- Email: [email protected]
PLASMA CALCITONIN IN MEDULLARY THYROID CARCINOMA
338
patients Danek and Bower’ explored the value of fibreoptic bronchoscopy and their experience has lately been endorsed by two other groups. In a four-year prospective study from Cape Town of 275 patients with suspected pulmonary tuberculosis despite smear-negative sputum examination, Willcox et a1.2analysed the contribution of fibreoptic bronchoscopy to the establishment of a final diagnosis. 89 patients (32%) were shown to have active disease, and in 60 (67%) of these the diagnosis was made from samples obtained at bronchoscopy. Bronchial brushings were positive in 56 patients-35 on direct smear, 21 only on culture. Transbronchial biopsy was done in only 18 patients and was positive in 9, accounting exclusively for the diagnosis in only 4 patients. An immediate diagnosis was therefore reached after bronchoscopy in 44% of patients who subsequently proved to have active tuberculosis. The remaining 29 patients judged to have active tuberculosis, despite negative bronchoscopies, were diagnosed on the basis of positive post-bronchoscopy sputum examination in 3 cases, response to chemotherapy in 12, and by various means in the remainder. Of the 186 patients judged not to have active tuberculosis 15 proved to have malignant disease. Of the 89 patients with active tuberculosis 4 had a co-existing carcinoma. Wallace et aI.,3 from San Diego, report their results in 56 similar patients. Of the 22 (39%) patients shown to have active tuberculosis, the immediate diagnosis was made from specimens obtained at bronchoscopy in 11 (50%). Transbronchial biopsy specimens were positive in 7 patients, giving an exclusive diagnosis in 6, while direct smears of bronchial brushings and washings were positive.in 4 patients and subsequent cultures in 10 patients. Other diagnoses were reached in 7 patients, including 1 carcinoma. Needle aspiration was also performed in 13 patients and a diagnosis of active tuberculosis was established by this technique in 2 patients. Needle aspiration and fibreoptic bronchoscopy doubled the overall diagnostic yield and increased the diagnostic yield for active tuberculosis by more than onesuch
third. These
reports confirm the value of fibreoptic bronchoscopy in sputum-negative patients with a chest X-ray suggestive of active disease. An immediate diagnosis can be reached in up to half such patients, and when cultures of specimens obtained at bronchoscopy are included the final diagnostic rate rises to almost 70%. Transbronchial biopsy, although performed on only a small minority of patients in the larger series, may be particularly useful in providing an immediate diagnosis. In a large review from the Brompton Hospital, it yielded positive results in 6 out of 17 patients with discrete peripheral lesions due to tuberculosis.4 Culture of Mycobacterium tuberculosis from bronchoscopy specimens may be difficult owing to the inhibitory effect of local anaesthetic agents on growth of the organism in culture;5,6 lignocaine seems to be the least inhibitory of the current range of local anaesthetic agents, and
even
this should be used
as
SJ, Bower JS. Diagnosis of pulmonary tuberculosis by flexible fibreoptic bronchoscopy. Am Rev Respir Dis 1979; 119: 677-79. Willcox PA, Benatar SR, Potgieter PD. Use of the flexible fibreoptic bronchoscope in diagnosis of sputum negative pulmonary tuberculosis. Thorax 1982; 37: 598-601. Wallace JM, Deutsch AL, Harrell JH, Moser KM. Bronchoscopy and transbronchial biopsy in evaluation of patients with suspected acute tuberculosis. Am J Med 1981;
sparingly as is compatible with adequate anaesthesia. Unsuspected carcinoma of the bronchus was detected in patients in both series, and in several instances coexisted with reactivated tuberculosis, strengthening thecase for an aggressive approach to early definitive diagnosis. The converse of this finding is that in regions of high tuberculosis prevalence, routine bronchial washings for M. tuberculosis proved positive in 14% of patients suspected of having nontuberculous disease before bronchoscopy, and in whom 7 sputum examination
was
negative.’
.
point: M. tuberculosis can be transferred by the bronchoscope from patient to patient. Having seen this happen Nelson et al. 8 tried the effects of various iodophors on the organism. With one, M. tuberculosis survived 30 minutes’ A final
exposure.
They now use glutaraldehyde or ethylene oxide for bronchoscopes.
disinfection of flexible
PLASMA CALCITONIN IN MEDULLARY THYROID CARCINOMA MOST plasma calcitonin measurements are done to exclude medullary thyroid carcinoma. Becker and co-workers,l1 however, point out that this tumour is one of the least common reasons for a raised calcitonin: others include malignant disease elsewhere (especially lung carcinoma), renal failure, pernicious anaemia, Zollinger-Ellison syndrome, pancreatitis, and hypercalcaemia. In addition, the normal adult level is exceeded in pregnancy and in childhood. A further difficulty arises from the different patterns found with different assays. For example, in breast cancer Coombes et al.2 reported a raised calcitonin in 8 of 8 cases, whereas Cove et al. reported normal levels in 77 of 77. At a meeting in London last year, there were stories of people who had had near-total thyroidectomy because of mild to moderate increases of plasma calcitonin, but whose thyroid glands had been reported grossly and microscopically normal. One explanation is that "C" cell hyperplasia was present and unrecognised-the picture is difficult to diagnose by routine histology-but in most cases the calcitonin remained above normal after the operation, so the likelihood is that some, at least, of these glands were normal. Therefore the clinician should be cautious of the interpretation of calcitonin in the, screening of family members of a patient with medullary thyroid carcinoma. Although most cases of medullary thyroid carcinoma are not familial, an occasional case which seems to be sporadic proves to be the index case of an affected family. This is the argument for screening of family members whenever a new case is diagnosed.4 The probability of the family being affected is small, and, if there is even a small chance of falsepositive interpretation, the screening policy is on shaky ground. There are similar reasons for questioning the practice of measuring calcitonin in every patient with one of the other components that may be associated with the multiple endocrine neoplasia type II syndrome (MEN2)-that is, phaeochromocytoma and hyperpara-
1. Danek 2. 3.
70: 1189-94. 4. Mitchell DM, Emerson CJ, Collins JV, Stableforth DE. Transbronchial lung biopsy with the fibreoptic bronchoscope analysis of results in 433 patients. Br J Dis Chest
1981: 75: 258-62.
Bacteriological studies and effects of anaesthesia solutions on bronchial secretions during bronchoscopy. Am Rev Respir Dis 1961; 84: 414-21. 6. Conte BA, Laforet EG. The role of the topical anaesthetic agents in modifying bacteriologic data obtained by bronchoscopy. N Engl J Med 1962; 267: 957-60. 5. Erlich H.
SK, Sharma TN, Purohit SD, Gupta ML, Gupta PR. The diagnostic value of routine culture of bronchial washings in tuberculosis. Br J Dis Chest 1982; 76: 358-60. 8. Nelson KE, Larson PA, Schraufnagel DE, Jackson J. Transmission of tuberculosis by flexible fiberscopes. Am Rev Respir Dis 1983; 127: 97-100. 1. Becker KL, Silva OL, Snider RH, Moore CF, Geelhoed GW. The surgical implications of hypercalcitonanemia. Surg Gynecol Obstet 1982; 154: 897-908. 2. Coombes RC, Greenberg PB, Hillyard C, MacIntyre I. Plasma immunoreactive calcitonin in patients with non-thyroid tumours. Lancet 1974; i: 1080-83. 3. Cove DH, Woods KL, Smith SCH, Burnett D, Leonard RJ, Grieve RJ, Howell A. Tumour markers in breast cancer. Br J Cancer 1979; 40: 710-18. 4. Emmertsen K, Nielsen HE, Hansen HH, Elbrønd O, Mosekilde L. Screening for familial medullary thyroid carcinoma. Dan Med Bull 1980; 27: 262-65. 7. Sarkar
339
thyroidism. Phaeochromocytomas may produce calcitonin,5 and hypercalcaemia itself is associated with a raised calcitonin in some assays. Despite all these difficulties, however, measurement of calcitonin (basal or after stimulation with agents such as alcohol, calcium, or pentagastrin) offers the best hope of detecting early, curable forms of the familial
malignant disease.6 Supposing that an affected family has been identified, at what age should screening start and stop, how often should the measurements be repeated, and what are the criteria for surgery? The workers who met in London have formed a study group in the hope of answering some of these questions. Two projects have already been mounted. The first is a prospective investigation to define the least complex pathological procedure for identifying C-cell hyperplasia in a resected thyroid and to confirm whether C-cell hyperplasia is (as has been reported7) a reliable indicator of the genetic form of the disease. The second is to collect data about age of onset and diagnosis of medullary thyroid carcinoma, in both familial and apparently sporadic cases. Cytogenetic studies of familial cases are in progress and various assays are being compared. The Medullary Thyroid Cancer Study Group (Secretary, Dr Bruce Ponder, Institute of Cancer Research, Royal Cancer Hospital, Haddow Laboratories, Clifton Avenue, Sutton, Surrey SM2 5PX) is eager to hear from other clinicians and non-clinical scientists with an interest in the condition.
ACUTE FATTY LIVER OF PREGNANCY
Sheehan is credited with the first description of the
syndrome of obstetric acute yellow atrophy as a cause of jaundice in late pregnancy. The apparent rarity of this condition is shown by the fact that fewer than 100 cases have been reported in English over 40 years, and to this Burroughs and colleagues2 have added 12 seen over as many years at the Royal Free Hospital, London. Idiopathic acute fatty liver of pregnancy (AFLP) typically presents with sudden onset of malaise, nausea, and vomiting in the last trimester of pregnancy, followed by abdominal pain and jaundice. As in other syndromes of acute liver failure there is a high incidence of haemorrhagic problems due to thrombocytopenia, defects in prothrombin synthesis, and consumption coagulopathy. Maternal and fetal mortality is high, but most observers agree that prompt delivery of the infant offers the best chance of survival for both mother and child; there are a few reports of the condition presenting in the puerperium. In affected pregnancies male fetuses preponderate, and in about 10% there are twin fetuses. A very similar condition, known as twin-lamb disease, has been described in sheep.3 The aetiology of the condition remains unknown. Despite the striking clinical evidence ofliver dysfunction, histological changes of acute hepatic necrosis are seldom impressive and RS, Ide LF. Immunoreactive calcitonin in phaeochromocytomas. Proc Soc Exp Biol Med 1980; 165: 215-17 6 Wells SA Jr, Baylin SB, Leight GS, Dale JK, Dilley WG, Farndon JR The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma. Ann Surg 1982; 195: 595-99. 7. Block MA, Jackson CE, Greenawald KA, Yott JB, Tashjian AH Jr. Clinical characteristics distinguishing hereditary from sporadic medullary thyroid carcinoma. Treatment implications Arch Surg 1980; 115: 142-48. 1. Sheehan HL. The pathology of acute yellow atrophy and delayed chloroform poisoning. J Obstet Gynaecol Br Emp 1940; 47: 49-62. 2 Burroughs AK, Seong NG, Dojcinov DM, Scheuer PJ, Sherlock SVP. Idiopathic acute fatty liver of pregnancy in 12 patients. Quart J Med 1982; 41: 481-97. 3 Parry HB Toxaemias of pregnancy in domestic animals with particular reference to the sheep. In: Sheehan HL, ed. Toxaemias of pregnancy. London: Ciba, 1950
the major light and electron microscopic feature is microvesicular fat vacuolation of the hepatocytes with a centrilobular distribution. In some cases routine histochemical stains may show little abnormality and the fat may be identified only by the use of specific stains such as oil red 0 on frozen sections. Tetracycline and sodium valproate administration can produce a similar clinical and histological picture in both pregnant and non-pregnant women. Reye’s syndrome also resembles AFLP, and transient deficiency of the urea cycle enzymes ornithine transcarbamylase and carbamyl synthetase have been described in both.4 In these conditions the fatty infiltrate consists largely of free fatty acids, in contrast to the triglyceride infiltrates of obesity, nutritional steatosis, diabetes, and alcoholism. As with Reye’s syndrome, many cases of AFLP follow an acute infective illness and one view is that metabolic failure is precipitated by acute stress acting on a susceptible liver6which is already coping with the demands of late pregnancy. The diagnosis during life must usually be made on clinical grounds alone since the coagulation disturbances tend to preclude liver biopsy. Toxaemia of pregnancy, benign cholestasis of pregnancy, virus hepatitis, or some other nonhepatic viral infection are the main differential diagnoses. In the Royal Free Hospital series, 7 of the 12 patients had proteinuria, hypertension, and peripheral oedema-an observation which underlines the difficulty of reaching an accurate diagnosis, and which also raises questions concerning the validity of statistics concerning AFLP. Toxaemia is a much commoner disorder than acute fatty liver. In England and Wales 29 deaths were attributed to hypertensive diseases of pregnancy (previously termed toxaemia of pregnancy) in the years 1976-78,compared with 7 due to liver disorders. 21 of these deaths were accounted for by cerebral haemorrhage, cerebral oedema, disseminated vascular coagulation, and hepatorenal failure-all well recognised complications of AFLP. While it would be absurd to suggest that AFLP and toxaemia of pregnancy are one and the same disorder, the distinction between them may not be as great and clear as has been assumed. Jaundice is a well recognised feature of toxaemia of pregnancy and hyperuricaemia is frequent in both toxaemia and AFLP. Even at necropsy the acute fatty liver may well go undiagnosed unless the liver is examined histologically, since a macroscopically normal liver may show severe fatty
infiltration.8 There
good reasons for precision in the diagnosis of liver of pregnancy. Since this condition is held to fatty be substantially more dangerous than toxaemia of pregnancy, its early recognition may lead to much more prompt induction of labour with consequent improved survival for both mother and child. Finally, more careful and accurate investigation of acute vomiting in late pregnancy (both fatal and non-fatal) might shed further light on fundamental aspects of hepatic metabolism of lipids with implications far beyond obstetrics. are
acute
5. Weinstein
Weber FL, Snodgrass PJ, Powell DE, Rao P, Huffman SL, Brady PG. Abnormalities of hepatic mitochondrial urea-cycle enzyme activities and hepatic ultra structure in acute fatty liver pregnancy. J Lab Clin Med 1979; 94: 27-41. 5. Eisele JW, Barker EA, Smuckler EA. Lipid content in the liver offatty metamorphosis 1975; 81: 545-55. of pregnancy. Am Pathol J 6. Hague WM, Fenton DW, Duncan SLB, Slater DN. Acute fatty liver of pregnancy. A review of the literature and six further cases. J Roy Soc Med (in press). 7. Department of Health and Social Security. Report on confidential enquiries into maternal deaths in England and Wales 1976-1978. London: H.M. Stationery Office, 1982. 8. Ferris TF, Herdson PB, Dunnill MS, Lee MR. Toxaemia of pregnancy in sheep: a clinical, physiological and pathological study J Clin Invest 1969; 48: 1643-55.
4.
patients Danek and Bower’ explored the value of fibreoptic bronchoscopy and their experience has lately been endorsed by two other groups. In a four-year prospective study from Cape Town of 275 patients with suspected pulmonary tuberculosis despite smear-negative sputum examination, Willcox et a1.2analysed the contribution of fibreoptic bronchoscopy to the establishment of a final diagnosis. 89 patients (32%) were shown to have active disease, and in 60 (67%) of these the diagnosis was made from samples obtained at bronchoscopy. Bronchial brushings were positive in 56 patients-35 on direct smear, 21 only on culture. Transbronchial biopsy was done in only 18 patients and was positive in 9, accounting exclusively for the diagnosis in only 4 patients. An immediate diagnosis was therefore reached after bronchoscopy in 44% of patients who subsequently proved to have active tuberculosis. The remaining 29 patients judged to have active tuberculosis, despite negative bronchoscopies, were diagnosed on the basis of positive post-bronchoscopy sputum examination in 3 cases, response to chemotherapy in 12, and by various means in the remainder. Of the 186 patients judged not to have active tuberculosis 15 proved to have malignant disease. Of the 89 patients with active tuberculosis 4 had a co-existing carcinoma. Wallace et aI.,3 from San Diego, report their results in 56 similar patients. Of the 22 (39%) patients shown to have active tuberculosis, the immediate diagnosis was made from specimens obtained at bronchoscopy in 11 (50%). Transbronchial biopsy specimens were positive in 7 patients, giving an exclusive diagnosis in 6, while direct smears of bronchial brushings and washings were positive.in 4 patients and subsequent cultures in 10 patients. Other diagnoses were reached in 7 patients, including 1 carcinoma. Needle aspiration was also performed in 13 patients and a diagnosis of active tuberculosis was established by this technique in 2 patients. Needle aspiration and fibreoptic bronchoscopy doubled the overall diagnostic yield and increased the diagnostic yield for active tuberculosis by more than onesuch
third. These
reports confirm the value of fibreoptic bronchoscopy in sputum-negative patients with a chest X-ray suggestive of active disease. An immediate diagnosis can be reached in up to half such patients, and when cultures of specimens obtained at bronchoscopy are included the final diagnostic rate rises to almost 70%. Transbronchial biopsy, although performed on only a small minority of patients in the larger series, may be particularly useful in providing an immediate diagnosis. In a large review from the Brompton Hospital, it yielded positive results in 6 out of 17 patients with discrete peripheral lesions due to tuberculosis.4 Culture of Mycobacterium tuberculosis from bronchoscopy specimens may be difficult owing to the inhibitory effect of local anaesthetic agents on growth of the organism in culture;5,6 lignocaine seems to be the least inhibitory of the current range of local anaesthetic agents, and
even
this should be used
as
SJ, Bower JS. Diagnosis of pulmonary tuberculosis by flexible fibreoptic bronchoscopy. Am Rev Respir Dis 1979; 119: 677-79. Willcox PA, Benatar SR, Potgieter PD. Use of the flexible fibreoptic bronchoscope in diagnosis of sputum negative pulmonary tuberculosis. Thorax 1982; 37: 598-601. Wallace JM, Deutsch AL, Harrell JH, Moser KM. Bronchoscopy and transbronchial biopsy in evaluation of patients with suspected acute tuberculosis. Am J Med 1981;
sparingly as is compatible with adequate anaesthesia. Unsuspected carcinoma of the bronchus was detected in patients in both series, and in several instances coexisted with reactivated tuberculosis, strengthening thecase for an aggressive approach to early definitive diagnosis. The converse of this finding is that in regions of high tuberculosis prevalence, routine bronchial washings for M. tuberculosis proved positive in 14% of patients suspected of having nontuberculous disease before bronchoscopy, and in whom 7 sputum examination
was
negative.’
.
point: M. tuberculosis can be transferred by the bronchoscope from patient to patient. Having seen this happen Nelson et al. 8 tried the effects of various iodophors on the organism. With one, M. tuberculosis survived 30 minutes’ A final
exposure.
They now use glutaraldehyde or ethylene oxide for bronchoscopes.
disinfection of flexible
PLASMA CALCITONIN IN MEDULLARY THYROID CARCINOMA MOST plasma calcitonin measurements are done to exclude medullary thyroid carcinoma. Becker and co-workers,l1 however, point out that this tumour is one of the least common reasons for a raised calcitonin: others include malignant disease elsewhere (especially lung carcinoma), renal failure, pernicious anaemia, Zollinger-Ellison syndrome, pancreatitis, and hypercalcaemia. In addition, the normal adult level is exceeded in pregnancy and in childhood. A further difficulty arises from the different patterns found with different assays. For example, in breast cancer Coombes et al.2 reported a raised calcitonin in 8 of 8 cases, whereas Cove et al. reported normal levels in 77 of 77. At a meeting in London last year, there were stories of people who had had near-total thyroidectomy because of mild to moderate increases of plasma calcitonin, but whose thyroid glands had been reported grossly and microscopically normal. One explanation is that "C" cell hyperplasia was present and unrecognised-the picture is difficult to diagnose by routine histology-but in most cases the calcitonin remained above normal after the operation, so the likelihood is that some, at least, of these glands were normal. Therefore the clinician should be cautious of the interpretation of calcitonin in the, screening of family members of a patient with medullary thyroid carcinoma. Although most cases of medullary thyroid carcinoma are not familial, an occasional case which seems to be sporadic proves to be the index case of an affected family. This is the argument for screening of family members whenever a new case is diagnosed.4 The probability of the family being affected is small, and, if there is even a small chance of falsepositive interpretation, the screening policy is on shaky ground. There are similar reasons for questioning the practice of measuring calcitonin in every patient with one of the other components that may be associated with the multiple endocrine neoplasia type II syndrome (MEN2)-that is, phaeochromocytoma and hyperpara-
1. Danek 2. 3.
70: 1189-94. 4. Mitchell DM, Emerson CJ, Collins JV, Stableforth DE. Transbronchial lung biopsy with the fibreoptic bronchoscope analysis of results in 433 patients. Br J Dis Chest
1981: 75: 258-62.
Bacteriological studies and effects of anaesthesia solutions on bronchial secretions during bronchoscopy. Am Rev Respir Dis 1961; 84: 414-21. 6. Conte BA, Laforet EG. The role of the topical anaesthetic agents in modifying bacteriologic data obtained by bronchoscopy. N Engl J Med 1962; 267: 957-60. 5. Erlich H.
SK, Sharma TN, Purohit SD, Gupta ML, Gupta PR. The diagnostic value of routine culture of bronchial washings in tuberculosis. Br J Dis Chest 1982; 76: 358-60. 8. Nelson KE, Larson PA, Schraufnagel DE, Jackson J. Transmission of tuberculosis by flexible fiberscopes. Am Rev Respir Dis 1983; 127: 97-100. 1. Becker KL, Silva OL, Snider RH, Moore CF, Geelhoed GW. The surgical implications of hypercalcitonanemia. Surg Gynecol Obstet 1982; 154: 897-908. 2. Coombes RC, Greenberg PB, Hillyard C, MacIntyre I. Plasma immunoreactive calcitonin in patients with non-thyroid tumours. Lancet 1974; i: 1080-83. 3. Cove DH, Woods KL, Smith SCH, Burnett D, Leonard RJ, Grieve RJ, Howell A. Tumour markers in breast cancer. Br J Cancer 1979; 40: 710-18. 4. Emmertsen K, Nielsen HE, Hansen HH, Elbrønd O, Mosekilde L. Screening for familial medullary thyroid carcinoma. Dan Med Bull 1980; 27: 262-65. 7. Sarkar
339
thyroidism. Phaeochromocytomas may produce calcitonin,5 and hypercalcaemia itself is associated with a raised calcitonin in some assays. Despite all these difficulties, however, measurement of calcitonin (basal or after stimulation with agents such as alcohol, calcium, or pentagastrin) offers the best hope of detecting early, curable forms of the familial
malignant disease.6 Supposing that an affected family has been identified, at what age should screening start and stop, how often should the measurements be repeated, and what are the criteria for surgery? The workers who met in London have formed a study group in the hope of answering some of these questions. Two projects have already been mounted. The first is a prospective investigation to define the least complex pathological procedure for identifying C-cell hyperplasia in a resected thyroid and to confirm whether C-cell hyperplasia is (as has been reported7) a reliable indicator of the genetic form of the disease. The second is to collect data about age of onset and diagnosis of medullary thyroid carcinoma, in both familial and apparently sporadic cases. Cytogenetic studies of familial cases are in progress and various assays are being compared. The Medullary Thyroid Cancer Study Group (Secretary, Dr Bruce Ponder, Institute of Cancer Research, Royal Cancer Hospital, Haddow Laboratories, Clifton Avenue, Sutton, Surrey SM2 5PX) is eager to hear from other clinicians and non-clinical scientists with an interest in the condition.
ACUTE FATTY LIVER OF PREGNANCY
Sheehan is credited with the first description of the
syndrome of obstetric acute yellow atrophy as a cause of jaundice in late pregnancy. The apparent rarity of this condition is shown by the fact that fewer than 100 cases have been reported in English over 40 years, and to this Burroughs and colleagues2 have added 12 seen over as many years at the Royal Free Hospital, London. Idiopathic acute fatty liver of pregnancy (AFLP) typically presents with sudden onset of malaise, nausea, and vomiting in the last trimester of pregnancy, followed by abdominal pain and jaundice. As in other syndromes of acute liver failure there is a high incidence of haemorrhagic problems due to thrombocytopenia, defects in prothrombin synthesis, and consumption coagulopathy. Maternal and fetal mortality is high, but most observers agree that prompt delivery of the infant offers the best chance of survival for both mother and child; there are a few reports of the condition presenting in the puerperium. In affected pregnancies male fetuses preponderate, and in about 10% there are twin fetuses. A very similar condition, known as twin-lamb disease, has been described in sheep.3 The aetiology of the condition remains unknown. Despite the striking clinical evidence ofliver dysfunction, histological changes of acute hepatic necrosis are seldom impressive and RS, Ide LF. Immunoreactive calcitonin in phaeochromocytomas. Proc Soc Exp Biol Med 1980; 165: 215-17 6 Wells SA Jr, Baylin SB, Leight GS, Dale JK, Dilley WG, Farndon JR The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma. Ann Surg 1982; 195: 595-99. 7. Block MA, Jackson CE, Greenawald KA, Yott JB, Tashjian AH Jr. Clinical characteristics distinguishing hereditary from sporadic medullary thyroid carcinoma. Treatment implications Arch Surg 1980; 115: 142-48. 1. Sheehan HL. The pathology of acute yellow atrophy and delayed chloroform poisoning. J Obstet Gynaecol Br Emp 1940; 47: 49-62. 2 Burroughs AK, Seong NG, Dojcinov DM, Scheuer PJ, Sherlock SVP. Idiopathic acute fatty liver of pregnancy in 12 patients. Quart J Med 1982; 41: 481-97. 3 Parry HB Toxaemias of pregnancy in domestic animals with particular reference to the sheep. In: Sheehan HL, ed. Toxaemias of pregnancy. London: Ciba, 1950
the major light and electron microscopic feature is microvesicular fat vacuolation of the hepatocytes with a centrilobular distribution. In some cases routine histochemical stains may show little abnormality and the fat may be identified only by the use of specific stains such as oil red 0 on frozen sections. Tetracycline and sodium valproate administration can produce a similar clinical and histological picture in both pregnant and non-pregnant women. Reye’s syndrome also resembles AFLP, and transient deficiency of the urea cycle enzymes ornithine transcarbamylase and carbamyl synthetase have been described in both.4 In these conditions the fatty infiltrate consists largely of free fatty acids, in contrast to the triglyceride infiltrates of obesity, nutritional steatosis, diabetes, and alcoholism. As with Reye’s syndrome, many cases of AFLP follow an acute infective illness and one view is that metabolic failure is precipitated by acute stress acting on a susceptible liver6which is already coping with the demands of late pregnancy. The diagnosis during life must usually be made on clinical grounds alone since the coagulation disturbances tend to preclude liver biopsy. Toxaemia of pregnancy, benign cholestasis of pregnancy, virus hepatitis, or some other nonhepatic viral infection are the main differential diagnoses. In the Royal Free Hospital series, 7 of the 12 patients had proteinuria, hypertension, and peripheral oedema-an observation which underlines the difficulty of reaching an accurate diagnosis, and which also raises questions concerning the validity of statistics concerning AFLP. Toxaemia is a much commoner disorder than acute fatty liver. In England and Wales 29 deaths were attributed to hypertensive diseases of pregnancy (previously termed toxaemia of pregnancy) in the years 1976-78,compared with 7 due to liver disorders. 21 of these deaths were accounted for by cerebral haemorrhage, cerebral oedema, disseminated vascular coagulation, and hepatorenal failure-all well recognised complications of AFLP. While it would be absurd to suggest that AFLP and toxaemia of pregnancy are one and the same disorder, the distinction between them may not be as great and clear as has been assumed. Jaundice is a well recognised feature of toxaemia of pregnancy and hyperuricaemia is frequent in both toxaemia and AFLP. Even at necropsy the acute fatty liver may well go undiagnosed unless the liver is examined histologically, since a macroscopically normal liver may show severe fatty
infiltration.8 There
good reasons for precision in the diagnosis of liver of pregnancy. Since this condition is held to fatty be substantially more dangerous than toxaemia of pregnancy, its early recognition may lead to much more prompt induction of labour with consequent improved survival for both mother and child. Finally, more careful and accurate investigation of acute vomiting in late pregnancy (both fatal and non-fatal) might shed further light on fundamental aspects of hepatic metabolism of lipids with implications far beyond obstetrics. are
acute
5. Weinstein
Weber FL, Snodgrass PJ, Powell DE, Rao P, Huffman SL, Brady PG. Abnormalities of hepatic mitochondrial urea-cycle enzyme activities and hepatic ultra structure in acute fatty liver pregnancy. J Lab Clin Med 1979; 94: 27-41. 5. Eisele JW, Barker EA, Smuckler EA. Lipid content in the liver offatty metamorphosis 1975; 81: 545-55. of pregnancy. Am Pathol J 6. Hague WM, Fenton DW, Duncan SLB, Slater DN. Acute fatty liver of pregnancy. A review of the literature and six further cases. J Roy Soc Med (in press). 7. Department of Health and Social Security. Report on confidential enquiries into maternal deaths in England and Wales 1976-1978. London: H.M. Stationery Office, 1982. 8. Ferris TF, Herdson PB, Dunnill MS, Lee MR. Toxaemia of pregnancy in sheep: a clinical, physiological and pathological study J Clin Invest 1969; 48: 1643-55.
4.