BRITISH MEDICAL JOURNAL
22 JANUARY 1977
213
MEDICAL PRACTICE
Clinicopaathological Conference
Diagnostic difficulties in a case of polypharmacy DEMONSTRATED AT THE ROYAL COLLEGE OF PHYSICIANS OF LONDON British Medical Journal, 1977, 1, 213-214
The fifteenth quarterly clinicopathological conference was held at the Royal College of Physicians of London on 29 July 1976. The conference was chaired by Professor Sheila Sherlock (1). She began by introducing Professor Jean-Pierre Benhamou (2), professor of gastroenterology at the Beaujon-Clichy Hospital, University of Paris, who was to open the discussion of the case. Professor Sherlock emphasised that this case had no great denouement but was more a talking point for various aspects of hepatology, a review of the state of the art. Dr James Scott (3) presented the case, and Dr R Dick (4) described the
radiological findings. Clinical summary A 54-year-old Negro
man was admitted to hospital on 12 March 1976 with sudden onset of severe occipital headache, confusion, and weakness of the right leg. He had been hypertensive and taking methyldopa for four years. On admission his blood pressure was 210/120 mm Hg. He was disorientated and had a right extensor plantar response. Lumbar puncture produced heavily bloodstained cerebrospinal fluid at a pressure of 320 mm Hg. He was treated with parenteral hydrallazine, prochlorperazine, and codeine phosphate. On 14 March he was transferred to a neurosurgical unit. Bilateral carotid arteriography under trichloroethylene anaesthesia showed an aneurysm with a very narrow neck arising from the left anterior communicating artery. On the 17th, left frontotemporal craniotomy to clip off the aneurysm was undertaken under halothane anaesthesia. Postoperatively he was given phenytoin and methyldopa by mouth and chlorpromazine by injection. There was a transient rise in blood urea from the preoperative concentration of 8-6 mmol/l (59 mg/100 ml) to 10 mmol/l (60 mg/100 ml) (normal range 2 5-7 5 mmol/l; 15-45 mg/100 ml). Liver function values and urine were normal. On 30 March carotid arteriography was repeated under trichloroethylene anaesthesia. The aneurysm had been successfully occluded. There was no other lesion. On 1 April he had a fever of 38°C and complained of pain in his right calf. Venography showed no thrombi. On 3 April he returned to the first hospital and was given phenylbutazone for the fever and calf pain.
These settled with no cause being found. On 14 April, however, a fever of 39°C developed and he became extremely confused. A generalised maculopapular rash appeared. On 16 April his liver was enlarged. His serum aspartate transaminase concentration was 180 IU/I (normal range 3-15 IU/1), alkaline phosphatase 45 KA units (normal range 3-13 KA units), and bilirubin 28 ,umol/l (1-6 mg/100 ml) (normal range 5-17 ,umol/l; 0-3-1-0 mg/100 ml). The fever, rash, and confusion persisted for the next week, and he also had a urinary infection with Escherichia coli, for which he was given ampicillin. Because of persistent severe confusion he was sent back to the neurosurgical unit, but no further neurological abnormalities were found. His blood urea was 10 5 mmol/l (63 mg/100 ml). On 19 April he became oliguric with a blood urea of 28 mmol/l (169 mg/100 ml). He was transferred to the Royal Free Hospital. On arrival his temperature was 39'C and blood pressure 90/50 mm Hg. He was noticeably confused, twitching, dehydrated, and had a severe generalised maculopapular rash. He had no lymphadenopathy or oedema or stigmata of chronic liver disease. His liver was firm and palpable 5 cm below the costal margin, but he had no ascites and his spleen was not palpable. The right plantar response was extensor, but he had no neck stiffness, and Kernig's sign was absent. His heart was normal but occasional rhonchi were heard in his chest. Results of investigations were: haemoglobin 10-1 g/dl; white cell count 19-6 x 109l1 (19 600/mm3) (neutrophils 63 %, lymphocytes 34 %, eosinophils
30%); platelet count 65 x 109/1 (65 000/mm3); prothrombin time prolonged
6 s after vitamin K; partial thromboplastin time and fibrinogen normal; fibrin degradation products absent; blood urea 30 mmol/l (180 mg/100 ml); serum potassium 4-7 mmol (mEq)/l; serum sodium 140 mmol (mEq)/l; serum bicarbonate 16 mmol (mEq)/l; serum creatinine 550 (6-2 mg/100 ml) (normal range 62-133 ,Lmol/l; 0-7-1-5 mg/100 ml); serum osmolality 320 mmol (mOsm)/l and urine osmolality 305 mmol (mOsm)/l; urine sodium 83 mmol (mEq)/l; urine potassium 45 mmol (mEq)/l; urine urea 14 9 mmol/l (0-9 g/l); urine protein 255 mg/l; urine deposit, occasional granular casts and red cells; serum calcium 2-1 mmol/l (8-4 mg/100 ml) (normal range 2-25-2-65 mmol/l; 9-0-10-6 mg/100 ml); serum phosphate 1-8 mmol/l (5-6 mg/100 ml) (normal range 0-8-1-8 mmol/l; 2-5-5-6 mg/100 ml); serum albumin 32 g/l (normal range 35-45 g/l); serum aspartate transaminase 105 IU/l; serum alkaline phosphatase 73 KA units; serum bilirubin 84 jsmol/l (5 0 mg/100 ml); gammaglobulin normal; serum amylase 800 IU/l (normal range less than 350 IU/1); LE cells, antinuclear antibodies, antimitochondrial antibodies, smooth-muscle antibodies, hepatitis B surface antigen, and cx-fetoprotein absent; Paul-Bunnell reaction negative; cytomegalovirus and toxoplasma complement fixation tests negative; blood cultures negative. Chest radiography and ECG showed cardiac enlargement but no other abnormality; abdominal radiography showed a large liver; radiotechnetium liver scan showed a diffusely enlarged liver but no splenomegaly. On 21 April needle liver biopsy was performed.
temol/l
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BRITISH MEDICAL JOURNAL
Treatment consisted of fluid restriction and mannitol challenge. All the previous drugs were stopped, and gentamicin with metronidazole were started. The fever and confusion persisted. On 22 April he was anuric. Chest radiography showed a right pneumothorax, for which a drain was inserted. He died the same day. Dr Scott listed the drugs that the patient had been given: during 1972-6 methyldopa; on 13 March 1976 hydrallazine, prochlorperazine, diazepam, and codeine phosphate; on the 15th trichloroethylene (for carotid arteriography); on the 17th halothane (for craniotomy), followed by phenytoin and methyldopa; on the 18th chlorpromazine; and on the 30th trichloroethylene. On 1 April he developed fever and calf pain, and on the 3rd he was given phenylbutazone; on the 14th he developed fever, confusion, and rash, and on the 16th hepatomegaly. On the 17th he was given ampicillin, and on the 19th he developed oliguria. He was then transferred to the Royal Free Hospital and treatment with gentamicin and metronidazole was begun. He died on 22 April. PROFESSOR SHEILA SHERLOCK: Thank you. I shall now ask Professor Benhamou to give his impressions of this case. PROFESSOR JEAN-PIERRE BENHAMOU: The story of this patient's illness may be divided into three periods. In the first periodfrom 1972 to 1976-he suffered from arterial hypertension and was treated with methyldopa. The second period began on 12 March, when he had a subarachnoid haemorrhage from a ruptured aneurysm of the anterior communicating artery. This was operated on, and apparently the postoperative course was uneventful except for right calf pain and fever, for which he was given phenylbutazone. The third period began on 14 April and was dominated by liver, skin, and renal manifestations. This period ended with the patient's death on 22 April, apparently due to renal failure. There is no diagnostic problem in the first or second period and I shall concentrate on the third period. I see several possible diagnoses. My first suggestion would be polyarteritis nodosa. This could explain arterial hypertension, arterial aneurysm, the skin manifestations, liver manifestations, and renal failure. But there are serious arguments against this diagnosis. In particular, renal failure is much more progressive in polyarteritis nodosa than was the case in this patient. Liver lesions in polyarteritis are either infarction or chronic active hepatitis, not acute liver cell necrosis as occurred here. So polyarteritis iodosa may be excluded. A second possible diagnosis would be viral hepatitis-that is, non-B viral hepatitis, as the hepatitis B surface antigen was not present. This could explain the liver lesion, the rash, and even renal failure. However, the rash, uncommon in viral hepatitis, usually antedates the appearance of liver damage, but here they appeared at the same time. Renal failure is common in fulminant viral hepatitis but usually develops late in its course. Here it appeared early. So I think viral hepatitis may be ruled out. My third diagnosis would be drug intolerance. When liver, skin, and renal lesions appear simultaneously then drug intolerance must be considered. This patient unfortunately had received many drugs. So I have picked out the drugs that are known to cause liver damage and looked to see which are also known to cause renal failure and rashes (see table). Only phenylbutazone is known to produce all three. So my choice would be phenylbutazone, which has two additional advantages. Phenylbutazone is known to induce lung lesions, probably by infiltration by inflammatory cells; at a late stage rhonchi were noted in this patient, which could be related to phenylbutazone intolerance. Phenylbutazone is also known to induce interstitial myocarditis, and cardiac enlargement was noted towards the end. Drugs that
cause
liver damage and also
cause
renal failure
or
rash
or
both
22 JANUARY 1977
Incidentally, on the last day of his life, the patient had a pneumothorax. I suppose this was the result of the needle biopsy of the liver, which had been done the day before. I expect the necropsy to have shown: (a) arterial lesions related to arterial hypertension; (b) aneurysm of the left anterior communicating artery (clipped); (c) liver cell necrosis, predominantly centrilobular, with moderate steatosis and congestion; (d) degenerative change in renal tubules; (e) interstitial myocarditis, possibly with granulomas; and (f) inflammatory infiltration of the lungs, plus pneumothorax due to perforation. I should like to add some comments about the mechanism of toxicity in this case. Toxicity to the liver can be caused either by the drug itself or by metabolites of the drug. These toxic metabolites are formed in the microsomes. Their production is increased by enzyme induction, and the liver toxicity to them is increased by enzyme induction. Phenylbutazone is known to produce reactive metabolites. So I speculate that in this case, although the other drugs were not directly relevant to the toxicity, they might have induced microsomal enzymes and therefore increased the toxicity of phenylbutazone. This would be supported by showing proliferation of the endoplasmic reticulum in the biopsy if the liver specimen had been examined. by electron microscopy.
Questions and answers PROFESSOR SHERLOCK: Would anybody like to question Professor Benhamou ? DR J H H MACRAE (5): Would Professor Benhamou care to comment on the neurological side? If I had been the general practitioner I might have wanted the arteriogram on the first day, but by the third day the condition would have stabilised itself. When it was done there was no extravasation, indicating that the haemorrhage had stopped and that surgery might have been delayed. PROFESSOR SHERLOCK: Professor Peter Thomas is going to comment on the neurological aspects. DR N COMPSTON (6): Would phenylbutazone jaundice be compatible with a leucocytosis of nearly 20 000 ? PROFESSOR BENHAMOU: Phenylbutazone induces eosinophilia and sometimes cytopenia. I have no explanation for the changes in this case. DR N K SHINTON (7): Was hydrallazine possibly the toxic drug in this patient ? PROFESSOR SHERLOCK: We'll save that for later. I think we will show our diagnosis at the time. DR SCOTT: Our clinical diagnoses were: (1) hypertension with cardiac and renal insufficiency; (2) subarachnoid haemorrhage from the left anterior communicating artery aneurysm; (3) druginduced hepatitis due to phenytoin; and (4) acute tubular necrosis superimposed on a chronic renal lesion; ? cause. PROFESSOR SHERLOCK: So we differ from Professor Benhamou in two respects. We think that the tubular necrosis was caused by hypotension not the drug; and we choose phenytoin as the toxic drug. Professor Peter Scheuer will give us the necropsy findings.
Pathological findings PROFESSOR P J SCHEUER (8): I shall try to fulfil some of Professor Benhamou's predictions. I shall start with the liver biopsy, which was done two days before death. Because the patient was then very ill we were asked to do a rapid frozen section, which is rather uncommon as the results are often disappointing. It did show more clearly than any other preparation the presence of bile plugs-morphological cholestasis. Much bile disappears during paraffin embedding. But we could not make a confident diagnosis on the frozen section. We waited for the paraffin section (fig 1), which showed acute hepatitis with variation in liver-cell appearance and staining and inflammatory-cell infiltration. This is not the picture of a pure necrosis such as is seen with trichloroethylene, for example. It
BRITISH MEDICAL
JOURNAL
215
22 JANUARY 1977 P
-t
_IiR* +E b A
ii
4 f
v ^!; *#>
W
); ^Q P
.
haemorrhage into the pancreas. This patient's pancreas was omal apart from some autolysis. (Necropsy was not carrie out until after the weekend after the patient died.) The kidneys were l 1Xj>
22 JANUARY 1977
213
MEDICAL PRACTICE
Clinicopaathological Conference
Diagnostic difficulties in a case of polypharmacy DEMONSTRATED AT THE ROYAL COLLEGE OF PHYSICIANS OF LONDON British Medical Journal, 1977, 1, 213-214
The fifteenth quarterly clinicopathological conference was held at the Royal College of Physicians of London on 29 July 1976. The conference was chaired by Professor Sheila Sherlock (1). She began by introducing Professor Jean-Pierre Benhamou (2), professor of gastroenterology at the Beaujon-Clichy Hospital, University of Paris, who was to open the discussion of the case. Professor Sherlock emphasised that this case had no great denouement but was more a talking point for various aspects of hepatology, a review of the state of the art. Dr James Scott (3) presented the case, and Dr R Dick (4) described the
radiological findings. Clinical summary A 54-year-old Negro
man was admitted to hospital on 12 March 1976 with sudden onset of severe occipital headache, confusion, and weakness of the right leg. He had been hypertensive and taking methyldopa for four years. On admission his blood pressure was 210/120 mm Hg. He was disorientated and had a right extensor plantar response. Lumbar puncture produced heavily bloodstained cerebrospinal fluid at a pressure of 320 mm Hg. He was treated with parenteral hydrallazine, prochlorperazine, and codeine phosphate. On 14 March he was transferred to a neurosurgical unit. Bilateral carotid arteriography under trichloroethylene anaesthesia showed an aneurysm with a very narrow neck arising from the left anterior communicating artery. On the 17th, left frontotemporal craniotomy to clip off the aneurysm was undertaken under halothane anaesthesia. Postoperatively he was given phenytoin and methyldopa by mouth and chlorpromazine by injection. There was a transient rise in blood urea from the preoperative concentration of 8-6 mmol/l (59 mg/100 ml) to 10 mmol/l (60 mg/100 ml) (normal range 2 5-7 5 mmol/l; 15-45 mg/100 ml). Liver function values and urine were normal. On 30 March carotid arteriography was repeated under trichloroethylene anaesthesia. The aneurysm had been successfully occluded. There was no other lesion. On 1 April he had a fever of 38°C and complained of pain in his right calf. Venography showed no thrombi. On 3 April he returned to the first hospital and was given phenylbutazone for the fever and calf pain.
These settled with no cause being found. On 14 April, however, a fever of 39°C developed and he became extremely confused. A generalised maculopapular rash appeared. On 16 April his liver was enlarged. His serum aspartate transaminase concentration was 180 IU/I (normal range 3-15 IU/1), alkaline phosphatase 45 KA units (normal range 3-13 KA units), and bilirubin 28 ,umol/l (1-6 mg/100 ml) (normal range 5-17 ,umol/l; 0-3-1-0 mg/100 ml). The fever, rash, and confusion persisted for the next week, and he also had a urinary infection with Escherichia coli, for which he was given ampicillin. Because of persistent severe confusion he was sent back to the neurosurgical unit, but no further neurological abnormalities were found. His blood urea was 10 5 mmol/l (63 mg/100 ml). On 19 April he became oliguric with a blood urea of 28 mmol/l (169 mg/100 ml). He was transferred to the Royal Free Hospital. On arrival his temperature was 39'C and blood pressure 90/50 mm Hg. He was noticeably confused, twitching, dehydrated, and had a severe generalised maculopapular rash. He had no lymphadenopathy or oedema or stigmata of chronic liver disease. His liver was firm and palpable 5 cm below the costal margin, but he had no ascites and his spleen was not palpable. The right plantar response was extensor, but he had no neck stiffness, and Kernig's sign was absent. His heart was normal but occasional rhonchi were heard in his chest. Results of investigations were: haemoglobin 10-1 g/dl; white cell count 19-6 x 109l1 (19 600/mm3) (neutrophils 63 %, lymphocytes 34 %, eosinophils
30%); platelet count 65 x 109/1 (65 000/mm3); prothrombin time prolonged
6 s after vitamin K; partial thromboplastin time and fibrinogen normal; fibrin degradation products absent; blood urea 30 mmol/l (180 mg/100 ml); serum potassium 4-7 mmol (mEq)/l; serum sodium 140 mmol (mEq)/l; serum bicarbonate 16 mmol (mEq)/l; serum creatinine 550 (6-2 mg/100 ml) (normal range 62-133 ,Lmol/l; 0-7-1-5 mg/100 ml); serum osmolality 320 mmol (mOsm)/l and urine osmolality 305 mmol (mOsm)/l; urine sodium 83 mmol (mEq)/l; urine potassium 45 mmol (mEq)/l; urine urea 14 9 mmol/l (0-9 g/l); urine protein 255 mg/l; urine deposit, occasional granular casts and red cells; serum calcium 2-1 mmol/l (8-4 mg/100 ml) (normal range 2-25-2-65 mmol/l; 9-0-10-6 mg/100 ml); serum phosphate 1-8 mmol/l (5-6 mg/100 ml) (normal range 0-8-1-8 mmol/l; 2-5-5-6 mg/100 ml); serum albumin 32 g/l (normal range 35-45 g/l); serum aspartate transaminase 105 IU/l; serum alkaline phosphatase 73 KA units; serum bilirubin 84 jsmol/l (5 0 mg/100 ml); gammaglobulin normal; serum amylase 800 IU/l (normal range less than 350 IU/1); LE cells, antinuclear antibodies, antimitochondrial antibodies, smooth-muscle antibodies, hepatitis B surface antigen, and cx-fetoprotein absent; Paul-Bunnell reaction negative; cytomegalovirus and toxoplasma complement fixation tests negative; blood cultures negative. Chest radiography and ECG showed cardiac enlargement but no other abnormality; abdominal radiography showed a large liver; radiotechnetium liver scan showed a diffusely enlarged liver but no splenomegaly. On 21 April needle liver biopsy was performed.
temol/l
214
BRITISH MEDICAL JOURNAL
Treatment consisted of fluid restriction and mannitol challenge. All the previous drugs were stopped, and gentamicin with metronidazole were started. The fever and confusion persisted. On 22 April he was anuric. Chest radiography showed a right pneumothorax, for which a drain was inserted. He died the same day. Dr Scott listed the drugs that the patient had been given: during 1972-6 methyldopa; on 13 March 1976 hydrallazine, prochlorperazine, diazepam, and codeine phosphate; on the 15th trichloroethylene (for carotid arteriography); on the 17th halothane (for craniotomy), followed by phenytoin and methyldopa; on the 18th chlorpromazine; and on the 30th trichloroethylene. On 1 April he developed fever and calf pain, and on the 3rd he was given phenylbutazone; on the 14th he developed fever, confusion, and rash, and on the 16th hepatomegaly. On the 17th he was given ampicillin, and on the 19th he developed oliguria. He was then transferred to the Royal Free Hospital and treatment with gentamicin and metronidazole was begun. He died on 22 April. PROFESSOR SHEILA SHERLOCK: Thank you. I shall now ask Professor Benhamou to give his impressions of this case. PROFESSOR JEAN-PIERRE BENHAMOU: The story of this patient's illness may be divided into three periods. In the first periodfrom 1972 to 1976-he suffered from arterial hypertension and was treated with methyldopa. The second period began on 12 March, when he had a subarachnoid haemorrhage from a ruptured aneurysm of the anterior communicating artery. This was operated on, and apparently the postoperative course was uneventful except for right calf pain and fever, for which he was given phenylbutazone. The third period began on 14 April and was dominated by liver, skin, and renal manifestations. This period ended with the patient's death on 22 April, apparently due to renal failure. There is no diagnostic problem in the first or second period and I shall concentrate on the third period. I see several possible diagnoses. My first suggestion would be polyarteritis nodosa. This could explain arterial hypertension, arterial aneurysm, the skin manifestations, liver manifestations, and renal failure. But there are serious arguments against this diagnosis. In particular, renal failure is much more progressive in polyarteritis nodosa than was the case in this patient. Liver lesions in polyarteritis are either infarction or chronic active hepatitis, not acute liver cell necrosis as occurred here. So polyarteritis iodosa may be excluded. A second possible diagnosis would be viral hepatitis-that is, non-B viral hepatitis, as the hepatitis B surface antigen was not present. This could explain the liver lesion, the rash, and even renal failure. However, the rash, uncommon in viral hepatitis, usually antedates the appearance of liver damage, but here they appeared at the same time. Renal failure is common in fulminant viral hepatitis but usually develops late in its course. Here it appeared early. So I think viral hepatitis may be ruled out. My third diagnosis would be drug intolerance. When liver, skin, and renal lesions appear simultaneously then drug intolerance must be considered. This patient unfortunately had received many drugs. So I have picked out the drugs that are known to cause liver damage and looked to see which are also known to cause renal failure and rashes (see table). Only phenylbutazone is known to produce all three. So my choice would be phenylbutazone, which has two additional advantages. Phenylbutazone is known to induce lung lesions, probably by infiltration by inflammatory cells; at a late stage rhonchi were noted in this patient, which could be related to phenylbutazone intolerance. Phenylbutazone is also known to induce interstitial myocarditis, and cardiac enlargement was noted towards the end. Drugs that
cause
liver damage and also
cause
renal failure
or
rash
or
both
22 JANUARY 1977
Incidentally, on the last day of his life, the patient had a pneumothorax. I suppose this was the result of the needle biopsy of the liver, which had been done the day before. I expect the necropsy to have shown: (a) arterial lesions related to arterial hypertension; (b) aneurysm of the left anterior communicating artery (clipped); (c) liver cell necrosis, predominantly centrilobular, with moderate steatosis and congestion; (d) degenerative change in renal tubules; (e) interstitial myocarditis, possibly with granulomas; and (f) inflammatory infiltration of the lungs, plus pneumothorax due to perforation. I should like to add some comments about the mechanism of toxicity in this case. Toxicity to the liver can be caused either by the drug itself or by metabolites of the drug. These toxic metabolites are formed in the microsomes. Their production is increased by enzyme induction, and the liver toxicity to them is increased by enzyme induction. Phenylbutazone is known to produce reactive metabolites. So I speculate that in this case, although the other drugs were not directly relevant to the toxicity, they might have induced microsomal enzymes and therefore increased the toxicity of phenylbutazone. This would be supported by showing proliferation of the endoplasmic reticulum in the biopsy if the liver specimen had been examined. by electron microscopy.
Questions and answers PROFESSOR SHERLOCK: Would anybody like to question Professor Benhamou ? DR J H H MACRAE (5): Would Professor Benhamou care to comment on the neurological side? If I had been the general practitioner I might have wanted the arteriogram on the first day, but by the third day the condition would have stabilised itself. When it was done there was no extravasation, indicating that the haemorrhage had stopped and that surgery might have been delayed. PROFESSOR SHERLOCK: Professor Peter Thomas is going to comment on the neurological aspects. DR N COMPSTON (6): Would phenylbutazone jaundice be compatible with a leucocytosis of nearly 20 000 ? PROFESSOR BENHAMOU: Phenylbutazone induces eosinophilia and sometimes cytopenia. I have no explanation for the changes in this case. DR N K SHINTON (7): Was hydrallazine possibly the toxic drug in this patient ? PROFESSOR SHERLOCK: We'll save that for later. I think we will show our diagnosis at the time. DR SCOTT: Our clinical diagnoses were: (1) hypertension with cardiac and renal insufficiency; (2) subarachnoid haemorrhage from the left anterior communicating artery aneurysm; (3) druginduced hepatitis due to phenytoin; and (4) acute tubular necrosis superimposed on a chronic renal lesion; ? cause. PROFESSOR SHERLOCK: So we differ from Professor Benhamou in two respects. We think that the tubular necrosis was caused by hypotension not the drug; and we choose phenytoin as the toxic drug. Professor Peter Scheuer will give us the necropsy findings.
Pathological findings PROFESSOR P J SCHEUER (8): I shall try to fulfil some of Professor Benhamou's predictions. I shall start with the liver biopsy, which was done two days before death. Because the patient was then very ill we were asked to do a rapid frozen section, which is rather uncommon as the results are often disappointing. It did show more clearly than any other preparation the presence of bile plugs-morphological cholestasis. Much bile disappears during paraffin embedding. But we could not make a confident diagnosis on the frozen section. We waited for the paraffin section (fig 1), which showed acute hepatitis with variation in liver-cell appearance and staining and inflammatory-cell infiltration. This is not the picture of a pure necrosis such as is seen with trichloroethylene, for example. It
BRITISH MEDICAL
JOURNAL
215
22 JANUARY 1977 P
-t
_IiR* +E b A
ii
4 f
v ^!; *#>
W
); ^Q P
.
haemorrhage into the pancreas. This patient's pancreas was omal apart from some autolysis. (Necropsy was not carrie out until after the weekend after the patient died.) The kidneys were l 1Xj>
