serumcholesterol are the rule .64 70 In a few instances, liver dis-ease will already have been so severe that cirrhosis andits complications appear in infancy. For most children aperiod of clinical wellbeing follows, with hepatomegalythe only abnormality, until cirrhosis arises in late child-hood or adolescence. The degree of irreversible liver

damage tends to reflect the clinical severity of the initialhepatitis, but not always: cirrhosis in infancy may fol-low a mild hepatitis;"and, by contrast, some patients arecirrhosis-free even in the third decade. Perhaps thosewho rated this complication as inevitable 71 were too pes-simistic. Further evidence of the range of severity ofhepatic,disease is reported in a prospective study of 118Swedish infants found to be alpha-1-antitrypsin deficientduring screening of 200 000 unselected newborn infants.11 % of the deficient infants had hepatitis with jaundicewhile a further 6% had an anicteric hepatitis with hepa-tosplenomegaly. 42% of the remainder who had no clini-cal features of liver disease had raised serum-transa-minases in the first three months of life and 62% hadraised gamma-glutamyl transpeptidase at one year. 74What the final outcome for these infants will be is uncer-tain.

In an attempt to provide some guide to prognosis,Gautier and her colleagues 70 have compared, in a groupof 15 children, liver-biopsy findings in the first sixmonths of life with subsequent clinical, biochemical, andpathological developments. Three clinicopathologicalpatterns were discerned. A group of 6 infants with little

portal-tract fibrosis in the initial biopsy specimen had noclinical features of cirrhosis when examined at 2-15years. However, 5 infants with obvious portal-tractfibrosis and bileduct proliferation had, by the age of 7years, hard livers with splenomegaly, 2 having provencirrhosis. 3 of 4 who as infants had intrahepatic biliaryhypoplasia and pruritus also acquired portal hyper-tension by the age of 12 years, but the 4th patient withsimilar initial clinical and pathological features was cirr-hosis-free at the age of 19. All 15 patients have persis-tently raised serum cholesterol and alkaline phospha-tase and the remainder may yet acquire cirrhosis, butwith a slower rate of progression than in the first groupof patients. Terminally, these children may have glomer-ulonephritis." -77 The pathogenesis of the renal lesion is

69. Fagerhol, M. K. in Aspects of Genetics in Pædiatrics (edited by D. Barltrop);p. 73. London, 1976.

70. Hadchouel, M., Gautier, M. J. Pediat. 1976, 89, 211.71. Mowat, A. P. in Recent Advances in Gastroenterology, No. 3 (edited by I.

Bouchier); p. 261. Edinburgh, 1976.72. Morez, S. P., Kutz, E., Cox, D. W., Sass-Kortsak, A. J. Pediat. 1976, 88,

19.73. Sharp, H. L. Hosp. Practice, 1971, 6, 83.74. Sveger, T., Aagenaes, O. in Liver Diseases in Infancy and Childhood (edited

by S. R. Berenberg); p. 41. Martinus, Nijhoff Medical Division, 1976.75. Kutz, E., Moroz, S. P., Balfe, J. W., Sass-Kortsak, A. K. Am. J. Path. 1974,

74, 12a.

83

speculative, but since alpha-1-antitrypsin has been foundin the glomeruli the organ involvement could be moregeneralised than was previously suspected.What causes liver disease in alpha-1-antitrypsin defi-

ciency?69A distinctive feature of the liver disease is pro-minent, magenta-coloured, periodic-acid/Schiff positiveglobules in periportal hepatocytes. These seem to corres-pond to the - amorphous material which distends the

endoplasmic reticulum on electronmicroscopy and fluor-esces with a specific fluorescein-tagged antibody to alpha-t-antitrypsin." These, however, occur in deficient indivi-duals whether liver disease is present or not. Since theincidence and severity of liver disease is greater in somefamilies than in others, it has been suggested that asecond associated genetic factor may be necessary forliver disease to occur. This second factor might have apart in controlling protease/antiprotease balance in tis-sues, since the most favoured pathogenesis of progressiveliver disease is deficiency of tissue antiprotease with un-inhibited action of viral, bacterial, or cellular proteasesreleased by tissue damage, however initiated. Ward andTalamo 78 suggest that a factor in causing emphysemacould be depressed concentrations of chemotactic-factorinhibitor, leading to an inordinate attraction of neutro-phils to the site of tissue injury. The work of Galdston 79indicates that the alpha-1-antitrypsin deficient individualwho avoids disease also has diminished leucocyte pro-teases. But disturbed intrahepatic protease/antiproteaseimbalance unique to the alpha-1-antitrypsin deficient in-dividual with liver disease has yet to be demonstrated.A further ætiological factor could be persistently dis-turbed cellular immunity, as evidenced by the lympho-cyte cytotoxicity for isolated rabbit hepatocytes seen inchildren with alpha-1-antitrypsin deficiency and liverdisease. 80If an exogenous factor initiates the liver damage it

must operate in utero or in the perinatal period. Veryfew of these patients acquire serious liver disease if theyhave not had obstructive jaundice in the first month oflife. The increased proportion of low-birth-weight in-fants with liver disease may point to prenatal injury. 74Hepatitis-B surface antigen came under suspicion, butthis association has not been confirmed.7’ Since muchliver disease may be subclinical, identification of thecause may prove difficult.

Determination of the primary aetiological factor inthis liver disease, and elucidation of additionalmechanisms of pathogenesis: these remain importantresearch objectives. But some of the effort must go intoisolation and purification of alpha-1-antitrypsin, sinceadministration to deficient infants in the first weeks oflife might conceivably control the liver damage. In thisarea there are formidable difficulties since alpha-1-anti-trypsin has an in-vivo half-life of only 6 days," andthere may be difficulty in preparing material which isnot antigenic. So far, no treatment has influenced thecourse of established liver disease.

76. Kutz, E., Moroz, S. P., Balfe, J. W., Sass-Kortsak, A. K. Pediatrics, 1976,57, 223.

77. Sharp, H. L. in Liver Diseases in Infancy and Childhood (edited by S. R.Berenberg); p. 52. Martinus, Nijhoff Medical Division, 1976.

78. Ward, P. A., Talamo, R. C. J. clin. Invest. 1973, 52, 516.79. Galdston, M., Janoff, A., David, A. L. Am. Rev. resp. Dis. 1973, 107, 718.80. Smith, A. L., Cochrane, A. N. G., Mowat, A. P., Eddleston, A. L. W. F.,

Williams, R. Archs Dis. Childh. 1976, 51, 731 (abstr.).81. Porter, C. A., Mowat, A. P., Cooke, P. J. L., Haynes, D. W. G., Shilkin,

K. B., Williams, R. Br. med. J. 1972, in, 435.82. Makino, S., Reed, C. E. J. Lab. clin. Med. 1969, 74, 987.

PLASMA-EXCHANGE IN NEPHRITIS

LAST year, Lockwood and his colleagues’ reportedencouraging results in Goodpasture’s syndrome with aregimen of intensive plasma-exchange, steroids, and

cytotoxic drugs. After treatment, lung haemorrhage de-creased and renal function improved (in the patientswithout advanced renal failure). The Hammersmithworkers suggested two possible mechanisms for theseseeming benefits-removal of circulating antibodies toglomerular basement membrane (G.B.M.), and depletionof inflammatory mediators such as fibrinogen and com-plement. This week (p. 63) the same group report theresults of this therapy in nine patients with rapidly pro-gressive "crescentic" nephritis of the type not associatedwith circulating antibodies to G.B.M.-i.e., nephritis pre-sumed to be due to circulating immune complexes.

Evaluation is difficult because crescentic nephritis, aswell as being rare, arises in diverse conditions. In mostcases of Goodpasture’s syndrome crescentic nephritis ismediated by antibodies to G.B.M., whereas in polyarter-itis nodosa, Wegener.’s syndrome,. Henoch-Schönleinpurpura, and mixed cryoglobulinsemia, the cause seemsto be immune complexes; sometimes there is no

clearly identifiable systemic disease. Such heterogeneousconditions are likely to differ both in their natural his-tory and in their response to the individual componentsof the therapeutic regimen. A further difficulty is in pre-dicting outcome. When 70% or more of glomeruli aresurrounded by crescents the prognosis is undeniablybleak (because glomeruli are irreversibly damaged), butwhat of lesser degrees of crescent formation? We have noready means of identifying those patients with crescenticnephritis who are likely to progress to renal failure, andpresent hopes rest on quantification of the immunologi-cal derangement-for example, in anti-G.B.M. disease bymeasuring the titre of circulating antibodies, or in

immune-complex disease by measurement of the con-centration of circulating immune complexes. Inanti-G.B.M. diseases we can draw no more than tentativeconclusions about the relationships between antibodytitres and disease activity: though patients with lowlevels of anti-G.B.M. antibody by the radioimmunoassaytechnique generally have little disease activity, thosewith higher titres are not always severely affected. Weneed more information about the relationships betweenthe properties of the antibody and its specificity, themediator systems, and damage in the target organs-glomerulus and lung. Assays for circulating immunecomplexes are still under development, and there is asyet little information on the relation of blood-levels to

nephrotoxic or vasculotoxic potential. Dr Lockwood andhis colleagues used the Clq-deviation test of Sobel et al.l,and the patients with high Clq-binding activity seemedto respond best. Indeed, the strongest evidence that

plasma-exchange influenced the course of disease wasobtained in two patients in whom serial assays showedthe Clq-binding test to mirror disease-activity. Plasma-exchange clearly needs further evaluation and shouldnot be applied widely until its worth is proved. A con-trolled trial will not be feasible without full-hearted sup-port from several centres.

1. Lockwood, C. M., Rees, A. J., Pearson, T. A., Evans, D. J., Peters, D. K.,Wilson, C B. Lancet, 1976, i, 711.

2 Sobel, A. I , Bokisch, V. A., Muller-Eberhard, H. J. J. exp. Med. 1975, 142,139.