Vitamin A Intoxication Presenting - Europe PMC

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Mar 9, 1986 - Farris WA, Erdman JW Jr: Protracted hypervitaminosis A following long- ... in an atopic child who developed hypervitaminosis A. Clin Pediatr ...
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chain facilitation of C-FDA (KC-FDA) thrombocytotoxicity. Hum Immunol 1983; 8:265-271 11. Bodmer W, Tripp M, Bodmer J: Application of a fluorochromatic cytotoxicity assay to human leukocyte typing, In Histocompatibility Testing. Copenhagen, Munksgaard, 1967, pp 341-350 12. Miller WV: Technical Manual of the American Association of Blood Banks, chap 17, 7th Ed. Philadelphia, JB Lippincott, 1977 13. Lau P, Sholtis CM, Aster RH: Post-transfusion purpura: An enigma of alloimmunization. Am J Hematol 1980; 9:331-336 14. Herzig RH, Herzig GP, Bull MI, et al: Correction of poorplatelet transfusion responses with leucocyte-poor HLA-matched platelet concentrates. Blood 1975; 46:743-750 15. Brand A, van Leeuwen A, Eernisse JG, et al: Platelet transfusion therapyOptimal donor selection with a combination of lymphocytotoxicity and platelet fluorescence tests. Blood 1978; 51:781-788 16. Minchinton RM, Waters AH: The occurrence and significance of neutrophil antibodies. BrJ Haematol 1984; 56:521-528 17. Miller WV, Harmon HA: Platelet-specific antigen systems and their detection. Prog Clin Biol Res 1984; 149:79-101

Vitamin A Intoxication Presenting With Ascites and a Normal Vitamin A Level FERNANDO S. MENDOZA, MD FRANCESCA JOHNSON, MD JOHN A. KERNER, MD BRUCE M. TUNE, MD STEPHEN J. SHOCHAT, MD Palo Alto, California

VITAMIN A SUPPLEMENTATION by health practitioners and the nonmedical public is becoming increasingly common. Unfortunately, the toxic risks of taking vitamin A are often not appreciated. We report here a case of vitamin A intoxication that was unusual in presentation, with ascites and a normal serum vitamin A level on initial determination.

Report of a Case The patient, a 3-year-old girl with failure to thrive, was seen after two months of lower extremity pain, periods of refusing to walk, irritability, lethargy, bleeding gums, peeling erythematous skin, pruritus and a protuberant abdomen. On physical examination her vital signs were normal, she was thin and irritable and had mild abdominal distension. Her weight was 11.0 kg (24 lb) and height 84 cm (33 in), both below the fifth percentile. Her head circumference was at the tenth percentile. She showed no abdominal organomegaly nor a fluid wave, and there were no joint abnormalities. The skin was somewhat dry, and results of the rest of the examination were normal. All of the following studies elicited normal values: a complete blood count, platelets, erythrocyte sedimentation rate (ESR), serum alanine aminotransferase (ALT [formerly SGPT]), calcium, uric acid and electrolytes. A urinalysis, urine culture, sweat chloride test and Epstein-Barr virus and cytomegalovirus titers were also negative. A plain film of the abdomen was normal. After two weeks of observation, she was admitted to hos-

pital because of ascites with respiratory distress. Her weight (Mendoza FS, Johnson F, Kerner JA, et al: Vitamin A intoxication presenting with ascites and a normal vitamin A level. West J Med 1988 Jan; 148:88-90) From the Division of General Pediatrics, Stanford-Children's Ambulatory Care Center, Stanford University School of Medicine, Palo Alto, California. Reprint requests to Fernando S. Mendoza, MD, Children's Hospital at Stanford, 520 Sand Hill Rd, Palo Alto, CA 94304.

ABBREVIATIONS USED IN TEXT ALT = alanine aminotransferase ESR = erythrocyte sedimentation rate RBP = retinol-binding protein

was 12.6 kg (27.8 lb), her temperature 38.0°C (100.4°F), respiratory rate 30 per minute, heart rate 120 beats per minute and blood pressure 110/60 mm of mercury. New physical findings included a greatly distended and tense abdomen without liver or spleen enlargement, a prominent venous pattern on the abdomen, decreased breath sounds and rales in the right lower lung field, a dry and erythematous skin and brittle hair with alopecia. The extremities were normal with a full range of motion and without pain. Except for irritability, no abnormalities were found on neurologic examination. The fundi were normal. A paracentesis showed clear and yellow fluid, a leukocyte count of 80 per yl with no polymorphonuclear neutrophils, erythrocytes 510 per /td, glucose 9.0 mg per dl, protein 3.4 mg per dl, albumin 2.3 mg per dl, amylase 14 IU per liter and lactic dehydrogenase 221 IU per liter. The fluid specimen was negative for bacteria, acid-fast bacilli and fungi, and cytologic tests were negative. Blood studies showed the following values: aspartate aminotransferase (formerly SGOT) 80, ALT 31 and alkaline phosphatase 153 IU per liter; total protein 5.2 mg per dl, and albumin 3.4 mg per dl. Results of all of the following studies were normal: prothrombin time; partial thromboplastin time; serum levels of electrolytes, creatinine, calcium, phosphate, uric acid, and amylase; ESR; fluorescent antinuclear antibody, C3 and C4 levels; DNA binding, quantitative immunoglobulins, and a bone marrow biopsy. Tests for tumor markers were negative. A chest x-ray film showed a normal-sized heart and a right pleural effusion. An abdominal ultrasonogram and a body computed tomographic scan showed massive ascites, a normal liver and spleen, a soft tissue mass in the region of the head ofthe pancreas and a small calcification in the upper pole of the right kidney. Bone and liver-spleen scans were normal. A lymphangiogram and a nuclear scan study using technetium Tc 99m-labeled antimony showed no lymphatic leakage into the peritoneal cavity. Upon further discussion, the parents reported that a chiropractor had prescribed vitamin A supplementation seven months earlier because of poor weight gain and eczema. The vitamin A was given at a dose of 100,000 IU per day for one week, then 50,000 IU per day for the following six months, ending one month before her presentation. By history, no other vitamin supplementation had been given. The patient was evaluated for vitamin A toxicity. Long-bone radiographs were normal. Serum vitamin A and carotene levels were 196 IU per dl (normal 65 to 275) and 17 pig per dl (normal 50 to

300), respectively. An exploratory laparotomy was done because of a suspected intra-abdominal tumor. It showed normal liver, spleen, kidneys, reproductive tract, pancreas, and lymph nodes. There was no inflammation of the serosal surface. A portal venogram showed a hepatic wedge pressure of 150 mm of water (upper limits of normal for adults) and no evidence of obstruction. A liver biopsy specimen showed mild patchy centrilobular sclerosis around the central vein, pericellular sclerosis surrounding individual hepatocytes, and focal prominence of Ito cells shown by fluorescence microscopy. There

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were no signs of inflammation. These findings were interpreted as consistent with, but not diagnostic of, vitamin A

intoxication. The patient's postoperative management consisted principally of diuretic therapy, fluid restriction, and nutritional supplementation. Vitamin A intake was minimized. After eight weeks of therapy the patient experienced worsening dermatitis, fissured lips, increased hair loss, irritability, and tenderness of the extremities. A repeat vitamin A level was 838 IU per dl, confirming the diagnosis ofvitamin A intoxication. To increase vitamin A mobilization by increasing the retinol-binding protein (RBP) level,' prednisone therapy was started at 2 mg per kg of body weight per day. Table 1 shows the patient's levels of vitamin A, retinol-binding protein, and carotene throughout the hospital stay. After starting the prednisone therapy, the patient's symptoms worsened. A vitamin A level two weeks later was 547 IU per dl, with an elevated RBP value at 11.7 mg per dl. At that time, tapering of the prednisone dose was begun. A week later the serum vitamin A level was 247 IU per dl and RBP 11.5 mg per dl, and total parenteral nutrition was added. The patient began to show decreasing ascites and resolution of her other symptoms. Over the next four weeks all diuretic therapy was stopped, and her ascites stabilized at a minimal level, allowing her to resume normal activities and to be discharged. Five weeks after discharge, the administration of prednisone was stopped, the vitamin A level and RBP levels were normal, and the ascites had resolved. During the subsequent year, she had no recurrence of her ascites.

Discussion Chronic vitamin A intoxication was well described by Oliver in 1958.2 The usual presenting symptoms are bone pain; irritability; anorexia; poor weight gain; dry, erythematous, peeling skin; fissured lips; bleeding gums; dry, brittle hair, and alopecia.2'3 Hepatosplenomegaly has been a common finding; results of liver function studies, however, are usually only mildly abnormal.2'5 Ascites as a presenting finding has been reported only twice before in children, and in both cases the child had received 100,000 to 300,000 IU of vitamin A per day for more than a year.6'7 In each of these cases, a liver biopsy was used to confirm the diagnosis, and in one case the hepatic vitamin A content was determined and

TABLE 1.-Vitamin A, Retinol-Binding Protein (RBP) and Carotene Levels in a 3-Year-Old Girl With Vitamin A Intoxication Week Clinical Course

1 2

3 4

8 10 11 12 14 15 20

Vitamin A, RBP, Carotene, lUldl*

Admission long-bone x-ray films normal ... Laparotomy .......... .......... Peripheral hyperalimentation. 196 Start prednisone daily dose ....... 838 Prednisone dose tapered ......... 547 Start total parenteral nutrition ..... 249 Decreasing ascites ............. 269 Decreasing ascites ............. 401 ..................... Discharge . Off steroid therapy ............. 109 *Normal 65 to 275 llJdl. tNormal 2.6 to 7.7 mg/dl. $Normal 50 to 300 Ag/dl.

mgldlt jAgId ...

...

...

5.1

17 50 70 38 37 25

...

...

4.4

75

...

11.7 11.5 ...

148

* 1

89

found to be elevated. Pathologic changes included sclerosis around the central vein, the perisinusoidal areas, and around the individual hepatocytes. The perisinusoidal fat-storing cells, or Ito cells, were prominent in both cases. In the present case, the child had had symptoms before admission that were consistent with chronic vitamin A intoxication. The 50,000 IU of vitamin A per day for six months was a lower intake than previously reported with ascites. A case

report, however, of a 6-year-old boy with protein-calorie

malnutrition who had a toxic reaction after receiving 20,000 IU of vitamin A per day for more than a year8 indicates significant variation in the toxic dose. Even with the history and clinical symptoms, the diagnosis was initially elusive. Long-bone x-ray films and the initial vitamin A level were normal. It was only after the child received nutritional supplementation (with minimal vitamin A intake) that her serum vitamin A level rose into a clearly toxic range. The diagnosis was thus established by the history and clinical symptoms, the elevated vitamin A level, and the liver biopsy specimen showing the histopathologic features of vitamin A intoxication. Reviewing other published cases indicates that establishing a diagnosis of chronic vitamin A intoxication can be difficult without a knowledge of the kinetics of vitamin A metabolism. Vitamin A is absorbed from the intestine in various forms and transported to the liver for storage, presumably in the Ito cells.9"l0 In the transfer of vitamin A from the liver to the peripheral tissues and to the kidney for catabolism, it is car-I ried by retinol-binding protein as retinol in a 1: 1 molar ratio. The binding of RBP to retinol restricts its activity to the

appropriate site of action. Unbound circulating retinol leads to the toxic symptoms of vitamin A overload that are thought to be a result of retinol's surface-active and membranolytic effects ."" Smith and Goodman observed that it was the molar ratio of retinol to RBP, and not the absolute level of vitamin A in the serum, that determined whether symptoms of intoxication occurred. I A molar ratio of greater than one, indicating the presence of unbound retinol, was associated with toxic symptoms. Furthermore, with low levels of RBP, high levels of vitamin A can exist in the liver because of decreased transport and result in low or normal vitamin A levels in the serum. 1.6

Retinol-binding protein is produced in the liver and associated with the microsomes. Its release from the liver is partly determined by vitamin A intake. In the presence of liver disease or protein-calorie malnutrition, however, this response is decreased because of a presumed decreased liver production of RBP. In this situation, release of vitamin A from the liver is also impaired. It is possible that in the present case, the child's poor nutritional state may have led to a decreased mobilization of vitamin A from the liver and an initial normal serum vitamin A level. Once her nutrition improved, the vitamin A was mobilized and the level rose. Although the vitamin A supplementation had been stopped a month before admission, the child's condition worsened with the development of overt ascites. It has been proposed that this delay in the onset of ascites is due to the effects of high-dose vitamin A administration on the liver, which appears to result in enlarging and transforming the Ito cells.9"l0 The enlargement caused by vitamin A in these cellsF decreases the sinusoidal spaces. Later, fibroblastic transformation of the Ito cells leads to a fibrocongestive hepatic lesion and ascites. This is presumed to be a dose- and time-related

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phenomenon and may not lead initially to enlargement of the liver. Given the worsening nature of the patient's ascites after vitamin A intake was discontinued, a way was sought to maximize the removal of the vitamin A by increasing the RBP levels. Nutritional supplementation was given to provide an adequate protein intake. A trial of prednisone was used to increase the mobilization of hepatic vitamin A by increasing the release of RBP from the liver.1 12 In summary, this case report describes an unusual presentation of chronic vitamin A intoxication. It suggests that children with malnutrition may be at a greater risk for intoxication because of impaired RBP production and can present with normal vitamin A levels. Determining the retinolbinding protein level is vital in the diagnosis and helpful in deciding the management. Last, although most patients' symptoms resolve simply by withdrawing the vitamin A supplementation and providing good nutrition, a trial of steroids may be considered in patients with persistent clinical symptoms. REFERENCES 1. Smith JE, Goodman DS: Retinol-binding protein and the regulation of vitamin A transport. Fed Proc 1979; 38:2504-2509 2. OliverTKJr: Chronic vitamin A intoxication. AmJ Dis Child 1958; 95:57-68 3. Muenter MD, Perry HO, Ludwig J: Chronic vitamin A intoxication in adults-Hepatic, neurologic and dermatologic complications. Am J Med 1971; 50:129-136 4. Farris WA, Erdman JW Jr: Protracted hypervitaminosis A following longterm, low-level intake. JAMA 1982; 247:1317-1318 5. Lippe B, Hensen L, Mendoza G, et al: Chronic vitamin A intoxication-A multisystem disease that could reach epidemic proportions. Am J Dis Child 1981; 135:634-636 6. Rosenberg HK, Berezin S, Heyman S, et al: Pleural effusion and ascites. Clin Pediatr (Phila) 1982; 21:435-440 7. Noseda A, Alder M, Ketelbant P, et al: Massive vitamin A intoxication with ascites and pleural effusion. J Clin Gastroenterol 1985; 7:344-349 8. Silverman SH, Lecks HI: Protein-calorie deficiency and vitamin indiscretion in an atopic child who developed hypervitaminosis A. Clin Pediatr (Phila) 1982; 21:172-174 9. Guarascio P, Portmann B, Visco G, et al: Liver damage with reversible portal hypertension from vitamin A intoxication: Demonstration of Ito cells. J Clin Pathol 1983; 36:769-771 10. Russell RM, Boyer JL, Bagheri SA, et al: Hepatic injury from chronic hypervitaminosis A resulting in portal hypertension and ascites. N Engl J Med 1974; 291:435-440 11. Smith FR, Goodman DS: Vitamin A transport in human vitamin A toxicity. N Engl J Med 1976; 294:805-808 12. Atukorala TMS, Basu TK, Dickerson JWT: Effect of corticosterone on the plasma and tissue concentrations of vitamin A in rats. Ann Nutr Metab 1981; 25:234-238

Dysgonic Fermenter-2 Infections RAMON E. PEREZ, MD

Anaheim, California DOG BITES have been known to cause dangerous sepsis. The most commonly known bacterium is Pasteurella multocida. A search of the English language literature was made using MEDLINE 1977-1986 files. Since 1976 there have been multiple reports of dysgonic fermenter (DF-2) infections, many of them following dog bites or casual exposure to dogs. Dysgonic

(Greek dys, "difficult," plus gonikos, "seed, offspring") fermenters are fastidious gram-negative rods easily missed by (Perez RE: Dysgonic fermenter-2 infections. West J Med 1988 Jan; 148:90-92) From the Division of Infectious Diseases, Department of Medicine, University of California, Irvine, California College of Medicine. Reprint requests to Ramon E. Perez, MD, Infectious Disease Department, University of California, Irvine, 50 S Anaheim Blvd, #244, Anaheim, CA 92805.

REOT

ABBREVIATIONS USED IN TEXT DF-2 = dysgonic fermenter HIA = heart infusion agar

routine culture media. They are found in the oropharynx of some dogs. Patients with the worst prognosis tend to have splenectomies, alcoholism, or chronic obstructive pulmonary disease. There have been 42 previously documented cases of DF-2 infections (one of them presumptive). The clinical spectrum has ranged from self-limited disease to fatal sepsis. The actual incidence is predictably higher than reported because of the difficulties with culture. DF-2 needs enriched media for growth and fermentation. Previous strains have reportedly been susceptible to penicillin. This is the first case description of penicillin resistance with DF-2.

Report of a Case The patient, a 65-year-old man, had suffered from chronic obstructive pulmonary disease, nephrolithiasis, and hypertension. He was bitten on the left third finger by a dog on March 9, 1986. The following day he described shaking chills and on March 11 had temperatures up to 400C (104°F). He was admitted to hospital the next day with a blood pressure of 85/70 mm of mercury, confusion, and fecal incontinence. The skin was acrocyanotic with ecchymotic, purpuric, and petechial lesions involving the extremities, face, and periumbilical area. Gangrene developed on the bitten finger without evidence of osteomyelitis. There were no mucosal or retinal lesions. The lungs were clear, and the heart had a II/VI systolic murmur at the apex and aortic valve area. The abdomen was soft without tenderness or organomegaly. There was no costovertebral angle tenderness despite complaints ofback pain. Initially the prothrombin time was 22 seconds, partial thromboplastin time 100 seconds, platelet count 14 x 109 per liter (14,000 per ,l), hematocrit 0.39 (38.7%), and hemoglobin 8.4 mmol per liter (13.5 grams per dl). The leukocyte count was 6.6 x 109 per liter (6,600 per td), with 0.54 (54%) neutrophils, 0.32 (32%) bands, 0.07 (7%) lymphocytes, and 0.06 (6%) metamyelocytes. Serum electrolyte values were normal except for a bicarbonate of 12 mmol per liter (12 mEq per liter). The blood urea nitrogen level was 22.1 mmol per liter (62 mg per dl) and the serum creatinine level 475 ,umol per liter (4.2 mg per dl). The patient was treated with a regimen of penicillin G benzathine, 12 million units per day, and ceftizoxime sodium, 6 grams per day, given intravenously. He became more alert, and his hemodynamic indicators improved after fluid replacement and correction ofthe metabolic acidosis. On March 15, he had a respiratory arrest requiring assisted ventilation. His condition continued to deteriorate, and he died on March 18, nine days after the dog bite. The main autopsy findings included a hemorrhagic spleen, congestion of the entire mucosa of the small and large intestines, and mucosal edema and hemorrhage of the major bronchi. The thyroid, adrenal, and pituitary glands were edematous. All the blood cultures from admission became positive in 48 hours (March 14), with a fastidious gram-negative rod by the Bactec 6A automated system (Johnstons Laboratories, Townson, Md). A preliminary identification of DF-2 was made on March 17, 1986, and was later corroborated by the State of California Microbial Diseases Laboratory. Its growth