- Email: [email protected]
CHEMONUCLEOLYSIS
1022
and low-density lipoproteins. The high plasma-lipids could be drastically reduced by diet or by diet and clofibrate therapy. Diet alone brought 25 out of 36 patients to normal, and a further 10 patients achieved normal plasma-lipid concentrations when diet was supplemented with clofibrate therapy. Xanthomas were present in 81 % of the definite type-m patients and 64% had the palmar deposits called xanthoma striata palmaris which are characteristic of this disease. Vascular disease was detected in 43% of the patients. Ischxmic heart-disease was present in 37%, peripheral vascular disease in 29%, while 22% had both. Symptoms of these appeared 10 years earlier in men than in women patients. In this survey 162 first-degree relatives of the patients had their plasma-lipids investigated. Only 2 out of 55 blood relatives under 20 had type-iv or endogenous hyperglyceridaemia. In contrast, hyperlipidarmia of some type was present in 46% of the adult relatives: 17% had definite type ill and 8% possible type ill, 16% had type IV, and 5% had type 11. Hyperlipidsemia appeared to be monogenically determined by mutation at one or more autosomal loci. An interesting survey of the occurrence of type ill in 108 members of one family4 supports an autosomal dominant type of inheritance. One of the original couple was investigated and proved normal, but her 6 living children all had hyperlipidasmia (4 type ill, 1 each type IV and type lib), and the 3 dead all died from atherosclerotic disease. In the third generation half the adult offspring showed type-III hyperlipidasmia. Hyperlipidaemia could not be demonstrated in’ any of the offspring under 19, confirming that even in a family known to contain the altered gene it cannot be detected in children. This investigation also confirmed the association of type iv (and occasionally type 11) with type ill: 7 adult offspring whose parents’ phenotypes were known showed a type-iv pattern and 1 showed a type- II pattern. This investigation shows clearly that type-lll hyperlipidaerl1ia is normally a dominant character ; and apparently it is not sex-linked. Unfortunately the emergence of the character is age-related. It was impossible to detect it in any of the relatives under 20, though some of the relatives investigated will very probably show a type-III pattern later on. for further investigation is the frequent of type iv in the relatives of those with type ill. This association has also been noticed in patients after myocardial infarction.5 There is evidence that the abnormal lipoproteins in type ill are fragments of chylomicrons and very-low-density lipoproteins.6,7 The cholesterol/triglyceride ratios in chylomicrons are also altered in type-lll hyperlipidaemia,8 and the very-low-density lipoproteins and chylomicrons may compete for removal of triglycerides,9 by the lipoprotein-lipase clearing mechanism.10 Possibly the
A
problem
occurrence
excess
production of very-low-density lipoprotein in
increases the pressure on a defective breakdown process, and the type-m pattern appears earlier. This work suggests that, by screening relatives of type-m patients, further affected individuals may be picked up before symptoms appear. Dietary control seems very effective. Unfortunately the determination of the cholesterol/triglyceride ratio2 requires preparative ultracentrifugation, but agarosegel electrophoretic separation 11 is probably adequate for screening until even better diagnostic tests are
type
iv
established.
‘
CHEMONUCLEOLYSIS DURING the past ten years a method of treating patients with sciatica due to invertebral-disc protrusions has been developed in North America called chemonucleolysis.12 It consists of injection of chymopapain into the offending disc space or spaces. Chymopapain is a proteolytic enzyme which acts on the nucleus pulposus by hydrolysing and dissolving the non-collagenous protein that connects long-chainmucopolysaccharides. It is highly specific, and the dose which acts on chondromucoprotein is some twenty times less than that which visibly affects the fibrous tissue of the adjacent anulus fibrosus. Experimental investigations have shown that the toxic dose of
chymopapain far exceeds the therapeutic dose. The main hazard in its clinical use is an anaphylactic reaction.13 In one report 14 there were nine such reactions in a series of 1200 cases. There were two in the last 600 patients who were prophylactically given hydrocortisone and diphenhydramine. This large series of patients all had recurrent low-back pain and sciatica and had not been relieved of symptoms after a strict conservative regimen. The invertebraldisc level for injection was chosen after assessment of the clinical picture supplemented by myelography and discography. Discography was done immediately before the inj ection of chymopapain. The inj ection may be given under either general or local anaesthesia using an image intensifier. 63 % of 455 patients assessed for follow-up were graded as either excellent or good result. 56 of the first 500 injected patients went on to
surgical exploration. The problem with a technique which relies on radiographic localisation is that one can never be absolutely certain of the extent of the disease-as one can with open operation. Furthermore, the chymois to be where there is comeffective papain unlikely of extrusion disc As Macnab et al.13 material. plete point out, chemonucleolysis is not a panacea for all manifestations of disc degeneration, and at present it should be regarded as the last step before operation in the management of lumbar-disc lesions.
4. 5. 6. 7. 8.
Hazzard, W. R., O’Donnell, T. F., Lee, Y. L. ibid. p. 141. Hazzard, W. R., et al. J. clin. Invest. 1973, 52, 1569. Sata, T., Havel, R. J., Jones, A. L. J. Lipid Res. 1972, 13, 757. Hazzard, W. R., Lindgren, F. T., Bierman, E. L. Biochim. Biophys. Acta, 1970, 202, 517. Hazzard, W. R., Porte, D., Bierman, E. L. J. clin. Invest. 1970, 49, 1853.
Brunzell, J. D., et al. ibid. 1973, 52, 1578. 10. Scanu, A. M. Adv. Lipid Res. 1965, 3, 63. 9.
11. Noble, R. F. J. Lipid Res. 1968, 9, 693. 12. Smith, L., Brown, J. E. J. Bone Jt Surg. 1967, 49B, 502. See Lancet, 1967, ii, 815. 13. Macnab, I., McCulloch, J. A., Weiner, D. S., Hugo, E. P., Galway, R. D., Dall, D. Can. J. Surg. 1971, 14, 280. 14. Wiltse, L. L., Widell, E. H., Yuan, H. A. J. Am. med. Ass. 1975, 231, 474.
and low-density lipoproteins. The high plasma-lipids could be drastically reduced by diet or by diet and clofibrate therapy. Diet alone brought 25 out of 36 patients to normal, and a further 10 patients achieved normal plasma-lipid concentrations when diet was supplemented with clofibrate therapy. Xanthomas were present in 81 % of the definite type-m patients and 64% had the palmar deposits called xanthoma striata palmaris which are characteristic of this disease. Vascular disease was detected in 43% of the patients. Ischxmic heart-disease was present in 37%, peripheral vascular disease in 29%, while 22% had both. Symptoms of these appeared 10 years earlier in men than in women patients. In this survey 162 first-degree relatives of the patients had their plasma-lipids investigated. Only 2 out of 55 blood relatives under 20 had type-iv or endogenous hyperglyceridaemia. In contrast, hyperlipidarmia of some type was present in 46% of the adult relatives: 17% had definite type ill and 8% possible type ill, 16% had type IV, and 5% had type 11. Hyperlipidsemia appeared to be monogenically determined by mutation at one or more autosomal loci. An interesting survey of the occurrence of type ill in 108 members of one family4 supports an autosomal dominant type of inheritance. One of the original couple was investigated and proved normal, but her 6 living children all had hyperlipidasmia (4 type ill, 1 each type IV and type lib), and the 3 dead all died from atherosclerotic disease. In the third generation half the adult offspring showed type-III hyperlipidasmia. Hyperlipidaemia could not be demonstrated in’ any of the offspring under 19, confirming that even in a family known to contain the altered gene it cannot be detected in children. This investigation also confirmed the association of type iv (and occasionally type 11) with type ill: 7 adult offspring whose parents’ phenotypes were known showed a type-iv pattern and 1 showed a type- II pattern. This investigation shows clearly that type-lll hyperlipidaerl1ia is normally a dominant character ; and apparently it is not sex-linked. Unfortunately the emergence of the character is age-related. It was impossible to detect it in any of the relatives under 20, though some of the relatives investigated will very probably show a type-III pattern later on. for further investigation is the frequent of type iv in the relatives of those with type ill. This association has also been noticed in patients after myocardial infarction.5 There is evidence that the abnormal lipoproteins in type ill are fragments of chylomicrons and very-low-density lipoproteins.6,7 The cholesterol/triglyceride ratios in chylomicrons are also altered in type-lll hyperlipidaemia,8 and the very-low-density lipoproteins and chylomicrons may compete for removal of triglycerides,9 by the lipoprotein-lipase clearing mechanism.10 Possibly the
A
problem
occurrence
excess
production of very-low-density lipoprotein in
increases the pressure on a defective breakdown process, and the type-m pattern appears earlier. This work suggests that, by screening relatives of type-m patients, further affected individuals may be picked up before symptoms appear. Dietary control seems very effective. Unfortunately the determination of the cholesterol/triglyceride ratio2 requires preparative ultracentrifugation, but agarosegel electrophoretic separation 11 is probably adequate for screening until even better diagnostic tests are
type
iv
established.
‘
CHEMONUCLEOLYSIS DURING the past ten years a method of treating patients with sciatica due to invertebral-disc protrusions has been developed in North America called chemonucleolysis.12 It consists of injection of chymopapain into the offending disc space or spaces. Chymopapain is a proteolytic enzyme which acts on the nucleus pulposus by hydrolysing and dissolving the non-collagenous protein that connects long-chainmucopolysaccharides. It is highly specific, and the dose which acts on chondromucoprotein is some twenty times less than that which visibly affects the fibrous tissue of the adjacent anulus fibrosus. Experimental investigations have shown that the toxic dose of
chymopapain far exceeds the therapeutic dose. The main hazard in its clinical use is an anaphylactic reaction.13 In one report 14 there were nine such reactions in a series of 1200 cases. There were two in the last 600 patients who were prophylactically given hydrocortisone and diphenhydramine. This large series of patients all had recurrent low-back pain and sciatica and had not been relieved of symptoms after a strict conservative regimen. The invertebraldisc level for injection was chosen after assessment of the clinical picture supplemented by myelography and discography. Discography was done immediately before the inj ection of chymopapain. The inj ection may be given under either general or local anaesthesia using an image intensifier. 63 % of 455 patients assessed for follow-up were graded as either excellent or good result. 56 of the first 500 injected patients went on to
surgical exploration. The problem with a technique which relies on radiographic localisation is that one can never be absolutely certain of the extent of the disease-as one can with open operation. Furthermore, the chymois to be where there is comeffective papain unlikely of extrusion disc As Macnab et al.13 material. plete point out, chemonucleolysis is not a panacea for all manifestations of disc degeneration, and at present it should be regarded as the last step before operation in the management of lumbar-disc lesions.
4. 5. 6. 7. 8.
Hazzard, W. R., O’Donnell, T. F., Lee, Y. L. ibid. p. 141. Hazzard, W. R., et al. J. clin. Invest. 1973, 52, 1569. Sata, T., Havel, R. J., Jones, A. L. J. Lipid Res. 1972, 13, 757. Hazzard, W. R., Lindgren, F. T., Bierman, E. L. Biochim. Biophys. Acta, 1970, 202, 517. Hazzard, W. R., Porte, D., Bierman, E. L. J. clin. Invest. 1970, 49, 1853.
Brunzell, J. D., et al. ibid. 1973, 52, 1578. 10. Scanu, A. M. Adv. Lipid Res. 1965, 3, 63. 9.
11. Noble, R. F. J. Lipid Res. 1968, 9, 693. 12. Smith, L., Brown, J. E. J. Bone Jt Surg. 1967, 49B, 502. See Lancet, 1967, ii, 815. 13. Macnab, I., McCulloch, J. A., Weiner, D. S., Hugo, E. P., Galway, R. D., Dall, D. Can. J. Surg. 1971, 14, 280. 14. Wiltse, L. L., Widell, E. H., Yuan, H. A. J. Am. med. Ass. 1975, 231, 474.