1222
endocrine cells.
The sharing of hormonal peptides by hypothalamic and gastrointestinal cells supports the concept of the neuroectodermal origin of the endocrine-peptide producing cells of the APUD series.29 However, the exact proof of similarity of central nervous system and gut G.H.-R.i.H. must await definitive sequencing studies. The actions of G.H.-R.I.H. can be contrasted to those of histamine, as the former is a powerful inhibitor of parietal-cell function while histamine is one of the most powerful stimulants. The mode of distribution of such local hormones and the factors controlling their release are, as yet, not understood. Further investigations must be carried out on physiological changes in G.H.-R.i.H. content of cells and plasma, by immunocytochemical methods, and by bioassay and radioimmunoassay. It will then be possible to assess changes that may occur in gastrointestinal disease. This work was done with the aid of a programme grant from the Medical Research Council and.a grant from the Cancer Campaign. We thank Miss M. Van Mourik for her skilful technical assistance. L. G. is a Royal Society European Science Exchange Programme fellow.
Requests for reprints should be addressed to J. M. P., Department of Histochemistry, Royal Postgraduate Medical School, London W12. REFERENCES
Mortimer, C. H., Tunbridge, W. M. G., Carr, D., Yeomans, L., Lind, T., Coy, D. H., Bloom, S. R., Kastin, A., Mallinson, C. N., Besser, G. M., Schally, A. V., Hall, R. Lancet, 1974, i, 697. 2. Besser, G. M., Mortimer, C. H., McNeilly, A. S., Thorner, M. O., Batistoni, G. A., Bloom, S. R., Kastrup, K. W., Hanssen, K. F., Hall, R., Coy, D. H., Kastin, A. J., Schally, A. V. Br. med. J. 1974, iv, 622. 3. Bloom, S. R., Mortimer, C. H., Thorner, M. O., Besser, G. M., Hall, R., Gomez-Pan, A., Roy, V. M., Russell, R. C. G., Coy, D. H., Kastin, A. J., Schally, A. V., Hall, R. Lancet, 1974, ii, 1106. 4. Barros D’Sa, A. A. J., Bloom, S. R., Baron, J. H. ibid. 1975, i, 886. 5. Gomez-Pan, A., Reed, J. D., Albinus, M., Shaw, B., Hall, R., Besser, G. M., Coy, D. H., Kastin, A. J., Schally, A. V. ibid. 1.
6. 7. 8. 9. 10. 11. 12. 13. 14.
15. 16. 17. 18. 19. 20.
21. 22. 23. 24.
25.
26.
27. 28. 29.
p. 888. Schofield, Y. G., Mira, F., Orci, L. Diabetologia, 1974, 10, 385. Luft, R., Efendic, S., Hökfelt, T., Johansson, O., Arimura, A. Med. Biol. 1974, 52, 428. Arimura, A., Sato, H., Du Pont, A., Nishi, N., Schally, A. V. Fedn Proc. 1975, 34, 273. Polak, Julia M., Pearse, A. G. E., Adams, C., Garaud, J.-C. Experientia, 1974, 30, 564. Pearse, A. G. E., Polak, J. M. Histochem. J. 1975, 7, 179. Hellman, B., Hellerström, C. Acta endocr. 1961, 36, 22. Grimelius, L. Acta Soc. Med. upsal. 1968, 73, 243. Pearse, A. G. E. Histochemistry, Theoretical and Applied; vol. II, p. 1379. Edinburgh, 1972. Solcia, E., Capella, C., Vassallo, G. Histochemie, 1969, 20, 116. Coons, A. H., Leduc, E. H., Connolly, J. M. J. exp. Med. 1955, 102, 49. Arimura, A., Sato, H., Coy, D. H., Schally, A. V. Proc. Soc. exp. Biol. Med., 1975, 148, 784. Polak, J. M., Pearse, A. G. E., Garaud, J.-C., Bloom, S. R. Gut, 1974, 15, 720. Polak, J. M., Pearse, A. G. E., Heath, C. M. ibid. 1975, 16, 225. Hellerström, C., Hellman, B. Acta endocr. 1960, 35, 518. Okada, N., Takaki, R., Kitigawa, M. J. Histochem. Cytochem. 1967, 16, 405. Hartroft, W. S., Wrenshall, G. A. Diabetes, 1955, 4, 1. Bloom, W. Anat. Rec. 1931, 49, 363. Fujita, T. Arch. Histol. Japon. 1968, 29, 1. Lacy, P. E., Greider, M. H. in Handbook of Physiology, section 7, vol. I (endocrine pancreas), p. 7. American Physiological Society, Washington, D.C., 1972. Creutzfeldt, W., Gregory, R. A., Grossman, M. I., Pearse, A. G. E. in Origin, Chemistry, Physiology and Pathophysiology of the Gastrointestinal Hormones (edited by W. Creutzfeldt); p. 95. Stuttgart, 1969. von Euler, U. S., Gaddum, J. H. J. Physiol., Lond. 1931, 192, 74. Pearse, A. G. E., Polak, J. M. Histochemistry, 1975, 41, 373. Nilsson, G., Larsson, L.-I., Håkanson, R., Brodin, E., Sundler, F., Pernow, B. ibid. 1975, 43, 1. Pearse, A. G. E. J. Histochem. Cytochem. 1969, 17, 303.
GREY-SCALE ULTRASONOGRAPHY FOR MONITORING INDUSTRIAL EXPOSURE TO HEPATOTOXIC AGENTS K.
J. W.
TAYLOR
Department of Nuclear Medicine, Royal Marsden Hospital, Sutton, Surrey D. M.
J.
WILLIAMS
B.P. Chemicals, Penarth,
Glamorgan
PAUL M. SMITH Welsh National School of Medicine,
Cardiff
B. W. DUCK B.P. Chemicals,
Sunbury-on-Thames
Industrial exposure to several potentially hepatotoxic agents, such as vinylchloride monomer, may occur, and there is a need for non-invasive, diagnostic techniques to detect and monitor progressive pathological processes in liver or
Summary
spleen.
Grey-scale ultrasonography permits display
of detailed anatomy and pathology in the liver, portal vein, and spleen. The combination of fine resolution, non-invasiveness, absence of ionising radiation hazard, and portable equipment makes the technique ideal for screening populations at risk. INDUSTRIAL exposure to vinyl-chloride monomer (V.C.M.) has been causally related to the subsequent development of acro-osteolysis u2 and periportal fibrosis causing portal hypertension with consequent oesophageal varices and splenomegaly.3 Much more rarely, angiosarcomas have been reported in exposed workers.4-6 Such tumours have been produced experimentally in mice exposed to only 50 p.p.m. of vinyl
chloride.’
Although most publicity has been focused on V.C.M. toxicity, this substance is only one of several potentially hepatotoxic agents to which industrial workers may be exposed. A non-invasive method is required to monitor any change in the liver or spleen during exposure to such chemicals, and the use of grey-scale ultrasonography for such investigations has many advantages.s Ultrasound examination involves no more than skin contact with a metallic transducer and some suitable coupling agent such as mineral oil. At diagnostic dosages, there is no evidence of any risk,9 unlike the dose accumulation which limits routine radiological procedures. Currently most ultrasound machines are designed for obstetric applications and merely produce the contours of organs, whereas the grey-scale modifications permit, in addition, the internal consistency of the liver and spleen to be displayed. The preliminary results reported here demonstrate the potential of the method for the visualisation of pathological lesions in the liver and spleen related to vinyl-chloride exposure.
The equipment used was custom-built, but machines of similar potential are slowly becoming commercially available. The liver was scanned in a series of sections parasagittal by moving the transducer through an arc as shown in fig. 1. The resultant scan in a normal subject showed the normal liver consistency and, in a suitable parasagittal plane, a portal vein of normal size and appearance (fig. 2). In patients with
1223
the portal (fig. 3). Although we
vein is enlarged and have seen evidence of fatty infiltration and fibrosis in these patients, the pathological appearance of the liver is much less obvious than that seen in patients with cirrhosis and an equivalent degree of portal hypertension. The spleen can be scanned along the left tenth intercostal space with the patient lying in the right lateral position. A measure of spleen size can be obtained When splenomegaly is from the longitudinal axis. to secondary portal hypertension, it has a characteristic pattern which may be differentiated from malignant A or chronic inflammatory causes of splenomegaly 1 spleen scan from a worker exposed to vinyl chloride and known to have portal hypertension is shown in At present, monitoring exposure to v.C.M. requires a full hsematological investigation (to detect evidence of hypersplenism) and liver-function tests. Liver-function tests may produce ambiguous results when alcohol intake is high and are relatively insensitive to the insidious onset of liver damage related to vinylchloride exposure. At best they provide a screening A test for invasive procedures such as liver biopsy. barium swallow may reveal oesophageal varices, but this represents an advanced pathological condition compared with the stage of the disease at which non-
portal hypertension, tortuous
Fig. 1-Schetna
to show movement of transducer
anatomical
(T)
to
display
features shown in fig. 2.
invasive grey-scale ultrasonography will demonstrate. abnormalities of the portal vein and spleen. Other methods have been suggested for screening purposes. A plain radiograph of the abdomen allows spleen size to be estimated but is relatively inaccurate and involves exposure to a small dose of ionising radiation. Splenoportography is too invasive for routine use. Radioisotopic examination of the liver and spleen can be used, although this tends to produce It an unacceptable proportion of equivocal scans 11 also involves exposure to a small but significant dose of ionising radiation. When grey-scale ultrasonography and radioisotopic examination were compared, it was found that ultrasound produced better and
resolution .
no
equivocal results.12
These observations suggest that grey-scale ultrasonography could be valuable for monitoring any liver or spleen changes related to vinyl-chloride exposure. A clinical trial is now required to define limits of confidence, and the development of fast, automated scanning techniques should be considered. Attractive features of the ultrasound apparatus include the potential mobility in a vehicle of similar dimensions to a
Fig. 3-Parasagittal section of liver from patient with vinylchloride-related portal hypertension. Portal vein is dilated and highly tortuous.
Fig. 4-Ultrasound
scan
of spleen along left tenth intercostal
space.
of liver 2 2-Parasagittal right of midline, Fig.showing normal liver consistency, portal vein, and inferior scan
vena cava.
cm. to
Longitudinal axis of spleen (arrowed) measures 18 cm. and low-level echoes of medium amplitude are returned. Appearances are those of moderate splenomegaly due to portal hypertension.
1224
mobile chest X-ray unit, and the lack of ionisingradiation hazards and domestic power requirements. These features would permit the safe, non-invasive screening of whole populations exposed to potentially hepatotoxic agents.
COMPARISON
INBORN
OF
ERRORS
WITH
ERRORS
IN
METABOLIC
REGULATION
We thank the Working-party on Vinyl Chloride Code of Practice, the Employment Medical Advisory Service, and the Department of Health and Social Security for data supplied; and Dr V. R. McCready for use of facilities of his department. Requests for reprints should be addressed to K. J. W. T., Department of Radiology, Yale University School of Medicine, "333 Cedar Street, New Haven, Connecticut 06510, U.S.A. REFERENCES
Harris, D. K., Adams, W. G. F. Br. med. J. 1967, iii, 712. Dinman, B. D., Cook, W. A., Whitehouse, W., Magnuson, H. J., Ditcheck, T. Archs environ. Hlth, 1971, 22, 61. 3. Thomas, L. B., Popper, H., Berk, P. D., Selikoff, I., Falk, H. New Engl. J. Med. 1975, 292, 17. 4. Creech, J. L., Johnson, M. N. J. occup. Med. 1974, 16, 150. 5. Block, J. B. J. Am. med. Ass. 1974, 229, 53. 6. Lee, F. I., Harry, D. S. Lancet, 1974, i, 1316. 7. Gordon, D. E., Thomas, L. B., Kent, G. Gastroenterology (in the 1. 2.
press).
protein so that the catalytic or translocatory properties of the protein are impaired (table). Errors in metabolic regulation consist of milder defects of protein structure than inborn errors, they are more common, and they could appear on an acquired as well as inherited basis. Acquired defects of enzyme action can develop as a result of somatic mutation or, possibly, induction by environmental of
Lancet, 1974, ii, 565. Taylor, K. J. W., Dyson, M. Br. J. Hosp. Med. 1972, 8, 571. Taylor, K. J. W., Milan, J. Br. J. Radiol. (in the press). Conn, H. O., Elkington, S. G. Gastroenterology, 1968, 54, 135. 12. Taylor, K. J. W., Carpenter, D. A. in Ultrasound in Medicine (edited by D. White); vol. i, p. 159. New York, 1975.
8. 9. 10. 11.
Hypothesis ERRORS IN METABOLIC REGULATION A COMMON GROUP OF METABOLIC DISORDERS
D. J. GALTON
J.
M. J. P. HIGGINS P. D. RECKLESS
Lipid Research Laboratory, St. Bartholomew’s Hospital, London EC1 It is postulated that errors in metabolic regulation occur when aminoacid substitutions or conformational changes occur at allosteric sites on proteins. The cell thus contains its full complement of enzymes, carrier proteins, and receptors, but these proteins do not respond normally to micro-
Sum ary
environmental agents such
activator or inhibitor metabolites. Regulatory errors differ from the classical inborn errors in a number of respects: they can be acquired as well as inherited, when due to defects at allosteric inhibitory sites they lead to loss of regulation of metabolic pathways with oversynthesis of metabolic products without gross accumulation of abnormal intermediates, and they can be treated, in principle, by enzyme inhibitors rather than by enzyme replacement, as for inborn errors. as
hormones
or
INTRODUCTION
THE concept of "errors in metabolic regulation" implies that a cell contains its full complement of enzymes, carrier proteins, and receptor proteins, but that these proteins are unable to respond normally to regulation by microenvironmental factors such as hormones or inhibitor or activator metabolites. These errors differ from the classical inborn errors of metabolism where there is a deficiency or abnormality
,
an
enzyme
or
carrier
agents. The metabolic effect of loss of negative feedback on a rate-determining enzyme would be an abnormal overuse of a metabolic sequence with, consequent overproduction of the terminal metabolite but not necessarily with accumulation of intermediates; or if activator sites were defective, the pathway would be inactivated by remaining allosteric inhibitory sites if present on the enzyme. Thus errors in metabolic regulation may be expected to lead to increased synthesis of metabolic products by use of normal metabolic pathways rather than accumulation of unusual metabolites before the enzyme defect, as in the classical inborn errors of metabolism. Within this framework we wish to describe two examples of loss of feedback regulation of rate-determining enzymes on the pathways of lipid synthesis which are associated in one instance with overproduction and tissue storage of triglyceride in adipocytes and in the other with overproduction of cholesterol by the liver and hypercholesterolsemia. LIPOMATOSIS
The
clone of cells that are biochemically and lipoma morphologically very similar to adjacent normal adipocytes, but associated with increased triglyceride synthesis and deposition. Several factors could contribute to the increased accumulation of triglyceride; these include increased rates of lipogenesis from glucose or decreased mobilisation of triglycerides. However, maximal rates of lipolysis stimulated by isoprenaline and rates of lipogenesis from glucose or palmitate are similar to those of normal adipocytes.1 A more subtle defect occurs in these lipoma cells. The metabolic segment, glucose to glycerideglycerol, is insensitive to inhibition by citrate.2 Citrate is an allosteric inhibitor of the key regulatory enzyme of glycolysis, phosphofructokinase (E.C.2.7.1.11), in many is
a
endocrine cells.
The sharing of hormonal peptides by hypothalamic and gastrointestinal cells supports the concept of the neuroectodermal origin of the endocrine-peptide producing cells of the APUD series.29 However, the exact proof of similarity of central nervous system and gut G.H.-R.i.H. must await definitive sequencing studies. The actions of G.H.-R.I.H. can be contrasted to those of histamine, as the former is a powerful inhibitor of parietal-cell function while histamine is one of the most powerful stimulants. The mode of distribution of such local hormones and the factors controlling their release are, as yet, not understood. Further investigations must be carried out on physiological changes in G.H.-R.i.H. content of cells and plasma, by immunocytochemical methods, and by bioassay and radioimmunoassay. It will then be possible to assess changes that may occur in gastrointestinal disease. This work was done with the aid of a programme grant from the Medical Research Council and.a grant from the Cancer Campaign. We thank Miss M. Van Mourik for her skilful technical assistance. L. G. is a Royal Society European Science Exchange Programme fellow.
Requests for reprints should be addressed to J. M. P., Department of Histochemistry, Royal Postgraduate Medical School, London W12. REFERENCES
Mortimer, C. H., Tunbridge, W. M. G., Carr, D., Yeomans, L., Lind, T., Coy, D. H., Bloom, S. R., Kastin, A., Mallinson, C. N., Besser, G. M., Schally, A. V., Hall, R. Lancet, 1974, i, 697. 2. Besser, G. M., Mortimer, C. H., McNeilly, A. S., Thorner, M. O., Batistoni, G. A., Bloom, S. R., Kastrup, K. W., Hanssen, K. F., Hall, R., Coy, D. H., Kastin, A. J., Schally, A. V. Br. med. J. 1974, iv, 622. 3. Bloom, S. R., Mortimer, C. H., Thorner, M. O., Besser, G. M., Hall, R., Gomez-Pan, A., Roy, V. M., Russell, R. C. G., Coy, D. H., Kastin, A. J., Schally, A. V., Hall, R. Lancet, 1974, ii, 1106. 4. Barros D’Sa, A. A. J., Bloom, S. R., Baron, J. H. ibid. 1975, i, 886. 5. Gomez-Pan, A., Reed, J. D., Albinus, M., Shaw, B., Hall, R., Besser, G. M., Coy, D. H., Kastin, A. J., Schally, A. V. ibid. 1.
6. 7. 8. 9. 10. 11. 12. 13. 14.
15. 16. 17. 18. 19. 20.
21. 22. 23. 24.
25.
26.
27. 28. 29.
p. 888. Schofield, Y. G., Mira, F., Orci, L. Diabetologia, 1974, 10, 385. Luft, R., Efendic, S., Hökfelt, T., Johansson, O., Arimura, A. Med. Biol. 1974, 52, 428. Arimura, A., Sato, H., Du Pont, A., Nishi, N., Schally, A. V. Fedn Proc. 1975, 34, 273. Polak, Julia M., Pearse, A. G. E., Adams, C., Garaud, J.-C. Experientia, 1974, 30, 564. Pearse, A. G. E., Polak, J. M. Histochem. J. 1975, 7, 179. Hellman, B., Hellerström, C. Acta endocr. 1961, 36, 22. Grimelius, L. Acta Soc. Med. upsal. 1968, 73, 243. Pearse, A. G. E. Histochemistry, Theoretical and Applied; vol. II, p. 1379. Edinburgh, 1972. Solcia, E., Capella, C., Vassallo, G. Histochemie, 1969, 20, 116. Coons, A. H., Leduc, E. H., Connolly, J. M. J. exp. Med. 1955, 102, 49. Arimura, A., Sato, H., Coy, D. H., Schally, A. V. Proc. Soc. exp. Biol. Med., 1975, 148, 784. Polak, J. M., Pearse, A. G. E., Garaud, J.-C., Bloom, S. R. Gut, 1974, 15, 720. Polak, J. M., Pearse, A. G. E., Heath, C. M. ibid. 1975, 16, 225. Hellerström, C., Hellman, B. Acta endocr. 1960, 35, 518. Okada, N., Takaki, R., Kitigawa, M. J. Histochem. Cytochem. 1967, 16, 405. Hartroft, W. S., Wrenshall, G. A. Diabetes, 1955, 4, 1. Bloom, W. Anat. Rec. 1931, 49, 363. Fujita, T. Arch. Histol. Japon. 1968, 29, 1. Lacy, P. E., Greider, M. H. in Handbook of Physiology, section 7, vol. I (endocrine pancreas), p. 7. American Physiological Society, Washington, D.C., 1972. Creutzfeldt, W., Gregory, R. A., Grossman, M. I., Pearse, A. G. E. in Origin, Chemistry, Physiology and Pathophysiology of the Gastrointestinal Hormones (edited by W. Creutzfeldt); p. 95. Stuttgart, 1969. von Euler, U. S., Gaddum, J. H. J. Physiol., Lond. 1931, 192, 74. Pearse, A. G. E., Polak, J. M. Histochemistry, 1975, 41, 373. Nilsson, G., Larsson, L.-I., Håkanson, R., Brodin, E., Sundler, F., Pernow, B. ibid. 1975, 43, 1. Pearse, A. G. E. J. Histochem. Cytochem. 1969, 17, 303.
GREY-SCALE ULTRASONOGRAPHY FOR MONITORING INDUSTRIAL EXPOSURE TO HEPATOTOXIC AGENTS K.
J. W.
TAYLOR
Department of Nuclear Medicine, Royal Marsden Hospital, Sutton, Surrey D. M.
J.
WILLIAMS
B.P. Chemicals, Penarth,
Glamorgan
PAUL M. SMITH Welsh National School of Medicine,
Cardiff
B. W. DUCK B.P. Chemicals,
Sunbury-on-Thames
Industrial exposure to several potentially hepatotoxic agents, such as vinylchloride monomer, may occur, and there is a need for non-invasive, diagnostic techniques to detect and monitor progressive pathological processes in liver or
Summary
spleen.
Grey-scale ultrasonography permits display
of detailed anatomy and pathology in the liver, portal vein, and spleen. The combination of fine resolution, non-invasiveness, absence of ionising radiation hazard, and portable equipment makes the technique ideal for screening populations at risk. INDUSTRIAL exposure to vinyl-chloride monomer (V.C.M.) has been causally related to the subsequent development of acro-osteolysis u2 and periportal fibrosis causing portal hypertension with consequent oesophageal varices and splenomegaly.3 Much more rarely, angiosarcomas have been reported in exposed workers.4-6 Such tumours have been produced experimentally in mice exposed to only 50 p.p.m. of vinyl
chloride.’
Although most publicity has been focused on V.C.M. toxicity, this substance is only one of several potentially hepatotoxic agents to which industrial workers may be exposed. A non-invasive method is required to monitor any change in the liver or spleen during exposure to such chemicals, and the use of grey-scale ultrasonography for such investigations has many advantages.s Ultrasound examination involves no more than skin contact with a metallic transducer and some suitable coupling agent such as mineral oil. At diagnostic dosages, there is no evidence of any risk,9 unlike the dose accumulation which limits routine radiological procedures. Currently most ultrasound machines are designed for obstetric applications and merely produce the contours of organs, whereas the grey-scale modifications permit, in addition, the internal consistency of the liver and spleen to be displayed. The preliminary results reported here demonstrate the potential of the method for the visualisation of pathological lesions in the liver and spleen related to vinyl-chloride exposure.
The equipment used was custom-built, but machines of similar potential are slowly becoming commercially available. The liver was scanned in a series of sections parasagittal by moving the transducer through an arc as shown in fig. 1. The resultant scan in a normal subject showed the normal liver consistency and, in a suitable parasagittal plane, a portal vein of normal size and appearance (fig. 2). In patients with
1223
the portal (fig. 3). Although we
vein is enlarged and have seen evidence of fatty infiltration and fibrosis in these patients, the pathological appearance of the liver is much less obvious than that seen in patients with cirrhosis and an equivalent degree of portal hypertension. The spleen can be scanned along the left tenth intercostal space with the patient lying in the right lateral position. A measure of spleen size can be obtained When splenomegaly is from the longitudinal axis. to secondary portal hypertension, it has a characteristic pattern which may be differentiated from malignant A or chronic inflammatory causes of splenomegaly 1 spleen scan from a worker exposed to vinyl chloride and known to have portal hypertension is shown in At present, monitoring exposure to v.C.M. requires a full hsematological investigation (to detect evidence of hypersplenism) and liver-function tests. Liver-function tests may produce ambiguous results when alcohol intake is high and are relatively insensitive to the insidious onset of liver damage related to vinylchloride exposure. At best they provide a screening A test for invasive procedures such as liver biopsy. barium swallow may reveal oesophageal varices, but this represents an advanced pathological condition compared with the stage of the disease at which non-
portal hypertension, tortuous
Fig. 1-Schetna
to show movement of transducer
anatomical
(T)
to
display
features shown in fig. 2.
invasive grey-scale ultrasonography will demonstrate. abnormalities of the portal vein and spleen. Other methods have been suggested for screening purposes. A plain radiograph of the abdomen allows spleen size to be estimated but is relatively inaccurate and involves exposure to a small dose of ionising radiation. Splenoportography is too invasive for routine use. Radioisotopic examination of the liver and spleen can be used, although this tends to produce It an unacceptable proportion of equivocal scans 11 also involves exposure to a small but significant dose of ionising radiation. When grey-scale ultrasonography and radioisotopic examination were compared, it was found that ultrasound produced better and
resolution .
no
equivocal results.12
These observations suggest that grey-scale ultrasonography could be valuable for monitoring any liver or spleen changes related to vinyl-chloride exposure. A clinical trial is now required to define limits of confidence, and the development of fast, automated scanning techniques should be considered. Attractive features of the ultrasound apparatus include the potential mobility in a vehicle of similar dimensions to a
Fig. 3-Parasagittal section of liver from patient with vinylchloride-related portal hypertension. Portal vein is dilated and highly tortuous.
Fig. 4-Ultrasound
scan
of spleen along left tenth intercostal
space.
of liver 2 2-Parasagittal right of midline, Fig.showing normal liver consistency, portal vein, and inferior scan
vena cava.
cm. to
Longitudinal axis of spleen (arrowed) measures 18 cm. and low-level echoes of medium amplitude are returned. Appearances are those of moderate splenomegaly due to portal hypertension.
1224
mobile chest X-ray unit, and the lack of ionisingradiation hazards and domestic power requirements. These features would permit the safe, non-invasive screening of whole populations exposed to potentially hepatotoxic agents.
COMPARISON
INBORN
OF
ERRORS
WITH
ERRORS
IN
METABOLIC
REGULATION
We thank the Working-party on Vinyl Chloride Code of Practice, the Employment Medical Advisory Service, and the Department of Health and Social Security for data supplied; and Dr V. R. McCready for use of facilities of his department. Requests for reprints should be addressed to K. J. W. T., Department of Radiology, Yale University School of Medicine, "333 Cedar Street, New Haven, Connecticut 06510, U.S.A. REFERENCES
Harris, D. K., Adams, W. G. F. Br. med. J. 1967, iii, 712. Dinman, B. D., Cook, W. A., Whitehouse, W., Magnuson, H. J., Ditcheck, T. Archs environ. Hlth, 1971, 22, 61. 3. Thomas, L. B., Popper, H., Berk, P. D., Selikoff, I., Falk, H. New Engl. J. Med. 1975, 292, 17. 4. Creech, J. L., Johnson, M. N. J. occup. Med. 1974, 16, 150. 5. Block, J. B. J. Am. med. Ass. 1974, 229, 53. 6. Lee, F. I., Harry, D. S. Lancet, 1974, i, 1316. 7. Gordon, D. E., Thomas, L. B., Kent, G. Gastroenterology (in the 1. 2.
press).
protein so that the catalytic or translocatory properties of the protein are impaired (table). Errors in metabolic regulation consist of milder defects of protein structure than inborn errors, they are more common, and they could appear on an acquired as well as inherited basis. Acquired defects of enzyme action can develop as a result of somatic mutation or, possibly, induction by environmental of
Lancet, 1974, ii, 565. Taylor, K. J. W., Dyson, M. Br. J. Hosp. Med. 1972, 8, 571. Taylor, K. J. W., Milan, J. Br. J. Radiol. (in the press). Conn, H. O., Elkington, S. G. Gastroenterology, 1968, 54, 135. 12. Taylor, K. J. W., Carpenter, D. A. in Ultrasound in Medicine (edited by D. White); vol. i, p. 159. New York, 1975.
8. 9. 10. 11.
Hypothesis ERRORS IN METABOLIC REGULATION A COMMON GROUP OF METABOLIC DISORDERS
D. J. GALTON
J.
M. J. P. HIGGINS P. D. RECKLESS
Lipid Research Laboratory, St. Bartholomew’s Hospital, London EC1 It is postulated that errors in metabolic regulation occur when aminoacid substitutions or conformational changes occur at allosteric sites on proteins. The cell thus contains its full complement of enzymes, carrier proteins, and receptors, but these proteins do not respond normally to micro-
Sum ary
environmental agents such
activator or inhibitor metabolites. Regulatory errors differ from the classical inborn errors in a number of respects: they can be acquired as well as inherited, when due to defects at allosteric inhibitory sites they lead to loss of regulation of metabolic pathways with oversynthesis of metabolic products without gross accumulation of abnormal intermediates, and they can be treated, in principle, by enzyme inhibitors rather than by enzyme replacement, as for inborn errors. as
hormones
or
INTRODUCTION
THE concept of "errors in metabolic regulation" implies that a cell contains its full complement of enzymes, carrier proteins, and receptor proteins, but that these proteins are unable to respond normally to regulation by microenvironmental factors such as hormones or inhibitor or activator metabolites. These errors differ from the classical inborn errors of metabolism where there is a deficiency or abnormality
,
an
enzyme
or
carrier
agents. The metabolic effect of loss of negative feedback on a rate-determining enzyme would be an abnormal overuse of a metabolic sequence with, consequent overproduction of the terminal metabolite but not necessarily with accumulation of intermediates; or if activator sites were defective, the pathway would be inactivated by remaining allosteric inhibitory sites if present on the enzyme. Thus errors in metabolic regulation may be expected to lead to increased synthesis of metabolic products by use of normal metabolic pathways rather than accumulation of unusual metabolites before the enzyme defect, as in the classical inborn errors of metabolism. Within this framework we wish to describe two examples of loss of feedback regulation of rate-determining enzymes on the pathways of lipid synthesis which are associated in one instance with overproduction and tissue storage of triglyceride in adipocytes and in the other with overproduction of cholesterol by the liver and hypercholesterolsemia. LIPOMATOSIS
The
clone of cells that are biochemically and lipoma morphologically very similar to adjacent normal adipocytes, but associated with increased triglyceride synthesis and deposition. Several factors could contribute to the increased accumulation of triglyceride; these include increased rates of lipogenesis from glucose or decreased mobilisation of triglycerides. However, maximal rates of lipolysis stimulated by isoprenaline and rates of lipogenesis from glucose or palmitate are similar to those of normal adipocytes.1 A more subtle defect occurs in these lipoma cells. The metabolic segment, glucose to glycerideglycerol, is insensitive to inhibition by citrate.2 Citrate is an allosteric inhibitor of the key regulatory enzyme of glycolysis, phosphofructokinase (E.C.2.7.1.11), in many is
a
