- Email: [email protected]
The Children's Hospital Medical Center, Boston, Mass.
CLINICAL
PATHOLOGICAL
CONFERENCE
THE
CHILDREN'S
BOSTON,
HOSPITAL
MEDICAL
CENTER,
MASS.
Sidney Farber, M. D., Editor Gordon F. Vawter, M.D., Assistant Editor
at bedtime (Phelantin capsule contains diphenylhydantoin 100 mg., phenobarbital 30 mg., and methamphetamine hydrochloride 2.5 rag.). The patient had been followed in the Outpatient Department because of seizures and mental retardation but was otherwise well until approximately one week prior to admission. At this time she had vomiting for 2 days, followed by several loose bowel movements, but had no other specific complaints. She was observed in the Medical Emergency Clinic where icterus was noted. The liver edge was not palpable. A test for biliuria was positive. She was sent home to follow a regimen of bed rest and g a m m a globulin was given to the rest of the family. She returned 4 days later since vomiting had increased and was admitted to the hospital. On examination the temperature was 98 ~ F., pulse 92 per minute, respiratio.ns 20 per minute, and blood pressure 120/80 m m Hg. She was a thin girl, deeply jaundiced, but seemed to be in no acute distress. T h e tongue was somewhat coated. Chest and heart were normal. The liver edge was not palpable and the spleen was not felt. Neuro-
T i-x i s was the fourth Children's Hospital Medical Center admission of this 14-year-old girl. Her chief complaint was jaundice and vomiting. H e r first adlnission began at 2 days of age when, after a difficult delivery which was considerably post-mature by date and was associated with yellow vernix and partial separation of placenta, she had generalized twitching (which improved later) and a poor color. L u m b a r and subdural punctures, skull x-rays, and cultures were normal. She has been followed in the Outpatient Department since that time, with two admissions for dental extractions and tonsillectomy. Her development was slow and she was evaluated in the Seizure Clinic at 4 years of age because of a history of seizures with fever. At 10 years of age she began having seizures without fever. She had been treated with diphenylhydantoin, 100 mg. twice a day since 6 years of age and had also received phenobarbital, mephobarbital, or primidone from 13 years of age. Until the present illness she had been receiving Phelantin, 1 tablet in the morning, mephobarbital 32 mg. at noon and bedtime, and diphenylhydantoin 50 mg. 1041
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Clinical pathological con[erence
logic examination revealed normal tendon reflexes without ataxia. Initial complete blood count revealed: hematocrit 49 per cent; hemoglobin 14 Gm. per cent; white blood cells 5,200 per cubic millimeter with 50 per cent polymorphonuclear leukocytes, 3 per cent bands, 30 per cent lymphocytes, 4 per cent atypical lymphocytes, and 13 per cent monocytes. Platelets were adequate on smear. Urinalysis was reported as follows: p H 6.5; specific gravity 1.022; no albumin or sugar; positive for bile; 5 to 10 white blood cells per high-power field of spun sediment. Subsequent urinalyses showed normal sediment and an occasional trace of albumin. Blood contained: total protein, 5.6 Gm. per cent; albumin 3.3 Gm. per cent; and globulins--alpha-l, 0.28 Gm. per cent; alpha-2, 0.39 Gm. per cent; beta, 0.56 Gm. per cent; gamma, 1.07 Gin. per cent. Serum glutamic oxalic transaminase was 950 units; serum glutamic pyruvic transminase, 245 units. Alkaline phosphatase was 12 units; cholinesterase, 24 units; bilirubin, 23 mg. per cent direct, 34 rag. per cent total. Thymol turbidity, 1-plus, thymol flocculation, 1-plus; cephalin flocculation, 1-plus; prothrombin time (on admission), 12 per cent; one day later, 1 per cent. On the third hospital day the prothrombin time was 17 per cent (after vitamin K). A lupus erythematosis cell preparation (L. E. cell) was negative. Results of other chemical examinations were as follows: on admission, blood urea nitrogen, 11 mg. per cent; on second day, blood sugar 68 mg. per cent; p H 7.4 and plasma carbon dioxide 27 mEq. per liter; sodium 128 mEq. per liter; potassium 5.9 mEq. per liter; and chloride, 91 mEq. per liter. On the third day, p H was 7.43; plasma carbon dioxide 36 mEq. per liter; sodium 145 mEq. per liter; potassium 2.2 mEq. per liter; chloride 88 mEq. per liter. On the fourth day, serum sodium was 144 mEq. per liter; potassium 2 mEq. per liter. On the sixth day, blood sugar was 157 rag. per cent; p H 7.4; carbon dioxide 36 mEq. per liter; serum sodium 155 mEq. per liter; potassium 2.9 mEq. per liter; and chloride 100 mEq.
November 1963
per liter. Urine potassium was 34 mEq. per liter and sodium was 23 mEq. per liter. Intravenous fluids were started on the evening of admission. Anticonvulsants were continued at first. On the day after admission the patient pulled out the intravenous tube and took fluids by mouth without vomiting. On the next day she became irrational and began to thrash about and scream. H e r pupils seemed dilated and reacted poorly. There was redness of the palms of her hands and the pulse became rapid and somewhat weak. She was started on neomycin, enemas, and intravenous feedings of 10 per cent dextrose and water and fresh plasma. Vitamin B complex, vitamin K oxide, and hydrocortisone were given intravenously (hydrocortisone in a dose of 100 mg. every 6 hours). Anticonvulsants were stopped. At this time a blood ammonia was 150 mcg. per cent (normal: 50). On the third hospital day the patient seemed decerebrate and became comatose. The pupils became dilated and fixed. In spite of added postassium, 300 mEq. intravenously, and potassium chloride, 1350 mg. per gavage in four days, the serum potassium remained low. By the fourth hospital day she was receiving 25 per cent dextrose and water. On the seventh hospital day, she became less rigid and showed more flaccidity of her limbs, and on the next day she suddenly stopped breathing and could not be resuscitated. Urinary output for the last 3 days was 1,645 c.c., 1,750 c.c., and 1,130 c.c., respectively. DR.
SIDNEY
FARBER.
We
are
delighted
to
welcome back an old friend, Dr. Klein. DR. ROBERT KLEIN."~ It is indeed a pleasure to be here, even when faced with today's problem. We are presented with a young lady who begins and ends her life with problems relating to jaundice and the central nervous system. I *Dr. Robert Klein is Professor of Pediatrics at Boston University School of Medicine, and Senior Visiting Physician at the Boston City Hospital.
Volume 63 Number 5
Clinical pathological con/erencu
have finally concluded that it is futile to attempt to link these two widely separated clinical events, having discarded such infections as toxoplasmosis, cytomegalic inclusion disease, and histoplasmosis. I also set aside such metabolic and enzymatic problems as deficiencies in glucuronide synthesis, Wilson's disease, and so on, and conclude that, if the difficulties of the beginning and end of her life are directly related, the nature of the process is new to me. However, we cannot escape the probability that we begin with a background of brain damage, only indirectly related, if at all, to her death. The final picture is one of acute yellow atrophy of the liver or, if you prefer, acute necrosis of the liver with hepatic coma and death. All of the laboratory findings corroborate this view, including the enzyme patterns, the blood urea nitrogen, the electrolytes, the blood ammonia, and so on. That the flocculation tests are not positive suggests a very acute process, with too little time for development of alterations in these parameters. In view of these values, the serum protein levels, including normal globulins and the negative lupus erythema-
10 4 3
tosis cell preparation, we may exclude so-called plasma cell or lupoid hepatitis, a subacute or chronic illness of young women, predominantly. Wilson's disease usually has a more insidious onset, but may present initially as hepatic disease. While cytomegalic inclusion viruses have been recovered from patients with liver disease in this age group, the hepatic lesion has been chronic and rather silent clinically in the cases thus far described. Although I cannot completely exclude such leptospiral diseases as Weil's disease, or canicola fever, there is no strong evidence in favor of these diagnoses. While the course is consistent with toxic hepatic injury, such as may follow carbon tetrachloride ingestion, we have no history of such exposures. Moreover, viral hepatitis may behave in just this way, and I think that it was right to offer gamma globulin to her family with such a possibility in mind. However, it might be possible that this hepatic disease could be related to therapy with diphenylhydantoin. There are some points against this, since no other symptoms of diphenylhydantoin toxicity, such as ataxia, hirsu-
Fig. 1. Liver. There has been total destruction of almost an entire hepatic lobule in the center of the field; only dilated sinusoids and swollen interstitial components remain. There is a mild inflammatory cell response. Below, and to the right, are distorted and interrupted hepatic cell cords with black intracanalicular plugs of bile. (Hematoxylin and eosin stain. Original magnification •
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Clinical pathological con/erence
tism, gingival hypertrophy, lymphadenopathy, rash, or exfoliative dermatitis, are noted. Too, eosinophilia, not seen here, has been a constant finding with diphenylhydantoin toxicity. Moreover, she had received diphenylhydantoin for 10 years without previous difficulty, but one recalls that hepatotoxicity has been reported with cinchophen after an exposure of 4 to 5 years. However, the length of exposure to diphenylhydantoin or its analogues, such as 5-phenyl-5thionyl hydantoinate, reported before hepatic symptoms occurred, is between 2 months and 2 years. 1-a A report in the Swiss literature indicates that, rarely, the L.E. cell preparations may be positive with diphenylhydantoin therapy, but this must be as rare as the polyarteritis which has been attributed to diphenylhydantoin, too. In the final analysis, I cannot choose critically between the possibilities of viral hepatitis and diphenylhydantoin toxicity and am content to know that the central problems are those of acute hepatic necrosis, which presents difficulties in management, even though I feel the situation here had progressed beyond medical remedies. Before turning to a discussion of the hypopotassemia noted in this patient, we would just
November 1963
note that she was, in many ways, given tile standard treatment for hepatic coma (hepatic failure) including neomycin (to decrease forma-. tion of ammonia by intestinal bacteria), vitamin B complex, vitamin K oxide, and glucose. The desperate straits of her clinical condition may justify the use of hydrocortisone, but as we shall see, this may actually have been an unfortunate move. Finally, we are told that anticonvulsant therapy was continued for a time. I am not worried about the continued use of diphenylhydantoin in this situation so much as with the possibility that this therapy included barbiturates which she had received before. The handicap that barbiturates present to a damaged liver is already too well known. While the group at the Mayo Clinic has described hyperkalemia as a complication of hepatic disease, I think that hypokalemia, as developed in this girl, is a more common complication of severe hepatic disease. I would guess that the derangements associated with this might actually have hastened her death. One reason for the seriousness of hypokalemia is that a relative alkalosis often coexists. While the initial studies in this girl include a serum p H of 7.4, the electrolyte and C O 2 values at the same time
Fig. 2. Liver. A higher power view from the lower right hand corner of Fig. 1 to show the distorted liver cells, the stromal and inflammatory cell response, and bile in canaliculi. (Hematoxylin and eosin stain. Original magnification x150.)
Volume 63 Number 5
indicate a relative alkalosis as may occur with hepatic disease. The danger of alkalosis lies in the fact that this leads to increased production of ammonia and that such ammonia is more likely to be in gaseous form which more readily penetrates to the brain. This, in turn, stimulates the respiratory center to produce a respiratory alkalosis--a vicious cycle. These events have
Fig. 3. Spleen. There are large, dark lymphocytoid cells and larger cells with distinct cytoplasm, possibly "proplasma cells." (Hematoxylin and eosin stain. Original magnification x150.)
Fig. 4. Adrenal. Beneath the broad fibrous capsule (right) lies an unusually prominent outer zone of pyknotic cortical cells, possibly related to aldosterone-secreting cells. (Hematoxylin and eosin stain. Original magnification x125.)
Clinical pathological conference
10 4 5
been shown experimentally; when patients with hepatic disease were given a low potassium diet, or potassium was removed by resins, serious hypokalemia, rising ammonia in the blood, and onset of coma with further slowing of electroencephalographic patterns all indicated a serious progression of their disease until potassium was replaced. * The diuretic action of chlorothiazide
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Clinical pathological conference
November 1963
Fig. 5. Kidney. There are occasional black bile casts. ProximaI convoluted tubule cells show pale apical vacuoles. (Hematoxylln and eosin stain. Original magnification x250.)
also is associated with this problem, presumably by leaching out potassium. As described here, the .amounts of potassium given this girl were picayune since it has been shown that adults in this situation will require as much as 250 mEq. of potassium intravenously every day for 4 days in addition to an orat intake of better than 30 mEq. per liter.4 In this child, then, the hypopotassemia may be the combined result of liver disease, alkalosis, ammonia intoxication, prior potassium loss by vomiting (assuming a weight of 50 kilograms, she might have had a deficit of 400 mEq. of potassium from this factor alone before she was admitted), low potassium intake, and dilution by the overhydration seen in hepatic disease. The retention of water that such patients evidence seems out of proportion and presumably is associated with inappropriate secretion of antidiuretic hormone and an increase in circulating aldosterone resulting from adrenal oversecretion and perhaps decreased metabolism by the liver. Under these circumstances, more sodium is reabsorbed, being exchanged for potassium in the kidney tubule. These factors operate in any hepatic disease. This girl was given hydrocortisone and large amounts of glucose, both of which might also contribute to hypopotassemia. Perhaps desoxyphedrine would also have tbis effect, since we do know that epinephrine and amphetamine do so. Interestingly enough, diphenylhydantoin in acute experiments shifts potassium into and sodium out of the cell, but whether this is true of chronic administration, I do not know.
We are not told how much chloride was given to this child, but with low sodium and inadequate chloride replacement, alkalosis is perpetuated even if potassium is given, although replacement of potassium is the more important of the two. One must also consider whether the patient has specific renal lesions, such as the gtomerular abnormality of cirrhosis and the lesion of Well's disease, but there is no particular reason to suspect these. I will conclude by saying, once again, that this girl probably had acute yellow atrophy, possibly related to therapy with diphenylhydantoin, and that I think alkalosis and hypokalemia were critical in her rapid progression, but that the ultimate prognosis of her hepatic lesion was that of inevitable progression to death. DR, CHARLES A. JANEWAY. I think that this child was given 300 mEq. of potassium intravenously per day, not as a total dose. Even this dose, which is the largest we have ever given here, may have been an insufficient amount. The development of flaccidity and respiratory paralysis clearly points to serious clinical hypopotassemia. However, I think, too, that the basic hepatic lesion was essentially irrecoverable. It is of interest that we relatively rarely see children dying in an acute attack of hepatic disease. Whether the injury was caused by diphenylhydantoin, or by hepatitis, I am not sure we will ever know, but we were, at the time, in an epidemic phase of the 7 to 8 year cycle of viral hepatitis. In such epidemics we see one or two
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Number 5
cases of acute yellow atrophy but in general the mortality in children is really quite low, perhaps the lowest among all ages, and certainly unlike that seen particularly in women over 40. This fact alone leads to some interesting speculations as to metabolic interrelations. On the other hand, acute yellow atrophy has been a not too uncommon complication of acute toxic injury. DR. GORDON F. VAWTER. Perhaps we should recall that this girl was 14 years old. Of course, our autopsy series of this sort of hepatic problem is too small for firm statements, but it is interesting that most of these situations have developed in children of prepubertal or pubertal age. DR. JOHN F. CRIGLER. I wonder if Dr. Klein would comment on the use of spirolactones as antagonists of aldosterone, in such a situation. DR. KLEIN. Several people have suggested the possible usefulness of such therapy since with spirolactones there is both decreased loss of potassium and increased excretion of sodium. Apparently, there is some benefit in such therapy in chronic hepatic disease, but I have no good information on whether it is any help in an acute situation, such as is presented today. Certainly, the few patients I have seen die with such an acute process as this have had viral hepatitis or the so-called lupoid or plasma cell hepatitis. A PI-IYSICIAN. Should the possibility of infectious mononucleosis be considered here? DR. KLEIN. I don't honestly know. M y impression is that hepatic involvement in infectious mononucleosis is usually much milder than the process seen in this girl. I suspect that in many patients w h o are said to have infectious mononucleosis with hepatic involvement the involvement of the liver is suggested, largely because there are changes in serum globulins with resultant abnormal flocculation tests. DR. SAMUEL L. KATZ. This question will obviously be difficult to answer until we have more precise diagnostic techniques, such as viral isolation in infectious mononucleosis and in viral hepatitis. Dr. Gellis and I followed a young man, in whom diagnoses of infectious mononucleosis with lymphadenopathy and positive heterophil reactions were made. This patient subsequently developed cirrhosis and died. This was the only patient with this type of sequence that Dr. Gellis had observed up to that time. I am intrigued by Dr. Klein's attempt to link
Clinical pathological con/erence
1 04 7
the neonatal illness with the final picture, and would just like to reiterate that Dr. Hanshaw has isolated cytomegalic virus from the urine and livers of older children with chronic hepatic disease. As yet, however, I do not think we know whether there are etiologic implications with regards to the hepatic disease, whether this is an instance of a fellow traveler or just exactly what the implications are, Could such a virus be activated from a latent phase by a special set of circumstances? We just do not know as yet. DR. FARBER. Dr. Fred Allen had the opportunity, a number of years ago, to study the pathology of infectious mononucleosis in aviators who died accidentally. Whereas there were widespread infiltrates in myocardium, kidneys, pancreas, liver, and so on, there were no lesions in these early or subclinical cases resembling acute yellow atrophy of the liver. Do we h a v e other diagnoses? T H I R D YEAR MEDICAL S T U D E N T . W e concluded that this girl had hepatic failure superimposed upon chronic disease, secondary to diphenylhydantoin therapy. FOURTH YEAR MEDICAL S T U D E N T . Most of us felt that the problem was that of acute viral hepatitis, but some dissenters raised a question of hepatic disease secondary to diphenylhydantoin. DR. VAWTER. In the final analysis, I am not sure that we can, with certainty, resolve the etiologic dilemma, but this is not the result of the fact that an autopsy was limited to a small abdominal incision and removal of small portions of liver, adrenal, kidney, pancreas, and spleen. Postmortem viral studies by Dr. Katz were negative, as were studies for leptospira. There was no ascitic fluid, but there was massive retroperitoneal edema and the subcutaneous tissues were quite moist. The liver was small, high under the costal margin, and presented a reddish minutely knobby surface of grayish, and only occasionally yellowish, small nodules. The external biliary tree was grossly normal. The kidneys and spleen were not obviously greatly enlarged, which probably means that they were not over twice usual volume. Microscopically (Figs. 1 and 2), the hepatic lesion consists of what Dr. Popper refers to as submassive necrosis, which implies sufficient distortion of structure that complete regeneration is probably never achieved. The process consists of necrosis already completed, often accentuated centrally in the lobule, but progressing by enlargement and confluence to produce large areas
10 4 8
Clinical pathological con[erence
of lobular destruction involving several contiguous lobules. There is no increase in connective tissue and I would suppose that this process could not be much more than 30 days' old, at most. There are bile plugs in canaliculi in groups of liver cells isolated by edema or by necrosis from the drainage systems. Such lesions are not thought typical of the usual acute viral hepatitis. Lymphocytes, mononuclear cells,'and very rare plasma cells occur as a mild, diffuse, and focally moderately dense infiltrate. The residual parenchymal cells show variation in size and have excessive variability in size, shape, and staining characteristics of nuclei. These last indicate that nuclei are reacting to injury and such changes are taken by many hepatologists as evidence for viral hepatitis, but we should remind ourselves that somewhat similar changes are encountered, apparently in relation to the use of antifolic drugs. There are areas of regenerative activity with mitoses in some liver cells. Unfortunately, there is no evidence for the necrosis of single cells, which is one of the hallmarks of viral hepatitis. Evidence of thrombosis, vasculitis, eosinophilia, and fatty change, such as may be found in drug reactions or toxic injury, is not present. However, we should remember that necrosis of this type has been ascribed to drug sensitivity and closely parallels the picture attributed to diphenylhydantoinY, 3 There is lymphoid hyperplasia in the spleen and atypical cells, such as may be found in lymph nodes after diphenylhydantoin therapy, are present. However, similar cellular responses have been associated with viral hepatitis (Fig. 3). The adrenal cortex is possibly thin, with focal eosinophilic degeneration of fascicular cells, but other areas seem functionally competent. The liver is one of the prime sites of metabolism of corticosteroids and there is thought to be a feed-back mechanism between a lack of destruction of steroids by the liver and pituitary function in a variety of hepatic abnormalities. By contrast with the zona fasciculata, the zone glomerulosa is relatively thicker and possibly absolutely increased in width. Cells of this zone have pyknotic nuclei, as if overtaxed (Fig. 4). Most evidence indicates that aldosterone is formed in the adrenal zona glomerulosa, and that such production is much less responsive to pituitary stimulus ( A C T H ) than the hormones of the fasciculata. With numerous exceptions, the width of the glomerulosa parallels the serum sodium level, or perhaps more accurately, the relative retention of sodium.
November 1963
In the kidney there is no major lesion; there are a few bile casts and the glomeruli are normal. The juxtaglomerular cells are hypertrophic but devoid of granules. One might have expected these cells to be filled with granules, a condition which has been correlated with increased renin production by the kidney, with subsequent activation of angiotensin which, in turn, seems to correlate with the prominence of the adrenal zona glomerulosa and with increased secretion of aldosterone. I suspect that these hypertrophic juxtaglomerular cells were indeed filled with granules when the serum sodium was low, as on admission, and that as the serum sodium rose, these granules were lost with persisting hypertrophy of the cells, s The renal tubules do not show lesions of prolonged or end-stage hypopotassemia or sodium and potassium depletion, but rather, large transfers of fluid (and electrolytes) are suggested. Perhaps the advanced typical alterations are somewhat obscured by other changes, such as bile nephrosis, so-called, a lesion often said to be of little functional significance, per se. However, some convoluted tubular cells have apical vacuoles as described in hypokalemia (Fig. 5). In summary, the liver shows severe submassire necrosis, compatible with a healing phase of viral hepatitis, but one recognizes that similar changes have been attributed to diphenylhydantoin. Changes in adrenal glands and kidneys are probably best interpreted as representing a changing flux of metabolic and functional import in the light of the hepatic lesion and the treatment given. DR. RANDOLPtI K. BYI~RS. I have no personal experience with hepatic injury with dilantin but my understanding is that other signs of dilantin toxicity are present. But, both diphenylhydantoin and barbiturates are known to affect hepatic function and if the girl's seizure status permitted, it would have been wise, I think, to stop both medications when symptoms first developed. DR. FARBER. As is our custom, Dr. Klein, you have the concluding word. DR. KLEIN. The fact that she received more potassium than I thought, but without extraordinary urinar~ loss, suggests that her initial depletion by vomiting was a major one. However, the need in problems of hypokalemia is to have some idea of what the intracellular potassium and electrolyte levels are, since there are many paradoxical situations. For example, potassium is beneficially given for digitalis intoxi-
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Number 5
cation but under numerous circumstances, potassium will aggravate digitalis intoxication. Obviously, other ions are implicated in such situations. Final diagnoses were:
Submassive necrosis o[ liver (? viral ? toxieation)--with-Alkalosis Hypopotassemia, muscle weakness, and respiratory [ailure Increased blood ammonia with hepatic coma Retroperitoneal edema Convulsions, ? Neonatal cerebral injury, type undetermined Chronic diphenylhydantoin and barbiturate therapy
Clinical pathological con/erence
1 04 9
REFERENCES 1. Ticker, J. B., and Enselovy, C. D.: Suicidal dilantin (sodium diphenylhydantoin) poisoning, New England J. Med. 245: 723, 1951. 2. Gropper, A. I.: Diphenylhydantoin sensitivity, New England J. Med. 254: 522, t956. 3. Pryles, C. V., Burnett, J. M., and Livingstone, S.. Acute hepatic necrosis with death during phethenylate sodium therapy, J. A. M. A. 148: 535, 1952. 4. Read, A. E., Laidlaw, J., Haslam, R. M., and Sherlock, S.: Neuropsychiatric complications following chlorothiazide therapy in patients with hepatic cirrhosis: possible relation to hypokalemia, Clin. Sc. 18: 409, 1959. 5. Hartroft, W. S., and Hartroft, P. M.: New approaches to the study of cardiovascuIar disease, aldosterone, renin, hypertension, and juxtaglomerular cells, Fed. Proe. 20: 845, 1961.
PATHOLOGICAL
CONFERENCE
THE
CHILDREN'S
BOSTON,
HOSPITAL
MEDICAL
CENTER,
MASS.
Sidney Farber, M. D., Editor Gordon F. Vawter, M.D., Assistant Editor
at bedtime (Phelantin capsule contains diphenylhydantoin 100 mg., phenobarbital 30 mg., and methamphetamine hydrochloride 2.5 rag.). The patient had been followed in the Outpatient Department because of seizures and mental retardation but was otherwise well until approximately one week prior to admission. At this time she had vomiting for 2 days, followed by several loose bowel movements, but had no other specific complaints. She was observed in the Medical Emergency Clinic where icterus was noted. The liver edge was not palpable. A test for biliuria was positive. She was sent home to follow a regimen of bed rest and g a m m a globulin was given to the rest of the family. She returned 4 days later since vomiting had increased and was admitted to the hospital. On examination the temperature was 98 ~ F., pulse 92 per minute, respiratio.ns 20 per minute, and blood pressure 120/80 m m Hg. She was a thin girl, deeply jaundiced, but seemed to be in no acute distress. T h e tongue was somewhat coated. Chest and heart were normal. The liver edge was not palpable and the spleen was not felt. Neuro-
T i-x i s was the fourth Children's Hospital Medical Center admission of this 14-year-old girl. Her chief complaint was jaundice and vomiting. H e r first adlnission began at 2 days of age when, after a difficult delivery which was considerably post-mature by date and was associated with yellow vernix and partial separation of placenta, she had generalized twitching (which improved later) and a poor color. L u m b a r and subdural punctures, skull x-rays, and cultures were normal. She has been followed in the Outpatient Department since that time, with two admissions for dental extractions and tonsillectomy. Her development was slow and she was evaluated in the Seizure Clinic at 4 years of age because of a history of seizures with fever. At 10 years of age she began having seizures without fever. She had been treated with diphenylhydantoin, 100 mg. twice a day since 6 years of age and had also received phenobarbital, mephobarbital, or primidone from 13 years of age. Until the present illness she had been receiving Phelantin, 1 tablet in the morning, mephobarbital 32 mg. at noon and bedtime, and diphenylhydantoin 50 mg. 1041
104 2
Clinical pathological con[erence
logic examination revealed normal tendon reflexes without ataxia. Initial complete blood count revealed: hematocrit 49 per cent; hemoglobin 14 Gm. per cent; white blood cells 5,200 per cubic millimeter with 50 per cent polymorphonuclear leukocytes, 3 per cent bands, 30 per cent lymphocytes, 4 per cent atypical lymphocytes, and 13 per cent monocytes. Platelets were adequate on smear. Urinalysis was reported as follows: p H 6.5; specific gravity 1.022; no albumin or sugar; positive for bile; 5 to 10 white blood cells per high-power field of spun sediment. Subsequent urinalyses showed normal sediment and an occasional trace of albumin. Blood contained: total protein, 5.6 Gm. per cent; albumin 3.3 Gm. per cent; and globulins--alpha-l, 0.28 Gm. per cent; alpha-2, 0.39 Gm. per cent; beta, 0.56 Gm. per cent; gamma, 1.07 Gin. per cent. Serum glutamic oxalic transaminase was 950 units; serum glutamic pyruvic transminase, 245 units. Alkaline phosphatase was 12 units; cholinesterase, 24 units; bilirubin, 23 mg. per cent direct, 34 rag. per cent total. Thymol turbidity, 1-plus, thymol flocculation, 1-plus; cephalin flocculation, 1-plus; prothrombin time (on admission), 12 per cent; one day later, 1 per cent. On the third hospital day the prothrombin time was 17 per cent (after vitamin K). A lupus erythematosis cell preparation (L. E. cell) was negative. Results of other chemical examinations were as follows: on admission, blood urea nitrogen, 11 mg. per cent; on second day, blood sugar 68 mg. per cent; p H 7.4 and plasma carbon dioxide 27 mEq. per liter; sodium 128 mEq. per liter; potassium 5.9 mEq. per liter; and chloride, 91 mEq. per liter. On the third day, p H was 7.43; plasma carbon dioxide 36 mEq. per liter; sodium 145 mEq. per liter; potassium 2.2 mEq. per liter; chloride 88 mEq. per liter. On the fourth day, serum sodium was 144 mEq. per liter; potassium 2 mEq. per liter. On the sixth day, blood sugar was 157 rag. per cent; p H 7.4; carbon dioxide 36 mEq. per liter; serum sodium 155 mEq. per liter; potassium 2.9 mEq. per liter; and chloride 100 mEq.
November 1963
per liter. Urine potassium was 34 mEq. per liter and sodium was 23 mEq. per liter. Intravenous fluids were started on the evening of admission. Anticonvulsants were continued at first. On the day after admission the patient pulled out the intravenous tube and took fluids by mouth without vomiting. On the next day she became irrational and began to thrash about and scream. H e r pupils seemed dilated and reacted poorly. There was redness of the palms of her hands and the pulse became rapid and somewhat weak. She was started on neomycin, enemas, and intravenous feedings of 10 per cent dextrose and water and fresh plasma. Vitamin B complex, vitamin K oxide, and hydrocortisone were given intravenously (hydrocortisone in a dose of 100 mg. every 6 hours). Anticonvulsants were stopped. At this time a blood ammonia was 150 mcg. per cent (normal: 50). On the third hospital day the patient seemed decerebrate and became comatose. The pupils became dilated and fixed. In spite of added postassium, 300 mEq. intravenously, and potassium chloride, 1350 mg. per gavage in four days, the serum potassium remained low. By the fourth hospital day she was receiving 25 per cent dextrose and water. On the seventh hospital day, she became less rigid and showed more flaccidity of her limbs, and on the next day she suddenly stopped breathing and could not be resuscitated. Urinary output for the last 3 days was 1,645 c.c., 1,750 c.c., and 1,130 c.c., respectively. DR.
SIDNEY
FARBER.
We
are
delighted
to
welcome back an old friend, Dr. Klein. DR. ROBERT KLEIN."~ It is indeed a pleasure to be here, even when faced with today's problem. We are presented with a young lady who begins and ends her life with problems relating to jaundice and the central nervous system. I *Dr. Robert Klein is Professor of Pediatrics at Boston University School of Medicine, and Senior Visiting Physician at the Boston City Hospital.
Volume 63 Number 5
Clinical pathological con/erencu
have finally concluded that it is futile to attempt to link these two widely separated clinical events, having discarded such infections as toxoplasmosis, cytomegalic inclusion disease, and histoplasmosis. I also set aside such metabolic and enzymatic problems as deficiencies in glucuronide synthesis, Wilson's disease, and so on, and conclude that, if the difficulties of the beginning and end of her life are directly related, the nature of the process is new to me. However, we cannot escape the probability that we begin with a background of brain damage, only indirectly related, if at all, to her death. The final picture is one of acute yellow atrophy of the liver or, if you prefer, acute necrosis of the liver with hepatic coma and death. All of the laboratory findings corroborate this view, including the enzyme patterns, the blood urea nitrogen, the electrolytes, the blood ammonia, and so on. That the flocculation tests are not positive suggests a very acute process, with too little time for development of alterations in these parameters. In view of these values, the serum protein levels, including normal globulins and the negative lupus erythema-
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tosis cell preparation, we may exclude so-called plasma cell or lupoid hepatitis, a subacute or chronic illness of young women, predominantly. Wilson's disease usually has a more insidious onset, but may present initially as hepatic disease. While cytomegalic inclusion viruses have been recovered from patients with liver disease in this age group, the hepatic lesion has been chronic and rather silent clinically in the cases thus far described. Although I cannot completely exclude such leptospiral diseases as Weil's disease, or canicola fever, there is no strong evidence in favor of these diagnoses. While the course is consistent with toxic hepatic injury, such as may follow carbon tetrachloride ingestion, we have no history of such exposures. Moreover, viral hepatitis may behave in just this way, and I think that it was right to offer gamma globulin to her family with such a possibility in mind. However, it might be possible that this hepatic disease could be related to therapy with diphenylhydantoin. There are some points against this, since no other symptoms of diphenylhydantoin toxicity, such as ataxia, hirsu-
Fig. 1. Liver. There has been total destruction of almost an entire hepatic lobule in the center of the field; only dilated sinusoids and swollen interstitial components remain. There is a mild inflammatory cell response. Below, and to the right, are distorted and interrupted hepatic cell cords with black intracanalicular plugs of bile. (Hematoxylin and eosin stain. Original magnification •
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tism, gingival hypertrophy, lymphadenopathy, rash, or exfoliative dermatitis, are noted. Too, eosinophilia, not seen here, has been a constant finding with diphenylhydantoin toxicity. Moreover, she had received diphenylhydantoin for 10 years without previous difficulty, but one recalls that hepatotoxicity has been reported with cinchophen after an exposure of 4 to 5 years. However, the length of exposure to diphenylhydantoin or its analogues, such as 5-phenyl-5thionyl hydantoinate, reported before hepatic symptoms occurred, is between 2 months and 2 years. 1-a A report in the Swiss literature indicates that, rarely, the L.E. cell preparations may be positive with diphenylhydantoin therapy, but this must be as rare as the polyarteritis which has been attributed to diphenylhydantoin, too. In the final analysis, I cannot choose critically between the possibilities of viral hepatitis and diphenylhydantoin toxicity and am content to know that the central problems are those of acute hepatic necrosis, which presents difficulties in management, even though I feel the situation here had progressed beyond medical remedies. Before turning to a discussion of the hypopotassemia noted in this patient, we would just
November 1963
note that she was, in many ways, given tile standard treatment for hepatic coma (hepatic failure) including neomycin (to decrease forma-. tion of ammonia by intestinal bacteria), vitamin B complex, vitamin K oxide, and glucose. The desperate straits of her clinical condition may justify the use of hydrocortisone, but as we shall see, this may actually have been an unfortunate move. Finally, we are told that anticonvulsant therapy was continued for a time. I am not worried about the continued use of diphenylhydantoin in this situation so much as with the possibility that this therapy included barbiturates which she had received before. The handicap that barbiturates present to a damaged liver is already too well known. While the group at the Mayo Clinic has described hyperkalemia as a complication of hepatic disease, I think that hypokalemia, as developed in this girl, is a more common complication of severe hepatic disease. I would guess that the derangements associated with this might actually have hastened her death. One reason for the seriousness of hypokalemia is that a relative alkalosis often coexists. While the initial studies in this girl include a serum p H of 7.4, the electrolyte and C O 2 values at the same time
Fig. 2. Liver. A higher power view from the lower right hand corner of Fig. 1 to show the distorted liver cells, the stromal and inflammatory cell response, and bile in canaliculi. (Hematoxylin and eosin stain. Original magnification x150.)
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indicate a relative alkalosis as may occur with hepatic disease. The danger of alkalosis lies in the fact that this leads to increased production of ammonia and that such ammonia is more likely to be in gaseous form which more readily penetrates to the brain. This, in turn, stimulates the respiratory center to produce a respiratory alkalosis--a vicious cycle. These events have
Fig. 3. Spleen. There are large, dark lymphocytoid cells and larger cells with distinct cytoplasm, possibly "proplasma cells." (Hematoxylin and eosin stain. Original magnification x150.)
Fig. 4. Adrenal. Beneath the broad fibrous capsule (right) lies an unusually prominent outer zone of pyknotic cortical cells, possibly related to aldosterone-secreting cells. (Hematoxylin and eosin stain. Original magnification x125.)
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been shown experimentally; when patients with hepatic disease were given a low potassium diet, or potassium was removed by resins, serious hypokalemia, rising ammonia in the blood, and onset of coma with further slowing of electroencephalographic patterns all indicated a serious progression of their disease until potassium was replaced. * The diuretic action of chlorothiazide
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November 1963
Fig. 5. Kidney. There are occasional black bile casts. ProximaI convoluted tubule cells show pale apical vacuoles. (Hematoxylln and eosin stain. Original magnification x250.)
also is associated with this problem, presumably by leaching out potassium. As described here, the .amounts of potassium given this girl were picayune since it has been shown that adults in this situation will require as much as 250 mEq. of potassium intravenously every day for 4 days in addition to an orat intake of better than 30 mEq. per liter.4 In this child, then, the hypopotassemia may be the combined result of liver disease, alkalosis, ammonia intoxication, prior potassium loss by vomiting (assuming a weight of 50 kilograms, she might have had a deficit of 400 mEq. of potassium from this factor alone before she was admitted), low potassium intake, and dilution by the overhydration seen in hepatic disease. The retention of water that such patients evidence seems out of proportion and presumably is associated with inappropriate secretion of antidiuretic hormone and an increase in circulating aldosterone resulting from adrenal oversecretion and perhaps decreased metabolism by the liver. Under these circumstances, more sodium is reabsorbed, being exchanged for potassium in the kidney tubule. These factors operate in any hepatic disease. This girl was given hydrocortisone and large amounts of glucose, both of which might also contribute to hypopotassemia. Perhaps desoxyphedrine would also have tbis effect, since we do know that epinephrine and amphetamine do so. Interestingly enough, diphenylhydantoin in acute experiments shifts potassium into and sodium out of the cell, but whether this is true of chronic administration, I do not know.
We are not told how much chloride was given to this child, but with low sodium and inadequate chloride replacement, alkalosis is perpetuated even if potassium is given, although replacement of potassium is the more important of the two. One must also consider whether the patient has specific renal lesions, such as the gtomerular abnormality of cirrhosis and the lesion of Well's disease, but there is no particular reason to suspect these. I will conclude by saying, once again, that this girl probably had acute yellow atrophy, possibly related to therapy with diphenylhydantoin, and that I think alkalosis and hypokalemia were critical in her rapid progression, but that the ultimate prognosis of her hepatic lesion was that of inevitable progression to death. DR, CHARLES A. JANEWAY. I think that this child was given 300 mEq. of potassium intravenously per day, not as a total dose. Even this dose, which is the largest we have ever given here, may have been an insufficient amount. The development of flaccidity and respiratory paralysis clearly points to serious clinical hypopotassemia. However, I think, too, that the basic hepatic lesion was essentially irrecoverable. It is of interest that we relatively rarely see children dying in an acute attack of hepatic disease. Whether the injury was caused by diphenylhydantoin, or by hepatitis, I am not sure we will ever know, but we were, at the time, in an epidemic phase of the 7 to 8 year cycle of viral hepatitis. In such epidemics we see one or two
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cases of acute yellow atrophy but in general the mortality in children is really quite low, perhaps the lowest among all ages, and certainly unlike that seen particularly in women over 40. This fact alone leads to some interesting speculations as to metabolic interrelations. On the other hand, acute yellow atrophy has been a not too uncommon complication of acute toxic injury. DR. GORDON F. VAWTER. Perhaps we should recall that this girl was 14 years old. Of course, our autopsy series of this sort of hepatic problem is too small for firm statements, but it is interesting that most of these situations have developed in children of prepubertal or pubertal age. DR. JOHN F. CRIGLER. I wonder if Dr. Klein would comment on the use of spirolactones as antagonists of aldosterone, in such a situation. DR. KLEIN. Several people have suggested the possible usefulness of such therapy since with spirolactones there is both decreased loss of potassium and increased excretion of sodium. Apparently, there is some benefit in such therapy in chronic hepatic disease, but I have no good information on whether it is any help in an acute situation, such as is presented today. Certainly, the few patients I have seen die with such an acute process as this have had viral hepatitis or the so-called lupoid or plasma cell hepatitis. A PI-IYSICIAN. Should the possibility of infectious mononucleosis be considered here? DR. KLEIN. I don't honestly know. M y impression is that hepatic involvement in infectious mononucleosis is usually much milder than the process seen in this girl. I suspect that in many patients w h o are said to have infectious mononucleosis with hepatic involvement the involvement of the liver is suggested, largely because there are changes in serum globulins with resultant abnormal flocculation tests. DR. SAMUEL L. KATZ. This question will obviously be difficult to answer until we have more precise diagnostic techniques, such as viral isolation in infectious mononucleosis and in viral hepatitis. Dr. Gellis and I followed a young man, in whom diagnoses of infectious mononucleosis with lymphadenopathy and positive heterophil reactions were made. This patient subsequently developed cirrhosis and died. This was the only patient with this type of sequence that Dr. Gellis had observed up to that time. I am intrigued by Dr. Klein's attempt to link
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the neonatal illness with the final picture, and would just like to reiterate that Dr. Hanshaw has isolated cytomegalic virus from the urine and livers of older children with chronic hepatic disease. As yet, however, I do not think we know whether there are etiologic implications with regards to the hepatic disease, whether this is an instance of a fellow traveler or just exactly what the implications are, Could such a virus be activated from a latent phase by a special set of circumstances? We just do not know as yet. DR. FARBER. Dr. Fred Allen had the opportunity, a number of years ago, to study the pathology of infectious mononucleosis in aviators who died accidentally. Whereas there were widespread infiltrates in myocardium, kidneys, pancreas, liver, and so on, there were no lesions in these early or subclinical cases resembling acute yellow atrophy of the liver. Do we h a v e other diagnoses? T H I R D YEAR MEDICAL S T U D E N T . W e concluded that this girl had hepatic failure superimposed upon chronic disease, secondary to diphenylhydantoin therapy. FOURTH YEAR MEDICAL S T U D E N T . Most of us felt that the problem was that of acute viral hepatitis, but some dissenters raised a question of hepatic disease secondary to diphenylhydantoin. DR. VAWTER. In the final analysis, I am not sure that we can, with certainty, resolve the etiologic dilemma, but this is not the result of the fact that an autopsy was limited to a small abdominal incision and removal of small portions of liver, adrenal, kidney, pancreas, and spleen. Postmortem viral studies by Dr. Katz were negative, as were studies for leptospira. There was no ascitic fluid, but there was massive retroperitoneal edema and the subcutaneous tissues were quite moist. The liver was small, high under the costal margin, and presented a reddish minutely knobby surface of grayish, and only occasionally yellowish, small nodules. The external biliary tree was grossly normal. The kidneys and spleen were not obviously greatly enlarged, which probably means that they were not over twice usual volume. Microscopically (Figs. 1 and 2), the hepatic lesion consists of what Dr. Popper refers to as submassive necrosis, which implies sufficient distortion of structure that complete regeneration is probably never achieved. The process consists of necrosis already completed, often accentuated centrally in the lobule, but progressing by enlargement and confluence to produce large areas
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Clinical pathological con[erence
of lobular destruction involving several contiguous lobules. There is no increase in connective tissue and I would suppose that this process could not be much more than 30 days' old, at most. There are bile plugs in canaliculi in groups of liver cells isolated by edema or by necrosis from the drainage systems. Such lesions are not thought typical of the usual acute viral hepatitis. Lymphocytes, mononuclear cells,'and very rare plasma cells occur as a mild, diffuse, and focally moderately dense infiltrate. The residual parenchymal cells show variation in size and have excessive variability in size, shape, and staining characteristics of nuclei. These last indicate that nuclei are reacting to injury and such changes are taken by many hepatologists as evidence for viral hepatitis, but we should remind ourselves that somewhat similar changes are encountered, apparently in relation to the use of antifolic drugs. There are areas of regenerative activity with mitoses in some liver cells. Unfortunately, there is no evidence for the necrosis of single cells, which is one of the hallmarks of viral hepatitis. Evidence of thrombosis, vasculitis, eosinophilia, and fatty change, such as may be found in drug reactions or toxic injury, is not present. However, we should remember that necrosis of this type has been ascribed to drug sensitivity and closely parallels the picture attributed to diphenylhydantoinY, 3 There is lymphoid hyperplasia in the spleen and atypical cells, such as may be found in lymph nodes after diphenylhydantoin therapy, are present. However, similar cellular responses have been associated with viral hepatitis (Fig. 3). The adrenal cortex is possibly thin, with focal eosinophilic degeneration of fascicular cells, but other areas seem functionally competent. The liver is one of the prime sites of metabolism of corticosteroids and there is thought to be a feed-back mechanism between a lack of destruction of steroids by the liver and pituitary function in a variety of hepatic abnormalities. By contrast with the zona fasciculata, the zone glomerulosa is relatively thicker and possibly absolutely increased in width. Cells of this zone have pyknotic nuclei, as if overtaxed (Fig. 4). Most evidence indicates that aldosterone is formed in the adrenal zona glomerulosa, and that such production is much less responsive to pituitary stimulus ( A C T H ) than the hormones of the fasciculata. With numerous exceptions, the width of the glomerulosa parallels the serum sodium level, or perhaps more accurately, the relative retention of sodium.
November 1963
In the kidney there is no major lesion; there are a few bile casts and the glomeruli are normal. The juxtaglomerular cells are hypertrophic but devoid of granules. One might have expected these cells to be filled with granules, a condition which has been correlated with increased renin production by the kidney, with subsequent activation of angiotensin which, in turn, seems to correlate with the prominence of the adrenal zona glomerulosa and with increased secretion of aldosterone. I suspect that these hypertrophic juxtaglomerular cells were indeed filled with granules when the serum sodium was low, as on admission, and that as the serum sodium rose, these granules were lost with persisting hypertrophy of the cells, s The renal tubules do not show lesions of prolonged or end-stage hypopotassemia or sodium and potassium depletion, but rather, large transfers of fluid (and electrolytes) are suggested. Perhaps the advanced typical alterations are somewhat obscured by other changes, such as bile nephrosis, so-called, a lesion often said to be of little functional significance, per se. However, some convoluted tubular cells have apical vacuoles as described in hypokalemia (Fig. 5). In summary, the liver shows severe submassire necrosis, compatible with a healing phase of viral hepatitis, but one recognizes that similar changes have been attributed to diphenylhydantoin. Changes in adrenal glands and kidneys are probably best interpreted as representing a changing flux of metabolic and functional import in the light of the hepatic lesion and the treatment given. DR. RANDOLPtI K. BYI~RS. I have no personal experience with hepatic injury with dilantin but my understanding is that other signs of dilantin toxicity are present. But, both diphenylhydantoin and barbiturates are known to affect hepatic function and if the girl's seizure status permitted, it would have been wise, I think, to stop both medications when symptoms first developed. DR. FARBER. As is our custom, Dr. Klein, you have the concluding word. DR. KLEIN. The fact that she received more potassium than I thought, but without extraordinary urinar~ loss, suggests that her initial depletion by vomiting was a major one. However, the need in problems of hypokalemia is to have some idea of what the intracellular potassium and electrolyte levels are, since there are many paradoxical situations. For example, potassium is beneficially given for digitalis intoxi-
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cation but under numerous circumstances, potassium will aggravate digitalis intoxication. Obviously, other ions are implicated in such situations. Final diagnoses were:
Submassive necrosis o[ liver (? viral ? toxieation)--with-Alkalosis Hypopotassemia, muscle weakness, and respiratory [ailure Increased blood ammonia with hepatic coma Retroperitoneal edema Convulsions, ? Neonatal cerebral injury, type undetermined Chronic diphenylhydantoin and barbiturate therapy
Clinical pathological con/erence
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REFERENCES 1. Ticker, J. B., and Enselovy, C. D.: Suicidal dilantin (sodium diphenylhydantoin) poisoning, New England J. Med. 245: 723, 1951. 2. Gropper, A. I.: Diphenylhydantoin sensitivity, New England J. Med. 254: 522, t956. 3. Pryles, C. V., Burnett, J. M., and Livingstone, S.. Acute hepatic necrosis with death during phethenylate sodium therapy, J. A. M. A. 148: 535, 1952. 4. Read, A. E., Laidlaw, J., Haslam, R. M., and Sherlock, S.: Neuropsychiatric complications following chlorothiazide therapy in patients with hepatic cirrhosis: possible relation to hypokalemia, Clin. Sc. 18: 409, 1959. 5. Hartroft, W. S., and Hartroft, P. M.: New approaches to the study of cardiovascuIar disease, aldosterone, renin, hypertension, and juxtaglomerular cells, Fed. Proe. 20: 845, 1961.