Tetracycline-induced fatty liver in nonpregnant patients

Tetracycline-Induced

Fatty Liver in

Nonpregnant

Patients

A Report of Six Cases ROBERT L. PETERS, M.D.,HUGH A. EDMONDSON, M.D.,WILLIAM P. MIKKELSEN, M.D.,AND DOROTHY TATTER, M.D.,Los Angeles, California

From the Departments of Pathology and Surgery, the University of Southern California and the Los Angeles County Hospital, Los Angeles, California. This work was supported in part by Grant No. AM 5801 of the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Maryland.

tolic murmur along the left sternal border, and tenderness in the right upper quadrant, right flank, and right costovertebral angle. Persistalsis was greatly reduced. Initial laboratory findings consisted of a hemoglobin of 14.4 gm. per cent, white blood cell count of 10,500 per cu. mm., erythrocyte sedimentation rate of 28 mm., serum urea nitrogen (SUN) of 9 mg. per cent, and a serum bicarbonate of 22 mEq./L. The serum potassium was 3.5 and sodium 138 mEq./L. The serum amylase was 4,400 Somogyi units (normal 80 to 150 units). The clinical diagnosis was acute pancreatitis, probably associated with cholelithiasis and choledocholithiasis. Treatment during the first five days consisted of continuous gastric suction, anticholinergic medication, and intravenous fluids to which 500 mg. of tetracycline per liter had been added. Within a few hours of admission the temperature rose to 101O~. and Auctuated between 100 and 102’~. On the fifth day a large tender mass was palpated in the right upper abdominal quadrant. During this interval the serum amylase level declined steadily to 80 Somogyi units. Further laboratory data at this time were as follows: hemoglobin, 12.2 gm. per cent; white blood cell count, 9,600 per CU. mm. ; SUN, 9 mg. per cent; serum sodium, 142 mEq./L., potassium, 3.7 mEq./L., bicarbonate, 2-1 mEq./L. The serum albumin was 3 and serum globulin 3.3 gm. per cent. Exploratory celiotomy was performed on the fifth hospital day with the patient under general anesthesia. Extensive fat necrosis and a 12 by 20 cm. pancreatic pseudocyst were found. The gallbladder contained multiple small calculi. Cholecystostomy, gastrostomy, and sump pancreatic cyst drainage were performed. During the subsequent twenty-four hours 500 mg. of tetracycline, 5 million units of penicillin, and 1 gm. of Chloromycetin@ were added to each of 3

LTHOUGH there have been several recent reports of the hepatotoxic effect of tetracycline when given intravenously to pregnant women [I-4], the deleterious effects of the drug in nonpregnant women have received much less attention, apparently reflecting a lower incidence of toxicity. This report includes six nonpregnant women who died rather unexpectedly after hospitalization for various medical or surgical conditions. A review of the clinical histories revealed that the terminal clinical and laboratory features of the patients were similar and that each had received substantial quantities of intravenous tetracycline. (Table I.)A study of the autopsy material disclosed that the liver had undergone the peculiar foamy type of fatty change that is characteristic of tetracycline toxicity [3].

A

CASE REPORTS CASE I.

A forty-eight year old Mexican woman

was hospitalized in February 1963 because of severe right-sided abdominal pain of four hours’ duration. For the preceding four months she had had intermittent episodes of mild to moderate pain in the epigastrium and right upper quadrant. Five months earlier she had been delivered of a normal infant after an uneventful pregnancy. On physical examination, blood pressure was 130/90 mm. Hg, pulse 64 per minute, and temperature 98’F. Findings were limited to obesity, a sys622

American Journal of Surgery

Tetracycline-Induced L (of the fluids given intravenously. In addition, 500 mK. of Chloromycetin, 1.2 million units of penicillin, and 1 pi. of strcJ)tomycin wrd given intramuscularly each tight hours for the next eight days. During this time the temperature gradually decreased to normal and all antibiotic therally was discontinued. The jieneral condition of the patient imJ)roved steadily. By the tenth postoperative day, oral alimentat ion was tolerated and ambulation begun. At this time the hemoglol)in was JO gm J)er cent, white blood ccl1 count 10.800 J)er cu. mm., serum urea sotlirim 1-U mEq./L., J)otassium 4.4 mEq.;L., and bicarbonate 29 mEq., I,. The patient remained afel,rile and continued to improve slowly until the eighteenth postoJ)erative dav when 3 spiking fever to over 10l”~. abruptly occurred. Despite the fever, the patient had no complaints and the physical examination was unremarkable. The clinical diagnosis was probable subphrenic abscess. Intravenous fluid therapy ~3s reinstituted; 3 or 1 L., to which tetracycline had been ;tdded. were given daily. A

total of 2fi.j gm. of tetracycline was administered intravenously during her hospitalization. ReJ”3ted x-rav and physical examinations failed to identify 3 sJ&ific lesion that could be responsible for the seJ)tic course. ‘l‘herc was a steady tleterioratt
mrtabolic acidosis. On the day of her death, the hemoglobin was I’? gm. J)er cent; white blood cell count 9,200 per cu. mm.; serum amylase 450 Somogyi units; SUN 88 mg. J)er cent; serum sodium 14s mEq.jI,., potassium 6.5 mBq./L., and hicarbonatc X mRq.: L. The blood pII was 9.22; lactate 17 m>Z. and serum pyruvate 1.18 mM./L.; blood gluUSC’ 2!) mg. J)er cent. The total strum bilirubin was 2.7 mg. J)er cent: 3 day earlier the patient had been anictcric. x spiking fcvcr to lo-lO~. persisted from onset on the eighteenth day until death occurred scvcn days later. on the twenty-fiith postoJ)crativc day. At necropsy the Jj3ticnt’s sclerae were icteric. There was liquefied necrotic material in the lesser omental sac and some Lit necrosis was found around a soft pancreas. The 2,”4A pi. liver was yellow-tan, soit, and friable, with some accentuation of the IAular pattern. The mucosal surface of the esophagus was blackened down to the cardia. There was a blue-green discoloration oi the 221 and 210 gm. kidneys. The 1. JtiO gm. brain w3s symmetric, unsoitrned, and unremarkable. On microscopic examination, the liver cells oi the central one third of all the lobules had 3 peculiar, foamy. fatty change in which the most disruptive alteration was about the central veins. In the midzonal areas, where the Icsion was less striking, the fat vacuoles appear-cd on the sinusoid31 side of the liver cell. disJAacing the cytoplasm to the canalicular side

Fatty

623

Ihcr

of the cells. Toward the centrolobular region, the intercelluiar membranes became indistinct, and the hepatic cords were thus converted into syncytial giant cells. Thrre were small canalicular bile plugs and the centrolobular Kupffer cells contained cellular deljris. IIcspitc signs of snme cellular death, there was no exudate.

cellular

necrosis.

or portal

reaction.

There was no renal tubular necrosis but thcrc was slight fatty change in occasional eJ)ithclial cell>. Scattered isoleucinc-like tubular J$ynented crvstals were Jlrcsent. Acute pancreatitis, acute ulceration of the esoJ)hagus. and a hemorrhagic cystitis were evident. The lungs were edematous, with occasional microscopic emboli. The intrinsic cerebral vessels contained rare intraluminal fat droplets, but there were no neuron31 changes.

Comment: This patient was apparently rccovering from surgery for a pseudocyst of the pancreas. She had received 1.5 Km. per day of intravenously administered tetracycline for five successive days. Antibiotics were then discontinued for ten days, but she had a recurrence of fever and abdominal pain and rcceived nearly 20 additional gm. of tetracycline intravenously on seven successive days. During this time her condition became worse and marked lactic acidosis developed. CASE II. i\ iortysix year Caucasian woman (E. Y. S.) was hospitalized on February 28, I!860 because of cramping, generalized abdominal J)ain 3ssociatcd

with vomiting

and obstipation

for six davs.

She had undergone appendectomy at seven years.of age, followed by an irreducible mass in the area oi the incision. Hysterectomy had been J)crformed 3t thirty-nine years of age. On JAysicaJ examination, blood Jn-essurc was 1% 70 mm. IJg. pulse X0 per minute, and temJ~erdture WI:. The abdomen was obese and not tender. A JO hy 10 cm, irrrducible, nontender hernial mass 1~3s JJalpahle in the right lower abdominal quadrant. Peristalsis was hyJ)oactive. with rushes nnd high pitched sounds. The laborntory lindings were as follows: hemoglobin, IS..> gm. J)er cent: white blood cell count. I I .?(OO J)cr cu. mm. ; serum glucose, 8” tng. per cent: sl!S. 21 mg. per cent; bicarbonate 24 mKq.;‘I,. and pot35sium 4 rnJ
Peters et al. TABLE CLINICAL FEATURES OF PATIENTS WITH

Case No.

I

II III

Age (yr.), Race, and Sex

48, Mex, F 46, C, F 62, C, F

I”

44, N, F

”

18, N, F

“I

25, N, F

. . . Admlttmg Diagnosis

Acute pancreatitis and pseudocyst Incarcerated intestinal hernia Carcinoma of ovary and perforation of bladder Hypertension and diabetes mellitus Chills, fever, and abdominal pain Pancreatitis

Tetracycline (gm.,day)

Route

2

IntrfVJenCltls

2

IlltraVeXlOUS Intravenous and intramuscular

l-3

Duration of Therapy (days)

Total Tetracycline

5 2 7

26.5

8

16.0

9

Lethargy Icterus

0

temesis or Other HemOrrhage

+

+

+

+

+

27

+

0

+

1 1

oral Intravenous

10 13

15

+

+

+

3 3

Intravenous Intravenous

3 6

9 18

0 +

+ 0

+ +

venously. Immediately before surgery, the SUN was 21 mg. per cent; bicarbonate 24 mEq./L. and potassium 3.2 mEq./L.; serum amylase 160 Somogyi units. At operation, with the patient under general anesthesia (CIHBand pentothal), a 5 inch segment of gangrenous small bowel that was entrapped in the hernia was resected. Postoperatively the patient remained febrile, the temperature ranging from 99 to 102’F. Jaundice and decreased urine output occurred on the first postoperative day. A program for the management of acute renal tubular necrosis was instituted and urine volumes increased steadily to over 2,000 ml. per twenty-four hours by the sixth postoperative day. The SUN reached a high of 108 mg. per cent on the fifth day, after which it began to fall. The serum potassium levels never exceeded 4.5 mEq./L. The serum bicarbonate, which was determined daily, remained within normal limits until the sixth day when it was recorded at 17 mEq./L. ; it reached a low of 12 mEq./L. on the next day. Arterial pH was 7.50 on the third and 7.38 on the fifth postoperative day; on the seventh day it was 7.20. Serum lactate levels were not determined. Intensive supportive management failed to prevent coma, and death occurred on the eighth postoperative day. Death was thought to be due primarily to metabolic acidosis. The initial serum bilirubin level of 6 mg. per cent on the first postoperative day remained unchanged until the patient’s death. The alkaline phosphatase level was within normal limits as were the serum albumin and globulin levels. Prothrombin activity remained normal until just before death when it was recorded as 40 per cent. Serum glutamic oxalacetic transaminase (SGOT) remained within normal limits until the seventh postoperative day when it was 325 units. The serum sodium level was normal, and serum chloride level remained normal until the last day when it became elevated to 110 mEq./L.

Between 2 and 3 gm. of tetracycline and 2 and 3 gm. of chloramphenicol were given daily by the intravenous route during the entire postoperative course. A total of 16 gm. of tetracycline was administered. Intramuscular administration of streptomycin and penicillin was also continued throughout the postoperative course. At necropsy the body was icteric; there was moderate intramuscular extravasation of blood at the surgical incision sites. The enteroenterostomy site was intact, but there was a serosal fibrinous exudate. The 1,820 gm. liver had a bulging yellowish parenchyma, and although there was a large gallstone in the gallbladder, the biliary tree was otherwise unremarkable. The pancreas, brain, and kidneys were unremarkable, and there were no gastrointestinal ulcerations. Histologic examination of the liver revealed a foamy, fatty vacuolization of the centrolobular one half of the parenchymal cells, similar to that in case I. The cellular membranes were less distinct in the centrolobular regions of the liver. There were occasional intracanalicular bile plugs and some of the Kupffer cells contained pigmented cellular debris. The renal tubules were swollen, but otherwise the kidneys, pancreas, gastrointestinal tract, and other organs were not remarkable.

Comment: Large amounts of tetracycline were administered to the patient after the development of an infarction in a segment of bowel. She may well have had reduced renal or hepatic plasma flow in the early period since she subsequently became oliguric. Five days after surgery,‘metabolic acidosis developed. Jaundice may have been present but undetected on the first day of hospitalization. CASE III.

A sixty-two year old Caucasian woman American

Journal

of Surgery

*

Tetracycline-Induced

625

Fatty Liver

I TETRACYCLINE-INDUCED

Urea

Nitrogen

--_(mg. Admission

%)-Final

9

88

31

100

10

195

33

198

. 9

FATTY

LIVER

Amylase -(Somogyi units)Admission Final

4,400

222

450

80

80 . ..

80

174

35

300

. ..

830 1,850

Bilirubin -_(mg. %IAdmission Final

co2 -_(mEq./L.)Admission

I967

Protbrombin ---Time---. Final Admission

SGOT ----(units)---. Admission

Final

...

2.7

22

8

6

5.9

24

12

...

...

22

27

34

118

. ..

. . .

28

12

60

52

. ..

7.4

. . .

27

._.

. . .

2.9

17

12

.. .

was hospitalized on October 6, 1960 for the evaluation and management of a large pelvic mass. Two years earlier, surgery had been performed for an ovarian tumor. On physical examination, blood pressure was 112/76 mm. Hg and there was diffuse lower abdominal tenderness. A large cystlike pelvic mass was palpable, and a friable, bleeding exophytic lesion was visualized at the apex of the vagina. Hemoglobin was 13.9 gm. per cent and white blood count was 7,800 per cu. mm. Serum albumin was 3.4 and globulin 3.4 gm. per cent, SUN 10 mg. per cent, bicarbonate 22 and potassium 4.2 mEq./L. The alkaline phosphatase and thymol turbidity were within normal limits. The preoperative diagnosis of recurrent pseudomutinous papillary cystadenocarcinoma of the ovary was confirmed at surgery performed with the patient under general anesthesia. The sigmoid colon and urinary bladder were adherent to the mass and both structures were entered during an unsuccessful effort to extirpate the lesion. Postoperatively 1 gm. of tetracycline was added to each of 3 L. of intravenous fluids daily. A total of 27 gm. of tetracycline was administered during the nine postoperative days before death occurred. On the sixth postoperative day, hemoglobin was 12 gm. per cent; SUN, 156 mg. per cent; bicarbonate 27 and potassium 4.5 mEq./L.; prothrombin, 20 per cent; serum amylase, normal; SGOT, 118 units. On the day before death, the SUN was 195 mg. per cent, potassium 5.4 mEq./L., and prothrombin 34 per cent. Additional tests of liver function were not performed. Death was thought to be due to sepsis, upper gastrointestinal bleeding, azotemia, and shock. At necropsy, a multilocular cystic mass filled the pelvis and involved the urinary bladder, rectosigrnoid colon, and vagina. The stomach contained multiple shallow ulcers and was filled with blood; the esophagus was eroded. The liver was enlarged, yellow, and Vol. 11.7. May

Final

Lactate (mM’L.)

17

NOrmill

40

56

20

.

.. .

325

960 34

210

greasy, and weighed 1,900 gm The kidneys, pancreas, and brain were not remarkable. Microscopically, there was a foamy syncytial cell change in the liver cells similar to that in cases I and II. Although the entirety of each lobule was involved, the changes in the central areas were the most striking. (Fig. 1.) ,4 focal ischemic type of necrosis of renal tubules was found as well as erosive esophagitis. The pancreas and brain were not remarkable. The pelvic tumor was a well differentiated mutinous adenocarcinoma.

Comment: This patient was seriously ill throughout her hospitalization, too ill for a “turn for the worse” to be recognized. The urinary flow was impaired by neoplastic ureteral obstruction. The absence of jaundice suggests that the fatty liver was not a major factor in death. CASE IV. -4 forty-four year old Negro woman (D. M. W.) was hospitalized on August 10, 1960 for investigation of headaches of four months’ duration. Associated symptoms consisted of polydipsia, fatigue, epistaxis, dizzy spells with occasional syncope, and a 30 pound weight loss. On physical examination, blood pressure was 270,’ 160 mm. Hg and pulse rate 120. There was a precordial systolic bruit heard best over the aortic area. The liver was questionably enlarged but not tender. Laboratory examination disclosed a hemoglobin of 13.5 gm. per cent and a white blood cell count of 11,300 per cu. mm. Urinalysis revealed albuminuria and pyuria. Urine culture resulted in the growth of Escherichia coli and a beta hemolytic streptococcus. Fasting blood sugar was 123 mg. per cent and the two hour postprandial value was 130 mg. per cent. SUN was 33 mg. per cent; serum bicarbonate was 28 and potassium 2.7 mEq./L. Two determinations of

626

Peters et al.

FIG. 1. CASE III. Foamy fatty change of centrolobular liver cells. Original magnification X 350; hematoxylin and eosin stain. FIG. 2. CASE IV. Low power photomicrograph showing progressive vacuolization from portal areas in center of photograph toward central region at top. Original magnification X 75; hematoxylin and eosin stain.

FIG. 3. CASE IV. Centrolobular region of liver showing syncytial formation of hepatic cords. Original magnification X 250; hematoxylin and eosin stain.

the urinary catecholamines were within normal limits. Serologic tests for syphilis gave positive results. Initial diagnoses were hypertensive cardiovascular disease, diabetes mellitus, and syphilis. Initial treatment consisted of 1 gm. of tetracycline and 4 gm. of Gantrisin@ per day, both given orally. Penicillin was administered intramuscularly. These were continued for ten days and the patient then left the hospital against medical advice before the evaluations were completed. Two days later the patient was rehospitalized because of vomiting. Blood pressure was then 195/110 mm. Hg. There was a grade III ocular retinopathy and the liver was now definitely enlarged to 4 cm. below the costal margin and was slightly tender. Laboratory examination showed the hemoglobin to be 11.3 gm. per cent and the white blood cell count to be 13,400 per cu. mm. Urinalysis indicated persistence of the albuminuria and pyuria. Blood sugar was 91 mg. per cent; SUN, 216 mg. per cent; bicarbonate 14, sodium 117, potassium 4.5, and calcium 4.9 mEq./L. The serum albumin was 3.4 and globulin 2.5 gm. per cent. An electrocardiogram showed sinus bradycardia and prolongation of the QT interval. A barium study of the upper gastro-

intestinal tract and a retrograde study of the urinary tract gave normal results, A Regitine@ test also gave normal results. Four days after admission the SUN had risen to 273 mg. per cent and the potassium to 5.2 mEq./L.; the bicarbonate was 17 mEq./L. Urine volume was low. Peritoneal dialysis was performed, with reduction of the SUN to 111 mg. per cent and the potassium to 3.5 mEq./L. The urinary output remained low, and by the eleventh hospital day the SUN had again risen to 225 mg. per cent. Concomitantly, the bicarbonate was 11, sodium 124, and potassium 3.7 mEq./L. Hemoglobin was 6 gm. per cent. Peritoneal dialysis was again performed, with reduction of the SUN to 70 mg. per cent; the bicarbonate was then 16, sodium 146, and potassium 3.6 mEq./L. Dialysis was required a third time on the sixteenth hospital day. Once again it was successful in reducing the again elevated serum urea nitrogen, but did not avert death which occurred nineteen days after the patient’s admission to the hospital. The final laboratory data on the day of death were as follows: SUN, 198 mg. per cent; potassium 6.1, sodium 148, bicarbonate 12, and chloride 114 mEq./L.; serum calcium, 7.7 mg. per cent; blood American Journal

of Surgery

Tetracycline-Induced sugar, 60 mg. per cent; serum albumin 2 and globulin 2.4 gm. per cent; prothrombin activity, 60 per cent; SGOT, 52 units. Throughout the hospital course the patient remained afebrile, with intermittent delirium, semicoma, and coma. Because of the persistent pyuria, 1 gm. daily of tetracycline was administered intravenously from the sixth day of hospitalization until death, for a total of thirteen days. Additional medications included Ritalin, reserpine, Compazine@, testosterone propionate, and phenobarbital, which were given intermittently. .4t necropsy the body was faintly icteric. The 1,520 gm. liver was pale orange, with a soft, greasy, bulging parenchyma. Each kidney weighed 120 gm. and had flea-bitten surfaces and thinned cortices. The heart weighed 450 gm. and had dilated chambcrs. There was esophageal mucosal erosion, a healed pyloric ulcer, and three irregularly shaped, shallow, serpiginous duodenal ulcers. There was an 0.1 cm. subserosal tumor in the ileum. The brain was edematous. Microscopically, the centrolobular liver parenchyma1 cells were foamy and fatty (Fig. 2 and 3) ; there were scattered bile plugs as well as Kupffer cells filled with pigmented debris. The kidneys had advanced arteriolar nephrosclerosis; there was no renal tubular fat. In the pancreas small inspissated proteinaceous secretions were present, but no inflammation or necrosis. The parathyroid glands were hyperplastic. The small nodule described grossly in the ileum was a carcinoid tumor.

Comment: This patient had severe hypertensive disease with marked nephrosclerosis. Although she was not initially azotemic, she had severe renovascular disease. Renal failure associated with tetracycline givenintravenously may have been sufficient to produce an unusually high level of the drug. CASE V. An eighteen year old Negro woman (C. C. B.) was hospitalized on January 26, 1961 because of abdominal pain followed by emesis, chills, and fever during the preceding two days. A yellowish vaginal discharge had been present for one month. During the previous week the patient had increased her alcoholic consumption, and there had been an increase in urinary volume and frequency. On physical examination, temperature was 104.Y F.,pulse 120, and blood pressure 100/54 mm. Hg. There was diffuse guarding and tenderness throughout the abdomen and peristalsis was notheard. Pelvic examination disclosed uterine and adnexal tenderness without a detectable mass. Initial laboratory data included a hemoglobin of 12 gm. per cent, a white blood cell count of 35,350 per cu. mm., with 91 per cent polymorphonuclear forms, of which 3% were juvenile, and an essentially normal

Fatty Liver

627

urinalysis. Serologic tests for syphilis gave negative results. The initial diagnostic impression was peritonitis secondary to acute salpingitis. Intravenous fluids that included 9 gm. of tetracycline were given during the first three days of hospitalization. Tetracvcline was not continued thereafter, but massive intravenous doses of chloramphenicol and penicillin, which had been started on the second day, were continued until death on the eighth day after hospital admission. After the first two days of hospitalization, the temperature became essentially normal and the abdominal complaints decreased steadily until by the third day oral feedings were started. Shortly thereafter, emesis followed by mild hematemesis occurred and this presented intermittently throughout the hospital course. Fever also recurred. The liver was slightly enlarged and tender from the third day until death, but there were no other abdominal findings. On the third day the SUN was 55 mg. per cent and remained at that level despite intensive fluid repletion, which produced urinary volumes up to 5,000 ml. daily. Terminally, however, it rose to 80 mg. per cent. The serum bicarbonate, potassium, and chloride levels were within normal limits. Serum amylase, initially 17-l Somogyi units, from the third day rose steadily to 830 units. Blood sugar levels fluctuated markedly between 56 and 490 mg. per cent; the urine remained free of reducing substances. The prothrombin activity was 32 per cent on the third day and thereafter fell to 20 per cent despite parenteral administration of vitamin K. On the fifth day of hospitalization, slight jaundice developed, with a serum bilirubin of 2.3 mg. per cent; bilirubin levels rose to i.4 mg. per cent on the day before death. Serum albumin and globulin concentrations, thymol turbidity, and alkaline phosphatase activity remained normal. The SGOT concentration was 290 units on the fifth day and 9GOunits on the seventh day. On the day before death, bromsulfalein retention was 8:! per cent (5 mg./kg.) in thirty minutes, leucine aminopeptidase 376 units, protein bound iodine 7.2 pg. per cent, serum calcium 6.9 per cent, and serum cholesterol 114 mg. per cent. Death on the eighth hospital day was associated with convulsive seizures and hypotension. At necropsy the liver weighed 1,390 gm. ; it was yellow, soft, and discolored by subcapsular hemorrhages There were a few scattered yellow necrotic foci in the pancreas measuring 0.1 to 0.2 cm. in diameter. ‘The kidneys were not remarkable; there was a bluish discoloration of the uterus, tubes, and ovaries. There were no gastrointestinal ulcers; the brain, heart, lungs, and other organs were not. remarkable. Microscopically, the liver parenchymal cells were foamy, particularly in the centrolobular regions; the

Peters et al. syncytial change of parenchymal cells described in the previous patients was also a feature. Scattered bile plugs and some pigment in Kupffer cells were noted. There was no exudative reaction. The kidney tubules contained bile-stained protein and there was slight degenerative change of some of the tubules. Other organs were not remarkable. Viral studies on postmortem material included inoculation into chick embryos and into juvenile and adult mice and tissue cultures. No viral agents were isolated from any of the postmortem material, Comment: Upon admission to the hospital, this Negro woman presumably had acute salpingitis and possibly peritonitis although evidence of this at autopsy was minimal. The clinical pattern quickly changed from that of pelvic inflammatory abscess to acute liver failure. Tetracycline was given in very large amounts initially and then discontinued. Despite discontinuation of tetracycline therapy, the patient’s condition became worse and she died in a fashion similar to the other patients. CASE VI. A twenty-five year old Negro woman (F. S.) was hospitalized on September 12, 1963 because of severe upper abdominal pain of six hours’ duration. Similar abdominal pain had occurred occasionally during the preceding four years; during the month prior to the present admission she had been hospitalized for one week with similar complaints believed to represent pancreatitis. On physical examination, temperature was 99’F., pulse 76, and blood pressure 116/72 mm. Hg. There was exquisite tenderness in the upper part of the abdomen associated with guarding. Hemoglobin was 11.7 gm. per cent, white blood cell count was 5,500 per cu. mm., and urinalysis was within normal limits. Serum amylase level was 300 Somogyi units (normal 80 to 150 units), urinary diastase 3,900 units (normal up to 600 units), and blood sugar 94 mg. per cent. The SUN was 9 mg. per cent; serum bicarbonate was 17, potassium 3.6, and sodium 143 mEq./L. The serum albumin was 4.1 and globulin 2.8 gm. per cent. The clinical diagnosis was recurrent pancreatitis, and the usual treatment regimen, including 3 to 4 L. of intravenously administered fluids daily, was instituted. From the seventh to the thirteenth hospital day, 1 gm. of tetracycline was added to each liter of fluid so that a total of 18 gm. was infused. Other antibiotics were not administered. On the thirteenth day after hospitalization the patient died. The patient had failed to improve with treatment, and a mild fever of less than 100’~. had developed. The upper part of the abdomen was persistently tender; there were no masses and x-ray studies were unrevealing. The amylase value diminished during the first three days, but then gradually increased

until the final day when the serum amylase was 1,850 units. The SUN, bicarbonate, and potassium remained at normal levels until just prior to death when the serum levels were 35 mg. per cent, and 12 and 3.2 mEq./L., respectively. Serum calcium level remained normal except on the sixth hospital day when it was 7.7 mg. per cent, Liver tests, including serum albumin, globulin, bilirubin, alkaline phosphatase, GOT, and GPT determinations, gave normal results until terminally when the serum bilirubin was 2.9 mg. per cent, alkaline phosphatase 2 Bessey-Lowry units (normal 1 to 3 units), lactic acid dehydrogenase 1,255 units (normal 100 to 350 units), and SGOT level greater than 210 units. Shock suddenly developed on the thirteenth hospital day and the patient died. At necropsy the only positive findings were in the liver and pancreas. The liver was light tan, soft, and weighed 1,200 gm. The head of the pancreas contained a 3 cm. fluid-filled cyst that was lined with shaggy yellow-flecked pancreatic parenchyma. There was no icterus or ascites, nor were there stones within the gallbladder or ducts. The other organs were normal. Microscopic examination of the liver disclosed a striking, uniform, fatty vacuolization of the parenchyma1 cells of the entire lobule. Some bile stasis was noted. There was very little exudative reaction in the pancreas but a zone of edema surrounded the large area of liquefactive necrosis. There was no tubular necrosis or fat in the kidneys.

Comment: From the clinical standpoint, the cause of this patient’s terminal illness was most puzzling. There was nothing to indicate that she had anything more than a mild attack of pancreatitis, but during the stage of recovery she suddenly went into shock and died. No abdominal signs or symptoms were present to indicate that the pancreatitis had suddenly become worse or that a terminal hemorrhagic phase had evolved ; it was only after the microscopic slides of the liver were reviewed and compared with those in other cases of liver injury after intravenous tetracycline therapy that the cause of death was established. CLINICAL LABORATORY FEATURES Although the clinical features of the patients in this report seem unrelated, certain features were common to the group. The course of each patient was characterized by the subtle onset of nausea, vomiting, altered consciousness, and usually fever, often after partial recovery from the diseases which necessitated hospitalization. All patients had received intravenous tetraAmerican

Journal of Surgery

Tetracycline-Induced cycline. In retrospect, the condition of three patients became worse after continued intravenous tetracycline therapy, but three patients were already quite ill when the agent was initiated. A review of the reported fatal examples of nonpregnant patients with fatty livers associated with administration of the tetracycline group of drugs [P-9] discloses that in most instances the role of the tetracyclines in the production of the clinical and pathologic features described is uncertain, since a majority of the patients were quite ill or moribund prior to the institution of the antibiotic therapy. Thus, Lepper et al. [5] noted that one of their patients (case 2) had received no Aureomycin’ in the final two months of life; another (case 4) had microscopic changes in the liver quite dissimilar to the microscopic changes in their other cases; one patient had liver disease from alcoholism with large fat droplets and died three days after institution of the antibiotic (case 5) and another (case 3) was icteric before tetracycline was started. Other reports are less completely documented than those of Lepper et al. [5], but from the accumulated reports it would seem that if a symptomatic change is to be recognized it will begin four to six days after initiation of intravenous tetracycline therapy. In half the patients in our series the morbid pattern of tetracycline toxicity developed postoperatively (cases I, II, and III). Three of the patients (cases I, v, and VI) had symptoms of acute pancreatitis, which was the initial disease in two patients but was mild in one. In three other patients (cases II, III, and IV) azotemia developed during hospitalization although initial serum urea levels were only minimally elevated. One of these three patients had diabetes mellitus and hypertension and was shown at autopsy to have advanced arteriolar nephrosclerosis; another had tumor involvement of the urinary bladder and became oliguric postoperatively; the third (case II) became oliguric after a surgical procedure to relieve a gangrenous incarcerated hernia. Although the hepatic changes were the major pathologic findings and considered to be the principal cause of death in four patients of the group, clinical and laboratory evidence of unequivocal hepatic failure was meager. Transaminase activity and bilirubin levels determined on the serum of three of the patients were only slightly Vol. 113, May 1967

629

Fatty Liver

elevated. However, the prothrombin activity was markedly depressed in the plasma of the three patients on whom the test was performed. All patients in this report are women, as are most of the patients reported in the literature. In contrast, reports of only four men were noted. Lepper et al. [5] included two men whose clinical and pathologic features differ from those of the other patients in his series; the patient reported on by Bateman et al. [6] died after massive parenteral tetracycline but did not have a fatty liver; however, a review of the slides on Winterling and Goldman’s [9] patient, a castrate, estrogen-treated man, showed hepatic change similar to those of our patients. PATHOLOGY

.4ND PATHOLOGIC

PHYSIOLOGY

The most striking microscopic finding in each of the patients was the peculiar fatty change in the liver. (Table II.) The change was usually most severe in the central one third to three fourths of each lobule and consisted of a fine, foamy vacuolization and a partial dissolution of intercellular membranes. Residual necrotic cells were rarely encountered, but pigment and cellular debris in Kupffer cells may be considered as evidence of cellular death. It is not apparent from the study of histologic patterns why prothrombin activity was altered more so than the other laboratory tests of liver cell function. The extent of morphologic alteration of the liver does not compare with that in patients dying from carbon tetrachloride intoxication, halothane necrosis, viral hepatitis, or liver disease from alcoholism. Pancreatitis in three patients was no longer acute by the time the patients died; two had pancreatic pseudocysts and one had resolving focal necrosis. The renal tubular changes were meager and nonspecific although half the patients with tetracycline-associated fatty liver during pregnancy had renal tubular lesions ; renal tubular fat was noted in one patient. There was no evidence that fat emboli were of importance in the course of any patient. Based on both clinical and pathologic findings, it would appear that four of the patients died from the tetracycline-induced disease that was unrelated to their initial disorder, but two others died of their pre-existing disease, possibly adversely affected by hepatic or renal dysfunction.

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et al.

TABLE XI PATHOLOGICFEATURES OF PATIENTS WITH TETRACYCLINE-INDUCED LIVER DISEASE

Case Cause of Death No. (Autopsy Diagnosis)

I

Acute pancreatitis

Shock, acute renal insufficiency, and fatty liver III Ovarian cnrcinoma, fatty liver, and gastrointestinal ulcers with hemorrhage IV Uremia and hypertensive cardiovascular disetrse Severe fatty liver of unknown

vr

Other Renal Lesions

GastromE;;xy centrat intestinal Hyaline Nervous UlCel-S Emboli System

+

0

Tubular crystals

+

+

0

1) 820 Central one half

0

0

0

Tubular swelling

0

0

0

1,900

Diffuse

0

0

Ischemic

Crystals and ischemic necrosis

f

f

0

1,720

Central three fourths

0

0

0

Severe nephrosclerosis

+

0

0

I.390

Entire lobule Entire lobule

Focal

0

...

+

+

Edema

f

0

0

0

0

0

cause

Fatty liver (acute fatty degeneration)

Pan- -Kidney---. crea-. Fat Tubular titis Necrosis

+

2,750

II

v

-Liver-Weight Fat (gm.) Distribution

1,200

Central one third

ETIOLOGY

It would be presumptuous to propose a complete explanation of the pathogenesis and cause of the hepatic alterations previously described herein. However, certain features are more than coincidental and warrant further evaluation. The patients, selected on the basis of similar hepatit alterations, had all received substantial quantities of intravenous tetracycline. Tetracycline inhibits protein anabapparently occurs in olism; the inhibition the step prior to the polymerization of amino acids, more specifically according to several investigators at the stage of binding of amino acid-messenger RNA complexes to ribosomes [JO]. According to Wruble et al. [P] the lipid accumulates in the endoplasmic reticulum cisternae, which is normally the site of protein production. Normal protein anabolism is an important factor in the maintenance of intracellular lipid balance since triglycerides are excreted from the liver as lipoproteins. The dietary deficiency of certain essential building blocks for proteins will result in a fatty liver as will the inclusion of certain other antagonists of protein formation into the diet [11-131. Lepper et al. [14] demonstrated that Aureomycin administered parenterally to mice and to dogs produced fatty livers but no illness in a number of the experimental animals. We have produced fatty livers and death in a significant percentage of an experimental group of pregnant rats by the in~aperitoneal

FOCal 0

Other

Cholelithiasis and cholecystitis Gangrene of small bowel

Parathyroid hyperplasia, cholelithiasis, and syphilis ... Pancreatic pseudocyst

administration of tetracycline. We were unable to duplicate these results when we administered the agent intravenously to pregnant rabbits. It is well established that a fatty liver will develop quite readily in the rat in response to a variety of insults. Obviously there is considerable variation among species. Although the fatty deposits in the liver are theoretically explainable by the antianabolic action of the tetracycline group of drugs, there is no satisfactory explanation for the lethargy and death that may result or an elucidation of the other predisposing factors that produce the clinical and pathologic features. Tapp and Carroll [15], recognizing the intracellular shift of calcium into damaged liver cells, showed that tetracycline administered to albino Wistar rats also preferentially entered liver cells previously damaged by carbon tetrachloride, chloroform, thioacetamide, and ally1 formate. Noting the afEnity of tetracycline for metallic ions, such as calcium, they postulated that the increase in tetracycline was due to the elevated intracellular calcium in the previously damaged liver cells. They showed further that if they created a very low cellular and serum calcium level in test animals, they could prevent the accumulation of fluorescent tetracycline in damaged liver cells. They raised the question of the hepatotoxic effect from the increased tetracycline content in damaged livers, secondary, they believed, to increased intracellular calcium. American

Jouvnol of Surgery

Tetracycline-Induced The concept of Tapp and Carroll is of interest since it would imply that tetracycline toxicity would likely be a hazard for the patient \vho had prior hepatic damage. However, the work must be repeated since the investigators may only have succeeded in inhibiting the fluorescence of tetracycline by blocking calcium influx rather than in reducing the intracellular content of the drug. Tetracycline fluorescence is dependent upon the formation of the tetracycline-calcium complex ; tetracycline alone will not show appreciable fluorescence. One might expect impaired renal plasma flow to cause the blood level of tetracycline to stay inordinately elevated. Two of our patients had pre-existing renal disease and died in uremia. The remainder may have had impaired renal blood plasma flow as a result of either prolonged abdominal surgical procedures or pancreatitis. In the patient reported on by Wruble et al. [F] symptoms developed postoperatively, simultaneously with renal failure. The possibility, therefore, of increased hazard in the postoperative period must be considered. X number of serious, usually fatal examples of tetracycline-associated fatty livers in pregnant subjects has suggested that both the third trimester of pregnancy and pyelonephritis may predispose the liver to the peculiar fatty alteration. Although pregnancy may increase the hazard of intravenously administered tetracycline, the pathologic findings in our cases indicate that it is not essential for the development of the hepatic lesion. The hepatic lesion is largely confined to women (or feminized men). This is consistent with the experimental production of fatty change in the liver of experimental animals by inhibiting protein assimilation. Farber [13], in animal showed that ethionine adexperimentation, ministration produced fatty livers only in female rats. However, since it seems questionable whether or not the hepatic lesion is responsible for the clinical symptoms and death in tetracycline toxicity, it is entirely possible that the hazards of drug usage may be similar in men and women. The scarcity of renal lesions in patients in this series compared with the high frequency of tubular focal necrosis in patients with tetracycline fatty liver in pregnancy is striking. Tapp and Lowe [16] showed renal lesions in tetracycline-treated rats that had received prior intravenously administered hemoglobin, Vol.

II3,

May

1967

Fatty

GSl

Liver

suggesting that tubular epithelial damage was a requirement for the subsequent tetracycline accumulation. The disease seems to be rare in infants and children. Dowling and Lepper [8] in their report mention a young boy with a fatty liver associated with tetracycline administration. To our knowledge no other instances of tetracycline-associated fatty livers have been reported in boys and only one case in a prepubertal girl [j]. In infants and children one must take care to exclude the encephalopathyfatty liver syndrome apparently associated with reovirus infection. The morphologic changes seem to be similar to those associated with tetracycline toxicity although clinical laboratory findings differ. Wruble et al. [4]. in reporting a single case of a nonpregnant woman who died after intravenous tetracycline therapy, proposed a dose-related relationship between tetracycline and hepatotoxicity. In our material, one of the patients with severe latent renal disease was given only 1 gm. per day intravenously for five days, and two patients received 1 to 1.5 gm. daily by the intravenous route. It would seem that the margin of safety afforded by the recommended 1 gm. daily is inadequate for some patients, if administered intravenously. SUMMARY

Six patients are reported on to show that the fatty liver response to intravenous administration of large quantities of tetracycline is not restricted to pregnant women. The histologic changes were the same as those found in pregnant women with tetracycline-induced fatty liver. It was concluded that four of the patients died from the effects of tetracycline. REFERENCES

1. SCHULTZ, J. C., ADAMSON, J. S., JR., WORKMAN, W. W., and NORMAN, T. D. Fatal liver disease after intravenous administration of tetracycline in high dosage. New England J. Med., 269: 999, 1963. 2. WHALLEY, P. J., ADAMS, R. H., and COMBES, B. Tetracycline toxicity in pregnancy: liver and pancreatic dysfunction. J.A.M.A., 189: 357, 1964. 3. KUNELIS, C. T., PETERS, R. L., and EDMONDSON, H. A. Fatty liver of pregnancy and its relationship to tetracycline therapy._ Am. J. Med.. 38: 359, 1965. 4. WRUBLE, L. D., LADMAN, A. J., BRITT, L. G., and CUMMINS, A. J. Hepatotoxicity produced by tetracycline. J.A.M.A., 192: 6, 1965.

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Peters et al.

5. LEPPER, M. H., WOLFE, C. K., ZIMMERMAN,H. J.,

6.

7.

8. 9.

10.

CALDWELL, E. R., JR., SPIES, H. W., and DOWLING. H. F. Effect of large doses of aureomvcin on human liver. Arch. Int.Med., 88: 271, 1951. BATEMAN, J. C., BARBERIO, J. R., GRICE, P., KLOPP, C. T., and PIERPOINT, H. Fatal complications of intensive antibiotic therapy in patients with neoplastic disease. Arch. Int. Med., 90: 763,1952. BATEMAN, J. C., BARBERIO, J. R., CROMER, J. K., and KLOPP, C. T. Investigation of mechanism and type of jaundice produced by large doses of parenterahy administered aureomycin. Antibiotics Es Chemother., 3: 1, 1953. DOWLING, H. F. and LEPPER, M. H. Hepatic reactions to tetracycline. J.A.M.A., 188: 307, 1964. WINTERLING, A. N. and GOLDMAN, R. L. Hepatic and renal lesions in a case of tetracycline toxicity during long term estrogen therapy after orchiectomy. Calqoornia Med., 102: 314, 1965. SUAREZ, G. and NATHANS, D. Inhibition of aminoacyl-sRNA binding to ribosomes by tetracycline. Biochem. Biophys. Res. Commun., 18: 743, 1965.

11. SIDRANSKY,H. and FARBER, E. Chemical pathology of acute amino acid deficiencies. I. Morphologic changes in immature rats fed threonine-, methionine-, or histidine- devoid diets. Arc/z. Path., 66: 119, 1958. 12. VILLA-TREVINO, S., SHULL, K. H., and FARBER, E. The role of adenosine triphosphate deficiency in ethionine-induced inhibition of protein synthesis.

J. Biol. Chem., 238: 1757, 1963. 13. FARBER, E. Studies on the chemical pathology of lesions produced by ethionine. Arch. Path., 67: 1, 1959.

14. LEPPER, M. H., ZIMMERMAN, H. J., CALDWELL, E. R., SPIES, H. W., WOLFE, C. K., and DOWLof large doses of aureomycin, terramycin and chloramphenicol on livers of mice and dogs. Arch. Int. Med., 88: 284, 1951. 15. TAPP, E. and CARROLL, R. Tetracycline accumulation in toxic liver damage. J. Path. 6’ Bact., 89: ING, H. F. Effects

715, 1965. 16. TAPP, E. and LOWE, B. Tetracycline toxicity haemoglobinuria. Brit. M. J., 1: 143, 1966.

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