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SUBCLINICAL HEPATITIS IN CONNECTIVE-TISSUE DISEASES
1095 in this country). Nevertheless, the increasing number of immigrants to Britain from high-risk countries means that tuberculosis should be high on the list, particularly since the presentation may often be atypical.16 The report by Kocen and Parsons 17 of 18 patients, 12 of them immigrants, with a variety of unusual neurological manifestations of tuberculosis is therefore particularly important at this time. 9 patients presented with a variety of focal lesions of the central nervous system, which are ascribed to focal tuberculomas.18,19 Kocen and Parsons emphasise that the cerebrospinal fluid may be normal at first, and repeated lumbar punctures are essential. In fact Taylor et al.20 mentioned a patient with multiple tuberculomas of the brain whose c.s.F. was normal at each of eight weekly punctures before death; and they pointed out that tubercle bacilli may be found without pleocytosis in the c.s.F. of Mantoux-negative patients or those on corticosteroid therapy. Moreover, when the onset of neurological tuberculosis is sudden, the c.s.F. cellcount may be over 500 per c.mm., mainly polymorphonuclear leucocytes, and that must not be taken to exclude the diagnosis of tuberculous meningitis. 20 Kocen and Parsons describe a further 9 patients with paraplegia in whom no radiological evidence of bone disease was found. In such patients small lesions in the bone may in fact exist, or the cause may be extradural granuloma2 or intradural tuberculoma, often with tuberculous meningitis. They emphasise that the opening picture of tuberculosis may simulate extradural metastases, prolapsed intravertebral discs, intramedullary tumours, or even multiple sclerosis. As for treatment, discussion continues about the place for intrathecal chemotherapy 4,7,21-24 and systemic or intrathecal corticosteroids.25-28 All, however, agree that early diagnosis and prompt systemic triple chemotherapy are of the utmost importance. SUBCLINICAL HEPATITIS IN CONNECTIVE-TISSUE DISEASES
ARTHRALGIA, skin rashes, hasmolytic anaemia, and glomerular lesions suggestive of some form of connective-tissue disease have been described in many young women with active chronic hepatitis and a positive L.E.-cell test, and the term " lupoid hepatitis " has been suggested for this condition.29,3o Nevertheless, clinical evidence of liver disease is distinctly uncommon in patients with overt systemic lupus
erythematosus.31,32 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
Wiseman, R. A., Mahmood, A. Br. J. clin. Pract. 1967, 21, 13. Kocen, R. S., Parsons, M. Q. Jl Med. 1970, 39, 17. Rich, A. R., McCordock, A. J. Bull. Johns Hopkins Hosp. 1933, 52, 5. MacGregor, A. R., Green, C. A. J. Path. Bact. 1937, 45, 613. Taylor, K. B., Smith, H. V., Vollum, R. L. J. Neurol. Neurosurg. Psychiat. 1955, 18, 165. Choremis, K., Zervos, N., Constantinides, V., Pantazis, S. Lancet, 1948, ii, 595. Lorber, J. Br. med. J. 1960, i, 1309. Weiss, W., Flippin, H. F. Am. J. med. Sci. 1961, 242, 423. Smith, H. V. Int. J. Neurol. 1964, 4, 134. Feldman, S., Behar, A. J., Weber, D. Archs Path. 1958, 65, 343. Khatua, S. P. Br. med. J. 1961, ii, 1597. Hockaday, J. M., Smith, H. M. V. Tubercle 1966, 47, 75. O’Toole, R. D., Thornton, G. F., Mukherjee, M. K., Nagh, R. L. Ann. intern. Med. 1969, 70, 39. Beam, A. G., Kunkel, H. G., Slater, R. J. Am.J. Med. 1956, 21, 3. Mackay, I. R., Taft, L. I., Cowling, D. C. Lancet, 1956, ii, 1323. Harvey, A. M., Shulman, L. E., Tumulty, P. A., Conley, C. L., Schoenrich, E. H. Medicine, Baltimore, 1954, 33, 291. Dubois, E. L. Lupus Erythematosus. New York, 1966.
Evidence 33,34 has lately been provided that clinically inapparent hepatitis does arise in a small number of patients with connective-tissue disease. Both investigations were based on the idea that the demonstration of mitochondrial antibody in the serum might be a useful screening test or marker for subclinical liver disease. Unlike antinuclear antibody, which is commonly found in systemic lupus without liver disease and in active chronic hepatitis without other evidence of a connective-tissue disease, mitochondrial antibody is found in the serum of 98% of cases of primary biliary cirrhosis, 28% of cases of active chronic hepatitis, and in 31 % of cases of cryptogenic cirrhosis, and it is much less common in any other condition.35 Berg et al. 36 found mitochondrial antibody in the serum of 0.8% of middle-aged healthy controls, in 2% of cases of rheumatoid arthritis, and in 8% of cases of systemic lupus erythematosus and other collagenoses. Walker et a1.33 have now investigated 35 persons without overt liver disease whose serum had been found to contain mitochondrial antibody. In the 35 patients biochemical tests and liver biopsy demonstrated a hepatic abnormality in 10, 2 of whom had systemic lupus, 2 rheumatoid arthritis with L.E. cells, and 3 recurring polyarthralgia (clinically apparent autoimmune thyroiditis was present in 1 of the systemic lupus patients and in 2 patients with subclinical hepatitis but no connective-tissue disease). The precise classification of the subclinical liver lesion proved difficult. Piecemeal necrosis of liver cells and plasma-cell infiltration of the liver pointed to mild active chronic hepatitis, but this diagnosis seemed unlikely since the serum levels of bilirubin and transaminase were normal or only slightly raised and most of the patients were elderly. 6 of the 10 had a serumalkaline-phosphatase of over 40 King-Armstrong units despite low bilirubin levels, 2 had portal granulomas, and 3 a doubtful history of itching. These features all suggest primary biliary cirrhosis, but Walker et al. preferred to regard the lesions as forms of autoimmune hepatitis.3’ Under this term they include typical active chronic hepatitis, primary biliary cirrhosis, and cryptogenic cirrhosis, disorders intermediate between these, and a subclinical and possibly non-progessive lesion analogous to focal autoimmune thyroiditis. Whaley et al. used a rather less sensitive test for mitochondrial antibody as a marker of liver disease. Their patients had been referred to a rheumaticdiseases clinic because they had rheumatoid arthritis or Sjogren’s syndrome (with or without rheumatoid arthritis). Mitochondrial antibody was found in 6% of cases of Sjorgren’s syndrome in the absence of rheumatoid arthritis and this was significantly more than in uncomplicated rheumatoid arthritis (1%). Of the patients with mitochondrial antibody, a third were found to have hepatomegaly and other clinical evidence of liver disease, and 5 of the remaining 7 had biochemical evidence of subclinical liver disease essentially similar to that observed by Walker et al. 33. Walker, J. G., Doniach, D., Doniach, I. Q. Jl Med. 1970, 39, 31. 34. Whaley, K., Goudie, R. B., Williamson, J., Nuki, G., Dick, W. C., Buchanan, W. W. Lancet, April 25, 1970, p. 861. 35. Doniach, D., Roitt, I. M., Walker, J. G., Sherlock, S. Clin. exp. Immun. 1966, 1, 237. 36. Berg, P. A., Doniach, D., Roitt, I. M. Klin. Wschr. 1969, 47, 1297. 37. Doniach, D., Walker, J. G. Lancet, 1969, i, 813.
1096
That hepatitis is found significantly more often than would be expected by chance in some of the connectivetissue diseases favours the view that an underlying immunological disorder predisposes to and has a role in the pathogenesis of liver disease. It is, however, by no means clear how the autoimmune process leads to liver lesions. With the exception of an antibody which reacts in vitro with proliferating bileducts and requires further study, 38 none of the autoantibodies which are found in liver disease are specific for an antigen peculiar to the liver. It therefore seems unlikely that a direct attack by autoantibody on liver tissue is a cause of the lesion. Doniach and Walker 37
provisionally suggest cell-mediated autoimmunity as the injurious mechanism, though the finding of impared cell-mediated immunity to exogenous antigens such as tuberculin and dinitrochlorobenzene in primary biliary cirrhosis is perhaps against this view.39 MUSCLE SYMPTOMS AND FAT OXIDATION
Inherited abnormalities in carbohydrate metabolism known to produce muscular symptoms, but abnormalities in fatty-acid metabolism have seldom been recorded in association with muscle symptoms. A 25-year-old married woman, the daughter of first cousins, had a myopathy affecting particularly the proximal limb and neck muscles.4O Histochemical examination of biopsy specimens of muscle showed that the type-II fibres were normal, but the type-l fibres had numerous vacuoles filled with abnormally large quantities of neutral glycerides and free fatty acids. The muscle mitochondria looked abnormal, and succinate-dehydrogenase activity was increased in type-I fibres, but adenosine triphosphatase and phosphorylase appeared to be normal. In view of the consanguinity, the myopathy was thought to be due to some inherited defect in fatty-acid metabolism which led to the accumulation of fat and free fatty acids in the muscles. Engel et al. 41 now describe an apparent defect in the breakdown of long-chain fatty acids in identical twins which is also associated with intermittent symptoms in skeletal muscle. From the age of 4 or 5 these 18-yearold girls had painful muscular cramps, often some hours after exercise. The symptoms were usually generalised but sometimes limited to particular muscles which had been exercised. There was no muscle weakness, but the attacks were sometimes accompanied by myoglobinuria. The only abnormality in muscle biopsy specimens was the presence of excess numbers of lipid droplets in type-l muscle fibres. Muscle pains and cramp appeared in both patients after fasting and were accompanied by striking increases in the activities of muscle enzymes such as lactate dehydrogenase, glutamic-oxaloacetic transaminase, creatine kinase, glutamate-pyruvate transaminase, and aldolase. The patients then had a few are
38. Paronetto, F., Schaffner, F., Mutter, R. D., Kniffen, J. C., Popper, H. J. Am. med. Ass. 1964, 187, 503. 39. Fox, R. A., James, D. G., Scheur, P. J., Sharma, O., Sherlock, S. Lancet, 1969, i, 959. 40. Bradley, W. G., Hudgson, P., Gardner-Medwin, D., Walton, J. N.
41.
ibid. p. 495. Engel, W. K., Vick, N. A., Glueck, C. J., Levy, Med. 1970, 202, 697.
R. I. New
Engl. J.
normal mixed baseline diet, during which serum-enzyme levels became normal and muscle condition improved. A further 48-hour fast again produced symptoms and increases in serum-enzymes. There were significantly fewer ketone bodies in both urine and plasma in the patients during fasting compared with 3 normal controls. Free fatty acids in the plasma were slightly higher in the patients, but there were no other abnormalities and the electrocardiograms remained normal. A high-fat diet produced muscle pain and nausea during the first 24 hours in both patients. There was a much smaller rise in plasma and urinary ketones in the patients than in 2 normal controls, but the difference was not as significant as the difference during fasting. Feeding an oral emulsion of medium-chain-length triglycerides
days
on a
(chiefly CS-C10 fatty acids), however, produced a prompt rise in ketone bodies. Plasma and urinary ketones in patients and normal controls were very similar in these conditions. The activity of long-chain fatty-acyl CoA synthetase in the patients’ muscle was not significantly different from the mean value in 15 other patients with neurological disease. These patients seemed to have some defect in the metabolism of long-chain fatty acids, since ketone bodies developed normally when medium-chainlength fatty acids were given. Several of the enzymes concerned with fatty-acid oxidation are specific for chain length, so the defect presumably lies in one of these. Shepherd et a1.42 have shown that in ratliver mitochondria the carnitine fatty-acid transferase activity is the rate-limiting step in the breakdown of long-chain fatty acids. Entman and Bressler 43 found that the vomiting sickness caused by hypoglycin affected long-chain fatty-acid oxidation by interfering with formation of the carnitine derivative. The vomiting, hypoglycxmia, and convulsions were relieved by giving carnitine. Muscle fatty-acyl CoA synthetase seemed to be normal, so the most likely defect may be in the fatty-acyl CoA dehydrogenase enzyme, though p-ketothiolases may also be chain-
length specific. Skeletal muscle does
not seem to use
its stored
during exercise 44 ; and during starvation it uses them only when death is near.45 Since most of the energy supply of skeletal muscle probably comes from plasma free-fatty-acids 46 it is surprising that abnormalities in fatty-acid metabolism
lipids
as
energy
source
associated with muscle symptoms have not been reported more often. It is also interesting that the heart muscle in these patients did not seem to be affected, for the evidence is that heart uses fatty acids as an energy source to a greater extent than skeletal muscle.46,47Further investigation of these patients and the patient described by Bradley et al. 40 should prove instructive. If both conditions are due to inherited changes in enzymes metabolising fatty acids, skeletal muscle seems to be much more susceptible to such alterations than the heart. Shepherd, D., Yates, D. W., Garland, P. B. Bioche. J. 1966, 98, 3C. Entman, M., Bressler, R. Molec. Pharmacol. 1967, 3, 333. Masoro, E. J., Rowell, L. B., McDonald, R. M., Steiert, B. J. biol. Chem. 1966, 241, 2626. 45. Masoro, E. J. ibid. 1967, 242, 1111. 46. Fritz, I. B. Physiol. Rev. 1961, 41, 52. 47. Bing, R. J. ibid. 1965, 45, 171. 42. 43. 44.
ARTHRALGIA, skin rashes, hasmolytic anaemia, and glomerular lesions suggestive of some form of connective-tissue disease have been described in many young women with active chronic hepatitis and a positive L.E.-cell test, and the term " lupoid hepatitis " has been suggested for this condition.29,3o Nevertheless, clinical evidence of liver disease is distinctly uncommon in patients with overt systemic lupus
erythematosus.31,32 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
Wiseman, R. A., Mahmood, A. Br. J. clin. Pract. 1967, 21, 13. Kocen, R. S., Parsons, M. Q. Jl Med. 1970, 39, 17. Rich, A. R., McCordock, A. J. Bull. Johns Hopkins Hosp. 1933, 52, 5. MacGregor, A. R., Green, C. A. J. Path. Bact. 1937, 45, 613. Taylor, K. B., Smith, H. V., Vollum, R. L. J. Neurol. Neurosurg. Psychiat. 1955, 18, 165. Choremis, K., Zervos, N., Constantinides, V., Pantazis, S. Lancet, 1948, ii, 595. Lorber, J. Br. med. J. 1960, i, 1309. Weiss, W., Flippin, H. F. Am. J. med. Sci. 1961, 242, 423. Smith, H. V. Int. J. Neurol. 1964, 4, 134. Feldman, S., Behar, A. J., Weber, D. Archs Path. 1958, 65, 343. Khatua, S. P. Br. med. J. 1961, ii, 1597. Hockaday, J. M., Smith, H. M. V. Tubercle 1966, 47, 75. O’Toole, R. D., Thornton, G. F., Mukherjee, M. K., Nagh, R. L. Ann. intern. Med. 1969, 70, 39. Beam, A. G., Kunkel, H. G., Slater, R. J. Am.J. Med. 1956, 21, 3. Mackay, I. R., Taft, L. I., Cowling, D. C. Lancet, 1956, ii, 1323. Harvey, A. M., Shulman, L. E., Tumulty, P. A., Conley, C. L., Schoenrich, E. H. Medicine, Baltimore, 1954, 33, 291. Dubois, E. L. Lupus Erythematosus. New York, 1966.
Evidence 33,34 has lately been provided that clinically inapparent hepatitis does arise in a small number of patients with connective-tissue disease. Both investigations were based on the idea that the demonstration of mitochondrial antibody in the serum might be a useful screening test or marker for subclinical liver disease. Unlike antinuclear antibody, which is commonly found in systemic lupus without liver disease and in active chronic hepatitis without other evidence of a connective-tissue disease, mitochondrial antibody is found in the serum of 98% of cases of primary biliary cirrhosis, 28% of cases of active chronic hepatitis, and in 31 % of cases of cryptogenic cirrhosis, and it is much less common in any other condition.35 Berg et al. 36 found mitochondrial antibody in the serum of 0.8% of middle-aged healthy controls, in 2% of cases of rheumatoid arthritis, and in 8% of cases of systemic lupus erythematosus and other collagenoses. Walker et a1.33 have now investigated 35 persons without overt liver disease whose serum had been found to contain mitochondrial antibody. In the 35 patients biochemical tests and liver biopsy demonstrated a hepatic abnormality in 10, 2 of whom had systemic lupus, 2 rheumatoid arthritis with L.E. cells, and 3 recurring polyarthralgia (clinically apparent autoimmune thyroiditis was present in 1 of the systemic lupus patients and in 2 patients with subclinical hepatitis but no connective-tissue disease). The precise classification of the subclinical liver lesion proved difficult. Piecemeal necrosis of liver cells and plasma-cell infiltration of the liver pointed to mild active chronic hepatitis, but this diagnosis seemed unlikely since the serum levels of bilirubin and transaminase were normal or only slightly raised and most of the patients were elderly. 6 of the 10 had a serumalkaline-phosphatase of over 40 King-Armstrong units despite low bilirubin levels, 2 had portal granulomas, and 3 a doubtful history of itching. These features all suggest primary biliary cirrhosis, but Walker et al. preferred to regard the lesions as forms of autoimmune hepatitis.3’ Under this term they include typical active chronic hepatitis, primary biliary cirrhosis, and cryptogenic cirrhosis, disorders intermediate between these, and a subclinical and possibly non-progessive lesion analogous to focal autoimmune thyroiditis. Whaley et al. used a rather less sensitive test for mitochondrial antibody as a marker of liver disease. Their patients had been referred to a rheumaticdiseases clinic because they had rheumatoid arthritis or Sjogren’s syndrome (with or without rheumatoid arthritis). Mitochondrial antibody was found in 6% of cases of Sjorgren’s syndrome in the absence of rheumatoid arthritis and this was significantly more than in uncomplicated rheumatoid arthritis (1%). Of the patients with mitochondrial antibody, a third were found to have hepatomegaly and other clinical evidence of liver disease, and 5 of the remaining 7 had biochemical evidence of subclinical liver disease essentially similar to that observed by Walker et al. 33. Walker, J. G., Doniach, D., Doniach, I. Q. Jl Med. 1970, 39, 31. 34. Whaley, K., Goudie, R. B., Williamson, J., Nuki, G., Dick, W. C., Buchanan, W. W. Lancet, April 25, 1970, p. 861. 35. Doniach, D., Roitt, I. M., Walker, J. G., Sherlock, S. Clin. exp. Immun. 1966, 1, 237. 36. Berg, P. A., Doniach, D., Roitt, I. M. Klin. Wschr. 1969, 47, 1297. 37. Doniach, D., Walker, J. G. Lancet, 1969, i, 813.
1096
That hepatitis is found significantly more often than would be expected by chance in some of the connectivetissue diseases favours the view that an underlying immunological disorder predisposes to and has a role in the pathogenesis of liver disease. It is, however, by no means clear how the autoimmune process leads to liver lesions. With the exception of an antibody which reacts in vitro with proliferating bileducts and requires further study, 38 none of the autoantibodies which are found in liver disease are specific for an antigen peculiar to the liver. It therefore seems unlikely that a direct attack by autoantibody on liver tissue is a cause of the lesion. Doniach and Walker 37
provisionally suggest cell-mediated autoimmunity as the injurious mechanism, though the finding of impared cell-mediated immunity to exogenous antigens such as tuberculin and dinitrochlorobenzene in primary biliary cirrhosis is perhaps against this view.39 MUSCLE SYMPTOMS AND FAT OXIDATION
Inherited abnormalities in carbohydrate metabolism known to produce muscular symptoms, but abnormalities in fatty-acid metabolism have seldom been recorded in association with muscle symptoms. A 25-year-old married woman, the daughter of first cousins, had a myopathy affecting particularly the proximal limb and neck muscles.4O Histochemical examination of biopsy specimens of muscle showed that the type-II fibres were normal, but the type-l fibres had numerous vacuoles filled with abnormally large quantities of neutral glycerides and free fatty acids. The muscle mitochondria looked abnormal, and succinate-dehydrogenase activity was increased in type-I fibres, but adenosine triphosphatase and phosphorylase appeared to be normal. In view of the consanguinity, the myopathy was thought to be due to some inherited defect in fatty-acid metabolism which led to the accumulation of fat and free fatty acids in the muscles. Engel et al. 41 now describe an apparent defect in the breakdown of long-chain fatty acids in identical twins which is also associated with intermittent symptoms in skeletal muscle. From the age of 4 or 5 these 18-yearold girls had painful muscular cramps, often some hours after exercise. The symptoms were usually generalised but sometimes limited to particular muscles which had been exercised. There was no muscle weakness, but the attacks were sometimes accompanied by myoglobinuria. The only abnormality in muscle biopsy specimens was the presence of excess numbers of lipid droplets in type-l muscle fibres. Muscle pains and cramp appeared in both patients after fasting and were accompanied by striking increases in the activities of muscle enzymes such as lactate dehydrogenase, glutamic-oxaloacetic transaminase, creatine kinase, glutamate-pyruvate transaminase, and aldolase. The patients then had a few are
38. Paronetto, F., Schaffner, F., Mutter, R. D., Kniffen, J. C., Popper, H. J. Am. med. Ass. 1964, 187, 503. 39. Fox, R. A., James, D. G., Scheur, P. J., Sharma, O., Sherlock, S. Lancet, 1969, i, 959. 40. Bradley, W. G., Hudgson, P., Gardner-Medwin, D., Walton, J. N.
41.
ibid. p. 495. Engel, W. K., Vick, N. A., Glueck, C. J., Levy, Med. 1970, 202, 697.
R. I. New
Engl. J.
normal mixed baseline diet, during which serum-enzyme levels became normal and muscle condition improved. A further 48-hour fast again produced symptoms and increases in serum-enzymes. There were significantly fewer ketone bodies in both urine and plasma in the patients during fasting compared with 3 normal controls. Free fatty acids in the plasma were slightly higher in the patients, but there were no other abnormalities and the electrocardiograms remained normal. A high-fat diet produced muscle pain and nausea during the first 24 hours in both patients. There was a much smaller rise in plasma and urinary ketones in the patients than in 2 normal controls, but the difference was not as significant as the difference during fasting. Feeding an oral emulsion of medium-chain-length triglycerides
days
on a
(chiefly CS-C10 fatty acids), however, produced a prompt rise in ketone bodies. Plasma and urinary ketones in patients and normal controls were very similar in these conditions. The activity of long-chain fatty-acyl CoA synthetase in the patients’ muscle was not significantly different from the mean value in 15 other patients with neurological disease. These patients seemed to have some defect in the metabolism of long-chain fatty acids, since ketone bodies developed normally when medium-chainlength fatty acids were given. Several of the enzymes concerned with fatty-acid oxidation are specific for chain length, so the defect presumably lies in one of these. Shepherd et a1.42 have shown that in ratliver mitochondria the carnitine fatty-acid transferase activity is the rate-limiting step in the breakdown of long-chain fatty acids. Entman and Bressler 43 found that the vomiting sickness caused by hypoglycin affected long-chain fatty-acid oxidation by interfering with formation of the carnitine derivative. The vomiting, hypoglycxmia, and convulsions were relieved by giving carnitine. Muscle fatty-acyl CoA synthetase seemed to be normal, so the most likely defect may be in the fatty-acyl CoA dehydrogenase enzyme, though p-ketothiolases may also be chain-
length specific. Skeletal muscle does
not seem to use
its stored
during exercise 44 ; and during starvation it uses them only when death is near.45 Since most of the energy supply of skeletal muscle probably comes from plasma free-fatty-acids 46 it is surprising that abnormalities in fatty-acid metabolism
lipids
as
energy
source
associated with muscle symptoms have not been reported more often. It is also interesting that the heart muscle in these patients did not seem to be affected, for the evidence is that heart uses fatty acids as an energy source to a greater extent than skeletal muscle.46,47Further investigation of these patients and the patient described by Bradley et al. 40 should prove instructive. If both conditions are due to inherited changes in enzymes metabolising fatty acids, skeletal muscle seems to be much more susceptible to such alterations than the heart. Shepherd, D., Yates, D. W., Garland, P. B. Bioche. J. 1966, 98, 3C. Entman, M., Bressler, R. Molec. Pharmacol. 1967, 3, 333. Masoro, E. J., Rowell, L. B., McDonald, R. M., Steiert, B. J. biol. Chem. 1966, 241, 2626. 45. Masoro, E. J. ibid. 1967, 242, 1111. 46. Fritz, I. B. Physiol. Rev. 1961, 41, 52. 47. Bing, R. J. ibid. 1965, 45, 171. 42. 43. 44.