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RENAL PAPILLARY NECROSIS AND PHENACETIN
1106
obvious constituent of synovial fluid is hyaluronic, it is presumably in the synthesis of this polysaccharide that these cells are engaged. Also present in the synovial cells of both types are lysosomes, subcellular vesicles first shown by De Duve to consist of a lipoprotein membrane enclosing a mixture of several hydrolytic enzymes with little in common except optimal activity in the acid pH range of 3 to 5. Since these include powerful proteolytic enzymes which, in some tissues at least, can attack collagen and can certainly break down the protein-polysaccharide bond in chondromucoprotein, their participation in the pathogenesis of arthritis is extremely probable. In this context the studies of D. Hamerman with the electron microscope are especially significant. At the E.R.C. symposium he described finding in the lining cells of the synovium of rheumatic joints conspicuous electron-dense bodies much larger than lysosomes but probably derived from them, judging by their rich content of acid phosphatase. The precipitation of lead phosphate in the first stage of Gomori’s method for the display of this enzyme makes this a particularly suitable subject for electron microscopy. These studies of the ultra-structure of synovial cells suggest, therefore, that injury 10 joint structures may indeed be mediated by enzymes elaborated in the affected synovial cells. What leads in the first instance to the abnormality of these cells, as revealed by the electron microscope, is still obscure, but the results of Bitensky and her colleaguesI on the influence of antibodies to ascites tumour cells upon their lysosomal acid phosphatase imply that immune reactions on cell surfaces may be one method by which such lysosomal injury could arise. RENAL PAPILLARY NECROSIS AND PHENACETIN
THE frequency of renal papillary necrosis in Denmark is again emphasised by an account of 66 cases seen in four years in one department of medicine in Copenhagen. Harvald2 points out that only 5 of these were in patients with diabetes and only 8 in patients with obstruction of the urinary tract (his two " traditional " conditions associated with its occurrence). Of the other patients the largest group had had recurrent attacks of acute pyelonephritis, but of special interest was a group without any urological symptoms but with refractory anxmia found to be due to renal insufficiency from chronic pyelonephritis. Harvald was particularly concerned with the abuse of analgesic drugs, especially phenacetin : " most of our patients with papillary necrosis have consumed six tablets or more per day for over ten years". A few had reasonable grounds for this consumption (rheumatoid arthritis or osteoarthritis), but the majority gave vague explanations such as tiredness, feeling of insufficiency, over-exertion, or ill-defined headache. Harvald admits that the mechanism by which analgesics injure the kidneys remains obscuresLindwa113suggested that phenacetin may render the kidney more susceptible to infection. Papillary necrosis is less common in this country for perhaps two reasons. First, aspirin, and not phenacetin, is the main constituent of our headache powders 4 5; and, secondly, we may be more acutely aware of the minor 1. Bitensky, L. Brit. med. Bull. 1963, 19, 241. 2. Harvald, B. Amer. J. Med. 1963, 35, 481. 3. Lindwall, N. Acta radiol., Stockh. 1960, suppl. 192. 4. See Lancet, 1959, i, 84. 5. See ibid. 1960, ii, 858.
grades of pyelonephritis and the indefinite symptoms they produce. Thus the recognition of inapparent and subclinical pyelonephritis,6 and the purposeful investigation of indefinite symptoms possibly due to this or more overt chronic pyelonephritis,’ may lead to earlier recognition and treatment of infections, thus discouraging self-medication not only with phenacetin but with other analgesics too. It is surely too late to wait for the " comparatively unalarming symptomatology, either as attacks of acute pyelonephritis with excretion of papillary tissue or as a slowly progressing renal insufficiency."2 Lindwall3 found the changes of chronic pyelonephritis, often with acute exacerbations, in all the resected or postmortem kidneys of the phenacetin patients, while Harvald2 quotes Spuhler and Zollinger as finding a chronic interstitial nephritis which corresponds with Talbot’schronic interstitial infiltration in chronic ascendIt has already been shown4 how such a lesion can affect the blood-supply to the renal papillx.
ing pyelonephritis.
CHRONIC PANCREATITIS
THE
frequency of chronic pancreatitis may be much underestimated, because the main manifestations, such as a raised fasting level of serum-amylase or serumlipase, steatorrhoea, pancreatic calcification, and diabetes, are found only in well-established cases. Early, developing, mild, or atypical cases have been missed mainly through lack of specific tests of pancreatic function. Fitzgerald et awl. lay emphasis on the value of evocative enzyme tests in this connection. These workers investigated 53 patients with chronic pancreatitis by means of cholecystography, barium-meal examinations, tests for faecal occult blood, &bgr;-cell function tests (fasting bloodsugar levels and glucose tolerance), and straight X-rays to demonstrate pancreatic calculi. But they regard the secretin-pancreozymin test described by Howat 10 and elaborated by Burton et al. 11 as the most helpful of all tests in the diagnosis of early chronic pancreatitis, and as providing earlier information of pancreatic derangement than examination of the duodenal contents. 69 secretinpancreozymin tests were carried out on 40 patients with pancreatitis. The serum-amylase rose from fasting levels of 0-7-4-4 mg. per ml. (40-242 units) with a mean of 2-53 mg. per ml. (157 units) to 2-5-8-2 mg. per ml. (137-451 units) with a mean of 3-41 mg. per ml. (188 units). In normal control cases the serum-amylase rose from a fasting level of 0-5-1-9 mg. per ml. (28-105 units) with a mean of 1.3 mg. per ml. (72 units) to a peak post-stimulatory level varying from 0-6 to 2-6 mg. per ml. (38 to 137 units) with a mean of 1-5 mg. per ml. (84 units). In only 2 of Fitzgerald’s patients did the serum-amylase level fail to rise over 2-9 mg. per ml. (160 units) after stimulation-an accuracy of 95% for the test. This is an important finding, because fasting amylase and lipase levels are often normal in quiescent phases of pancreatitis, and may be raised in other diseases such as acute gallbladder disease and perforated duodenal ulcer and after
the administration of morphine-like narcotics.i2 Results from serum-lipase in the secretin-pancreo6. See ibid. 1959, i, 1265. 7. See ibid. 1961, ii, 89. 8. Talbot, H. S. J. Amer. med. Ass. 1958, 168, 1595. 9. Fitzgerald, O., Fitzgerald, P., Fennelly, J., McMullin,
J. P., Sylvester, J. B. Gut, 1963, 4, 193. Howat, H. T. Modern Trends in Gastro-enterology (edited by F. Avery Jones); p. 776. London, 1952. 11. Burton, P., Hammond, E. M., Harper, A. A., Howat, H. T., Scott, J. E., Varley, H. Gut, 1960, 1, 125. 12. Bogoch, A., Roth, J. L. A., Bockus, H. L. Gastroenterology, 1954, 26, 697. 10.
obvious constituent of synovial fluid is hyaluronic, it is presumably in the synthesis of this polysaccharide that these cells are engaged. Also present in the synovial cells of both types are lysosomes, subcellular vesicles first shown by De Duve to consist of a lipoprotein membrane enclosing a mixture of several hydrolytic enzymes with little in common except optimal activity in the acid pH range of 3 to 5. Since these include powerful proteolytic enzymes which, in some tissues at least, can attack collagen and can certainly break down the protein-polysaccharide bond in chondromucoprotein, their participation in the pathogenesis of arthritis is extremely probable. In this context the studies of D. Hamerman with the electron microscope are especially significant. At the E.R.C. symposium he described finding in the lining cells of the synovium of rheumatic joints conspicuous electron-dense bodies much larger than lysosomes but probably derived from them, judging by their rich content of acid phosphatase. The precipitation of lead phosphate in the first stage of Gomori’s method for the display of this enzyme makes this a particularly suitable subject for electron microscopy. These studies of the ultra-structure of synovial cells suggest, therefore, that injury 10 joint structures may indeed be mediated by enzymes elaborated in the affected synovial cells. What leads in the first instance to the abnormality of these cells, as revealed by the electron microscope, is still obscure, but the results of Bitensky and her colleaguesI on the influence of antibodies to ascites tumour cells upon their lysosomal acid phosphatase imply that immune reactions on cell surfaces may be one method by which such lysosomal injury could arise. RENAL PAPILLARY NECROSIS AND PHENACETIN
THE frequency of renal papillary necrosis in Denmark is again emphasised by an account of 66 cases seen in four years in one department of medicine in Copenhagen. Harvald2 points out that only 5 of these were in patients with diabetes and only 8 in patients with obstruction of the urinary tract (his two " traditional " conditions associated with its occurrence). Of the other patients the largest group had had recurrent attacks of acute pyelonephritis, but of special interest was a group without any urological symptoms but with refractory anxmia found to be due to renal insufficiency from chronic pyelonephritis. Harvald was particularly concerned with the abuse of analgesic drugs, especially phenacetin : " most of our patients with papillary necrosis have consumed six tablets or more per day for over ten years". A few had reasonable grounds for this consumption (rheumatoid arthritis or osteoarthritis), but the majority gave vague explanations such as tiredness, feeling of insufficiency, over-exertion, or ill-defined headache. Harvald admits that the mechanism by which analgesics injure the kidneys remains obscuresLindwa113suggested that phenacetin may render the kidney more susceptible to infection. Papillary necrosis is less common in this country for perhaps two reasons. First, aspirin, and not phenacetin, is the main constituent of our headache powders 4 5; and, secondly, we may be more acutely aware of the minor 1. Bitensky, L. Brit. med. Bull. 1963, 19, 241. 2. Harvald, B. Amer. J. Med. 1963, 35, 481. 3. Lindwall, N. Acta radiol., Stockh. 1960, suppl. 192. 4. See Lancet, 1959, i, 84. 5. See ibid. 1960, ii, 858.
grades of pyelonephritis and the indefinite symptoms they produce. Thus the recognition of inapparent and subclinical pyelonephritis,6 and the purposeful investigation of indefinite symptoms possibly due to this or more overt chronic pyelonephritis,’ may lead to earlier recognition and treatment of infections, thus discouraging self-medication not only with phenacetin but with other analgesics too. It is surely too late to wait for the " comparatively unalarming symptomatology, either as attacks of acute pyelonephritis with excretion of papillary tissue or as a slowly progressing renal insufficiency."2 Lindwall3 found the changes of chronic pyelonephritis, often with acute exacerbations, in all the resected or postmortem kidneys of the phenacetin patients, while Harvald2 quotes Spuhler and Zollinger as finding a chronic interstitial nephritis which corresponds with Talbot’schronic interstitial infiltration in chronic ascendIt has already been shown4 how such a lesion can affect the blood-supply to the renal papillx.
ing pyelonephritis.
CHRONIC PANCREATITIS
THE
frequency of chronic pancreatitis may be much underestimated, because the main manifestations, such as a raised fasting level of serum-amylase or serumlipase, steatorrhoea, pancreatic calcification, and diabetes, are found only in well-established cases. Early, developing, mild, or atypical cases have been missed mainly through lack of specific tests of pancreatic function. Fitzgerald et awl. lay emphasis on the value of evocative enzyme tests in this connection. These workers investigated 53 patients with chronic pancreatitis by means of cholecystography, barium-meal examinations, tests for faecal occult blood, &bgr;-cell function tests (fasting bloodsugar levels and glucose tolerance), and straight X-rays to demonstrate pancreatic calculi. But they regard the secretin-pancreozymin test described by Howat 10 and elaborated by Burton et al. 11 as the most helpful of all tests in the diagnosis of early chronic pancreatitis, and as providing earlier information of pancreatic derangement than examination of the duodenal contents. 69 secretinpancreozymin tests were carried out on 40 patients with pancreatitis. The serum-amylase rose from fasting levels of 0-7-4-4 mg. per ml. (40-242 units) with a mean of 2-53 mg. per ml. (157 units) to 2-5-8-2 mg. per ml. (137-451 units) with a mean of 3-41 mg. per ml. (188 units). In normal control cases the serum-amylase rose from a fasting level of 0-5-1-9 mg. per ml. (28-105 units) with a mean of 1.3 mg. per ml. (72 units) to a peak post-stimulatory level varying from 0-6 to 2-6 mg. per ml. (38 to 137 units) with a mean of 1-5 mg. per ml. (84 units). In only 2 of Fitzgerald’s patients did the serum-amylase level fail to rise over 2-9 mg. per ml. (160 units) after stimulation-an accuracy of 95% for the test. This is an important finding, because fasting amylase and lipase levels are often normal in quiescent phases of pancreatitis, and may be raised in other diseases such as acute gallbladder disease and perforated duodenal ulcer and after
the administration of morphine-like narcotics.i2 Results from serum-lipase in the secretin-pancreo6. See ibid. 1959, i, 1265. 7. See ibid. 1961, ii, 89. 8. Talbot, H. S. J. Amer. med. Ass. 1958, 168, 1595. 9. Fitzgerald, O., Fitzgerald, P., Fennelly, J., McMullin,
J. P., Sylvester, J. B. Gut, 1963, 4, 193. Howat, H. T. Modern Trends in Gastro-enterology (edited by F. Avery Jones); p. 776. London, 1952. 11. Burton, P., Hammond, E. M., Harper, A. A., Howat, H. T., Scott, J. E., Varley, H. Gut, 1960, 1, 125. 12. Bogoch, A., Roth, J. L. A., Bockus, H. L. Gastroenterology, 1954, 26, 697. 10.