- Email: [email protected]
Vitamin A toxicity secondary to excessive intake of yellow-green vegetables, liver and laver
Journal ofHepatology 1999; 31: 142-148 Printed in Denmark AN rights resrrved Munksgaard. Copenhagen
Copyright 0 European Association .for the Study of the Liver 1999 Journal of Hepatology ISSN 0168-8278
Case Report
Vitamin A toxicity secondary to excessive intake of yellow-green vegetables, liver and laver Kazuki Nagai’, Departments
Hiroo Hosaka’,
Shuichi Kubo’, Takeshi Nakabayashi’, Noriko Nakamura2
of ‘Internal Medicine and 2Pathology,
Saiseikai
Yasuhiro Amagasaki’
Yokohama-shi Nanbu Hospital,
and
Yokohama, Japan
Mb report a case of sudden onset of vitamin A poisoning. A 20-year-old Japanese woman had been eating pumpkin and only a very limited amount of other foods on a daily basis for 2 years. She was overly concerned about weight reduction. Aurantiasis cutis and abnormal liver function tests were noted by her family doctor in 1995 when she was 18 years old. At that time, she stopped eating pumpkin. However, she secretly continued an excessive intake of other betacarotene-rich vegetables, liver and laver for about 2 years Two and one-half years after being seen by her family physician, she experienced sudden onset of low-
grade fever, limb edema, cheilitis, dry skin, and beadache. These symptoms worsened daily. A liver needle biopsy was performed, and it showed a normal portal tract along with fat-laden Ito cells in the space of Disse. A final diagnosis of vitamin A poisoning and hepatic injury secondary to an eating disorder was made. Her symptoms and serum beta-carotene levels returned to normal with successful adjustment of her diet.
A
of polar bear liver with its enormous quantities of vitamin A. This has been recognized for more than 50 years (2). The main clinical features of vitamin A poisoning are fever, anorexia, nausea, vomiting, headache, drowsiness, skin changes, and papilledema. To date, many cases of hepatic injury associated with the clinical use of vitamin A have been reported in the United States and Western Europe (3-5) but cases resulting from excessive intake of yellow-green vegetables are rare. We report such a case of vitamin A poisoning and hepatic injury secondary to an eating disorder. To our knowledge, this is the first such case to be reported in Japan evidenced by liver needle biopsy.
advertisement encouraging high intake of yellow-green vegetables was distributed widely through the mass media in Japan. The Japanese people believe strongly that yellow-green vegetables are health-promoting foods with many benefits (1). In Japan, as in many industrialized countries, it is fashionable for young women to be thin. Most of them believe that a high intake of yellow-green vegetables is healthy and also that it is the best means of attaining or maintaining their desired body weight. Yellow-green vegetables are low in calories, their ingestion makes the skin beautiful, and they are thought to be harmless, but excessive intake can lead to toxicity. This is because the majority of yellow-green vegetables eaten are carrots, pumpkin, and other beta-carotene-rich vegetables, all containing vitamin A. In the past, most cases of systemic and hepatic toxicity due to vitamin A resulted from excessive ingestion RECENT
Received
I9 August
1998; revised 2 February; accepted 2 February 1999
Kazuki Nagai, Department of Internal Medicine, Saiseikai Yokohama-shi Nanbu Hospital, 3-2-10, Konan-ku, Yokohama City, Kanagawa, 233-8503, Japan. Tel: 8145 832 1111. Fax: 8145 832 8335. Correspondence:
142
Key words: Beta-carotene-rich; Hepatic injury; Hypercarotenemia; Laver; Liver; Vitamin A poisoning.
Case Report A 20-year-old Japanese woman had suffered from secondary amenorrhea from age 16 years. Her daily diet for several years comprised mainly pumpkin, both the flesh and the rind, with a little rice, red meat, and fish. She was preoccupied with weight reduction. In 1995, when she was 18 years old, aurantiasis cutis and abnormal liver function tests were noted by her family doctor. At that time, she stopped her intake of pumpkin.
Vitamin A toxicity TABLE 1 Laboratory data at admission Hematology WBC Eos. RBC Hb Ht PLT PT HPT ESR
3800 0.3 311 10.3 30.8 15.0 78 77 24
Serology CRP IgG IgA IgM Thyroid functions TSH F-T3 F-T,
Autoantibodies Anti-mitochondrial Anti-nuclear Ab Anti-DNA Ab
X 1@/mm’ g/d1 % x 1v/mm3 % %
(50.05) (880-2090) (92406) (52-315)
mg/dl mg/dl mg/dl mg/dl
1.03 (0.35-3.73) 2.0 (2.2-4.1) 0.89 (0.81-1.67)
$U/ml Pg/ml ngldl
0.5 0.1 0.7 1.2 58 41 596 163 45 5.8 3.9 151 30 Ab
% (376500) (11.3-15.2) (33.4-44.9) (13.0-36.9) (70-l 10) (7&l 30) (3-l 1)
3.46 859 114 156
Blood chemistry Total bilirubin Direct bilirubin l-l-T ZTT AST ALT LDH ALP y-GTP Total protein Albumin Total cholesterol Triglyceride
(3500-91OO)/mm3
(0.1-0.8) (0.0-0.3) (0.24.6) (4.2-12.2) (532) &34j (250-440) (93-271) (8-60) (6.3-8.1) (3.8-5.2) (125-233) (49-l 69)
mg/dl mg/dl KU KU 1un IU/l IU/l IU/l 1un g/d1 g/d1 mg/dl mg/dl
-- ;r; (-) -
( ): normal range
Fig. 5. Liver needle biopsy showed normal portal tracts and fat-laden Ito cells (arrows) in the space of Disse. Stained with (A, B) hematoxylin and eosin, and (C) Masson trichrome. (Original magnification A: X25, B: X 50, C: x 100. )
Fig. 1. Aurantias,is cutis: the patient’s skin appeared yelloworange, (J on the right is that of a healthy volunteer).
Early in August 1997, she experienced sudden onset of low-grade fever, headache, and swelling of her fingers. She was admitted to our hospital in late August for
additional work-up. She was taking no recreational drugs or medications and had consumed no alcohol. She had never received a blood transfusion. No remarkable diseases were noted from her family history. On physical examination, she appeared somewhat poorly nourished, her height was 148 cm, her weight was 42 kg, and her body temperature was 37.4”C. Her conjunctiva appeared slightly pale but were not icteric. Her skin was severely discolored and appeared yellow143
K. Nugai et ul.
AS1 MT
M9
#30
911
915
9110
9115
9n0
--
9l25
9128
Fig. 2. Clinical course during hospitalization.
Fig. 3. Serial chest radiographs. Pleural effusion increased gradually.
Vitamin A toxicity
orange (Fig. 1). Her chest and heart were normal, and there was no abdominal tumor or hepatosplenomegaly. Swelling was noted in her fingers bilaterally. A right cervical lymph node was palpable and was estimated to be approximately 15 mm in diameter. There was slight neck stiffness, but her neurological function was normal. Laboratory data on admission were as follows. Hematological tests showed her white blood cell count at 3800/mm3 eosinophils at 0.3%, red blood cell count at 311 X 104/mm3, hemoglobin at 10.3 g/dl, and ESR at 24 mm/h (normal 3-11 mm/h). Her serology showed C-reactive protein (CRP) 3.46 mg/dl (normal ~0.5 mg/ dl), and IgG 859 mg/dl (normal 880-2090 mg/dl), and thyroid functions showed thyroid stimulating hormone (TSH) 1.03 (@U/ml (normal 0.35-3.73 pIU/ml), free 3,5,3’-triiodothyronine (F-T3) 2.0 pg/ml, free thyroxine (F-T,) 0.89 ng/dl (normal 0.81-1.67 ng/dl). Her blood chemistry showed total bilirubin 0.5 mg/dl, aspartate aminotransferase (AST) 58 IU/l (normal ~32 IV/l), alanine aminotransferase (ALT) 41 IU/l (normal ~35 IU/l), lactic dehydrogenase (LDH) 596 IU/l (normal 25&450 IU/l), alkaline phosphatase (ALP) 163 IU/l (normal 93-271 IU/l), and triglyceride 30 mg/dl (normal 49-169 mg/dl). Other biochemical markers were within normal limits. Autoantibodies were all negative (Table 1). Viral markers were negative for anti-IgM antibody to hepatitis A (IgM-HAV-Ab), hepatitis B surface-Ag (HBs-Ag), and antibody to hepatitis C (HCV-Ab). Other viral markers were negative for antiIgM antibody to Epstein-Barr virus (EBV), and cytomegalovirus (CMV), and antibody to measles, herpessimplex virus, and mumps. Furthermore, serum hepatitis C viral RNA (HCV-RNA) was not detected. During the clinical course (Fig. 2), her headaches became quite severe, and cheilitis developed soon after she was hospitalized. Her neck stiffness was mild. Clinical features suggested viral meningitis. Lumbar puncture was performed on hospital day 2 after admission, but her cerebrospinal fluid was normal. Her headache, nausea, and cheilitis worsened, and a high fever ensued. Skin desquamation, mouth ulceration, insomnia, somnolence, joint pain and stiffness developed on hospital day 4, and she could not take solids or liquid orally. On hospital day 5, her blood gas analysis showed: pH 7.472, PaOz, 57.8 mmHg, PaCO2 44.7 mmHg, HC03 32.6 mmolll, base excess 8.8 mmol/l. Pleural effusion developed (Fig. 3) as well as ascites and hepatosplenomegaly by hospital day 7 (Fig. 4). Her neck stiffness became severe. Serum concentrations of AST, ALT, LDH, ALP, and CRP gradually increased, and calcium increased about two-fold by hospital day 10. Repeat lumbar puncture was per-
Fig. 4. Abdominal CT. Ascites and hepatosplenomegaly seen on hospital day 7.
are
formed; cerebrospinal fluid was again normal. Brain CT and MRI revealed no ventricular enlargement or space-occupying lesion. Anti-viral agent, gammaglobulin, antibiotic, and hyperalimentation therapies were started, but there were no remarkable changes in her symptoms, hepatic transaminases, hemoglobin, or calcium levels. Her condition continued to worsen, and somnolence developed. We began to suspect that she was suffering from malignant lymphoma, since the origin of her fever was unknown, and laboratory data and the right cervical lymph node swelling were suspicious for this. Biopsy of the right cervical lymph nodes was performed, revealing sinus histiocytosis, a non-specific finding. After day 18, her symptoms began to subside. and she became more alert. She began oral intake of liquids and solid foods. However, alopecia developed suddenly on day 28. Liver needle biopsy was performed on day 29. The specimen showed normal portal tracts. Fat-laden Ito cells were seen in the space of Disse (Fig. 5). These clinical features were consistent 145
K. Nagai et al.
Fig. 6. Clinical parameters
in relation to the patient’s daily diet.
with vitamin A poisoning and hepatic injury secondary to an eating disorder. She was discharged on September 28. On October 7, we again reviewed her history. She had stopped her excessive intake of pumpkin more than 2 years previously but had substituted for it an excessive intake of carrots, beta-carotene-rich vegetables, liver, and laver, still concerned with weight reduction (Fig. 6). Thus, the final diagnosis was vitamin A poisoning due to excessive intake of these foods, and hepatic injury related to an eating disorder. Her symptoms resolved as her diet was changed. She was instructed about maintaining a normal diet. After discharge, her alopecia continued for about 6 months, but her general condition stabilized. Her body weight increased by 6 kg in 6 months. Just prior to discharge, her serum vitamin-A and beta-carotene levels were 681 ng/ml retinol (normal 410-1200 ng/ml) and 272 beta-carotene (normal 37.0 pg/dl). During follow-up, serum vitamin-A levels showed almost no change and beta-carotene levels declined gradually to within normal limits. AST, ALT, hemo-
146
globin, TG, and CRP reached normal limits by the end of December. The patient has remained healthy, and menstruation resumed in January 1998 (Fig. 7).
Discussion Excessive intake of the yellow-green vegetables can lead to vitamin A toxicity. This is because most of the yellow-green vegetables consumed are carrots, pumpkin, and other beta-carotene-rich vegetables, all containing vitamin A. Most cases of vitamin A poisoning are a result of excessive vitamin A supplementation, accidental ingestion of vitamin A, or improper vitamin A therapy (6-10). Vitamin A poisoning from excessive intake of yellow-green vegetables, liver, and laver is very rare indeed. In particular, vitamin A poisoning associated with an excessive intake of laver is extremely rare. Laver (Nori) is a seaweed consumed in Japan, which contains approximately 250 pg/g beta-carotene. Our patient ate about 10 to 20 g of Nori per day. The vitamin A content was about 1400 to 2800 IU per day. She ate other beta-carotene-rich vegetables daily as well.
Vitamin A toxicity
Fig. 7. Vitamin A (retinol) andj3-carotene levels September 22 to December 24. On September 22, the patient’s blood chemistry test showed retinol681 nglml (normal 41&1200 nglml), B-carotene 272 pgldl (normal 687.0 pgidl). Retino1 levels were nearly unchanged, but p-carotene levels gradually declined to within normal limits with decreased intake of yellow-green vegetables, liver, and laver.
Hypercarotenemia causes yellow-orange pigmentation of the skin. This pigmentation has earlier been described under the names “aurantiasis” and “carotenosis” cutis. It is primarily a result of elevation of vitamin A active carotenoids, especially beta-carotene (11). In this case, although the serum beta-carotene level was high, serum retinol levels were almost within normal limits. In other severe cases reported, serum retinol levels were also normal (6). This may be partly due to impaired synthesis of the transport proteins, retinol binding protein, and transthyretin, and possibly also to impaired hepatic release of vitamin A (12). Additionally, although some 60-70% of dietary beta-carotene is converted into retinol in the human gut, excess beta-carotene intake does not cause hypervitaminosis A. This is mainly due to the inhibition of vitamin A production from beta-carotene when dietary intake of betacarotene is high. When beta-carotene is not converted into retinol, it is taken up unchanged by the intestine. As a result, beta-carotene is generally recognized as a safe nutrient and dietary supplement for humans (13). In this case, the final diagnosis was vitamin A poisoning due to excessive intake of these foods with resultant hepatic injury associated with the eating disorder. However, two important questions remain. The first is why the patient’s symptoms developed acutely under the condition of chronic toxicity. The toxic potential of retinoids may be dramatically affected by simultaneous exposure to other toxic substances. Examples of conditions enhancing vitamin A toxicity are the consumption of alcohol, a low protein intake and possibly a high intake of other fat-soluble vitamins such as E and perhaps D. The threshold for vitamin A toxicity may also be lowered by liver diseases such as
viral hepatitis (9,13). Another factor involved in vitamin A toxicity is age. Elderly persons may have quite a tolerance for high retinoid intake, whereas children can be intoxicated by low amounts (13). Therefore, a partial explanation for our patient’s acute onset might have been her age, secondary to the eating disorder. Another explanation might be an unknown virus, which did not seem to affect the liver, since there was no liver failure. We ruled out only HAV, HBV, HCV, EBV, CMV, Herpes simplex, measles, and mumps. The second issue was whether her hepatic injury was caused directly by vitamin A or by her eating disorder. Ascites and hepatomegaly developed acutely within just a few days. Liver needle biopsy showed fat-laden Ito cells in the space of Disse. These clinical features suggest hepatic injury caused by vitamin A. In vitamin A poisoning, liver function test abnormalities are nonspecific, and there are minor elevations of AST and ALT as well as a slight increase in ALP (13). Moreover, common effects of vitamin A poisoning in the human liver include hepatomegaly due to numerous, enlarged fat-storing cells, resulting in portal hypertension, with obstruction of blood flow in the sinusoids and obliteration of the space of Disse (13-15). There are also minor elevations of AST and ALT with eating disorders. Therefore, there is evidence that her hepatic injury was caused by vitamin A and possibly by other aspects of her eating disorder. The patient has remained healthy. But a strict follow-up will be necessary, because vitamin A overdose can also give rise to an insidious development of cirrhosis, which does not regress after withdrawal of vitamin A (16). Our experience with this patient was instructive from both a clinical and a public health perspective. The excessive intake of vitamin A-rich foods and juices should be addressed publicly and recognized as potentially hepatotoxic. This case highlights the need for greater educational efforts to prevent the consumption of excessive amounts of these foods.
References
K. Nagai et al. 7. Kransinki SD, Russel RM, Otradovec CL, Sadowski JA, Hartz SC, Jacob RA, et al. Relationship of vitamin A and vitamin E intake to fasting plasma retinol, retinolbinding protein, retinyl esters, carotene, alpha-tocopherol, and cholesterol among elderly people and young adults: increased plasma retinyl ester among vitamin A supplement users. Am J Clin Nutr 1989; 49: 112-20. 8. Herbert V Toxicity of 25.000 ILJ vitamin A supplements in health food users. Am J Clin Nutr 1982; 36: 185-6. 9. Hathcock JN, Hattan DG, Jenkins MY, McDonald JT, Ramnathan Sundaresan P Wilkening VL. Evaluation of vitamin A toxicity. Am J Clin Nutr 1990; 52: 183-202. 10. A de Francisco. K Zaman, HR Chowdhury, Waked MA, Chakraborty J, Yunus Mohamed. Accidental ingestion of vitamin A. Tropical Doctor 1995; 25: 187. 11. Curran CJ, Erdman JW, Nelson RA. Alteration in vitamin A and thyroid hormone status in anorexia nervosa and associated disorders. Am J Clin Nutr 1985; 42: 1183-91.
148
12. Geoffrey CF. Hypervitaminosis A. In: Drug-induced hepatic tibrosis and cirrhosis. Drug-induced Liver Disease 1994; 19: 44552. 13. Hendriks HFJ, Bosma A, Brouwer A. Fat-storing cells: hyperand hypovitaminosis A and the relationships with liver fibrosis. Semin Liver Dis 1993; 13: 72-80. 14. Russell RM, Boyer JL, Bagheri SA, Hruban Z. Hepatic injury from chronic hypervitaminosis A resulting in portal hypertension and ascites. N Engl J Med 1974; 291: 435-40. 15. Hruban Z, Russell RM, Boyer JL, Glagov S, Bagheri SA. Ultrastructural changes in livers of two patients with hypervitaminosis A. Am J Path01 1974; 76: 451-66. 16. Geubel AR Galogcy C. Dive C, Rahier J, Alves N. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology 1991; 100: 1701-9.
Copyright 0 European Association .for the Study of the Liver 1999 Journal of Hepatology ISSN 0168-8278
Case Report
Vitamin A toxicity secondary to excessive intake of yellow-green vegetables, liver and laver Kazuki Nagai’, Departments
Hiroo Hosaka’,
Shuichi Kubo’, Takeshi Nakabayashi’, Noriko Nakamura2
of ‘Internal Medicine and 2Pathology,
Saiseikai
Yasuhiro Amagasaki’
Yokohama-shi Nanbu Hospital,
and
Yokohama, Japan
Mb report a case of sudden onset of vitamin A poisoning. A 20-year-old Japanese woman had been eating pumpkin and only a very limited amount of other foods on a daily basis for 2 years. She was overly concerned about weight reduction. Aurantiasis cutis and abnormal liver function tests were noted by her family doctor in 1995 when she was 18 years old. At that time, she stopped eating pumpkin. However, she secretly continued an excessive intake of other betacarotene-rich vegetables, liver and laver for about 2 years Two and one-half years after being seen by her family physician, she experienced sudden onset of low-
grade fever, limb edema, cheilitis, dry skin, and beadache. These symptoms worsened daily. A liver needle biopsy was performed, and it showed a normal portal tract along with fat-laden Ito cells in the space of Disse. A final diagnosis of vitamin A poisoning and hepatic injury secondary to an eating disorder was made. Her symptoms and serum beta-carotene levels returned to normal with successful adjustment of her diet.
A
of polar bear liver with its enormous quantities of vitamin A. This has been recognized for more than 50 years (2). The main clinical features of vitamin A poisoning are fever, anorexia, nausea, vomiting, headache, drowsiness, skin changes, and papilledema. To date, many cases of hepatic injury associated with the clinical use of vitamin A have been reported in the United States and Western Europe (3-5) but cases resulting from excessive intake of yellow-green vegetables are rare. We report such a case of vitamin A poisoning and hepatic injury secondary to an eating disorder. To our knowledge, this is the first such case to be reported in Japan evidenced by liver needle biopsy.
advertisement encouraging high intake of yellow-green vegetables was distributed widely through the mass media in Japan. The Japanese people believe strongly that yellow-green vegetables are health-promoting foods with many benefits (1). In Japan, as in many industrialized countries, it is fashionable for young women to be thin. Most of them believe that a high intake of yellow-green vegetables is healthy and also that it is the best means of attaining or maintaining their desired body weight. Yellow-green vegetables are low in calories, their ingestion makes the skin beautiful, and they are thought to be harmless, but excessive intake can lead to toxicity. This is because the majority of yellow-green vegetables eaten are carrots, pumpkin, and other beta-carotene-rich vegetables, all containing vitamin A. In the past, most cases of systemic and hepatic toxicity due to vitamin A resulted from excessive ingestion RECENT
Received
I9 August
1998; revised 2 February; accepted 2 February 1999
Kazuki Nagai, Department of Internal Medicine, Saiseikai Yokohama-shi Nanbu Hospital, 3-2-10, Konan-ku, Yokohama City, Kanagawa, 233-8503, Japan. Tel: 8145 832 1111. Fax: 8145 832 8335. Correspondence:
142
Key words: Beta-carotene-rich; Hepatic injury; Hypercarotenemia; Laver; Liver; Vitamin A poisoning.
Case Report A 20-year-old Japanese woman had suffered from secondary amenorrhea from age 16 years. Her daily diet for several years comprised mainly pumpkin, both the flesh and the rind, with a little rice, red meat, and fish. She was preoccupied with weight reduction. In 1995, when she was 18 years old, aurantiasis cutis and abnormal liver function tests were noted by her family doctor. At that time, she stopped her intake of pumpkin.
Vitamin A toxicity TABLE 1 Laboratory data at admission Hematology WBC Eos. RBC Hb Ht PLT PT HPT ESR
3800 0.3 311 10.3 30.8 15.0 78 77 24
Serology CRP IgG IgA IgM Thyroid functions TSH F-T3 F-T,
Autoantibodies Anti-mitochondrial Anti-nuclear Ab Anti-DNA Ab
X 1@/mm’ g/d1 % x 1v/mm3 % %
(50.05) (880-2090) (92406) (52-315)
mg/dl mg/dl mg/dl mg/dl
1.03 (0.35-3.73) 2.0 (2.2-4.1) 0.89 (0.81-1.67)
$U/ml Pg/ml ngldl
0.5 0.1 0.7 1.2 58 41 596 163 45 5.8 3.9 151 30 Ab
% (376500) (11.3-15.2) (33.4-44.9) (13.0-36.9) (70-l 10) (7&l 30) (3-l 1)
3.46 859 114 156
Blood chemistry Total bilirubin Direct bilirubin l-l-T ZTT AST ALT LDH ALP y-GTP Total protein Albumin Total cholesterol Triglyceride
(3500-91OO)/mm3
(0.1-0.8) (0.0-0.3) (0.24.6) (4.2-12.2) (532) &34j (250-440) (93-271) (8-60) (6.3-8.1) (3.8-5.2) (125-233) (49-l 69)
mg/dl mg/dl KU KU 1un IU/l IU/l IU/l 1un g/d1 g/d1 mg/dl mg/dl
-- ;r; (-) -
( ): normal range
Fig. 5. Liver needle biopsy showed normal portal tracts and fat-laden Ito cells (arrows) in the space of Disse. Stained with (A, B) hematoxylin and eosin, and (C) Masson trichrome. (Original magnification A: X25, B: X 50, C: x 100. )
Fig. 1. Aurantias,is cutis: the patient’s skin appeared yelloworange, (J on the right is that of a healthy volunteer).
Early in August 1997, she experienced sudden onset of low-grade fever, headache, and swelling of her fingers. She was admitted to our hospital in late August for
additional work-up. She was taking no recreational drugs or medications and had consumed no alcohol. She had never received a blood transfusion. No remarkable diseases were noted from her family history. On physical examination, she appeared somewhat poorly nourished, her height was 148 cm, her weight was 42 kg, and her body temperature was 37.4”C. Her conjunctiva appeared slightly pale but were not icteric. Her skin was severely discolored and appeared yellow143
K. Nugai et ul.
AS1 MT
M9
#30
911
915
9110
9115
9n0
--
9l25
9128
Fig. 2. Clinical course during hospitalization.
Fig. 3. Serial chest radiographs. Pleural effusion increased gradually.
Vitamin A toxicity
orange (Fig. 1). Her chest and heart were normal, and there was no abdominal tumor or hepatosplenomegaly. Swelling was noted in her fingers bilaterally. A right cervical lymph node was palpable and was estimated to be approximately 15 mm in diameter. There was slight neck stiffness, but her neurological function was normal. Laboratory data on admission were as follows. Hematological tests showed her white blood cell count at 3800/mm3 eosinophils at 0.3%, red blood cell count at 311 X 104/mm3, hemoglobin at 10.3 g/dl, and ESR at 24 mm/h (normal 3-11 mm/h). Her serology showed C-reactive protein (CRP) 3.46 mg/dl (normal ~0.5 mg/ dl), and IgG 859 mg/dl (normal 880-2090 mg/dl), and thyroid functions showed thyroid stimulating hormone (TSH) 1.03 (@U/ml (normal 0.35-3.73 pIU/ml), free 3,5,3’-triiodothyronine (F-T3) 2.0 pg/ml, free thyroxine (F-T,) 0.89 ng/dl (normal 0.81-1.67 ng/dl). Her blood chemistry showed total bilirubin 0.5 mg/dl, aspartate aminotransferase (AST) 58 IU/l (normal ~32 IV/l), alanine aminotransferase (ALT) 41 IU/l (normal ~35 IU/l), lactic dehydrogenase (LDH) 596 IU/l (normal 25&450 IU/l), alkaline phosphatase (ALP) 163 IU/l (normal 93-271 IU/l), and triglyceride 30 mg/dl (normal 49-169 mg/dl). Other biochemical markers were within normal limits. Autoantibodies were all negative (Table 1). Viral markers were negative for anti-IgM antibody to hepatitis A (IgM-HAV-Ab), hepatitis B surface-Ag (HBs-Ag), and antibody to hepatitis C (HCV-Ab). Other viral markers were negative for antiIgM antibody to Epstein-Barr virus (EBV), and cytomegalovirus (CMV), and antibody to measles, herpessimplex virus, and mumps. Furthermore, serum hepatitis C viral RNA (HCV-RNA) was not detected. During the clinical course (Fig. 2), her headaches became quite severe, and cheilitis developed soon after she was hospitalized. Her neck stiffness was mild. Clinical features suggested viral meningitis. Lumbar puncture was performed on hospital day 2 after admission, but her cerebrospinal fluid was normal. Her headache, nausea, and cheilitis worsened, and a high fever ensued. Skin desquamation, mouth ulceration, insomnia, somnolence, joint pain and stiffness developed on hospital day 4, and she could not take solids or liquid orally. On hospital day 5, her blood gas analysis showed: pH 7.472, PaOz, 57.8 mmHg, PaCO2 44.7 mmHg, HC03 32.6 mmolll, base excess 8.8 mmol/l. Pleural effusion developed (Fig. 3) as well as ascites and hepatosplenomegaly by hospital day 7 (Fig. 4). Her neck stiffness became severe. Serum concentrations of AST, ALT, LDH, ALP, and CRP gradually increased, and calcium increased about two-fold by hospital day 10. Repeat lumbar puncture was per-
Fig. 4. Abdominal CT. Ascites and hepatosplenomegaly seen on hospital day 7.
are
formed; cerebrospinal fluid was again normal. Brain CT and MRI revealed no ventricular enlargement or space-occupying lesion. Anti-viral agent, gammaglobulin, antibiotic, and hyperalimentation therapies were started, but there were no remarkable changes in her symptoms, hepatic transaminases, hemoglobin, or calcium levels. Her condition continued to worsen, and somnolence developed. We began to suspect that she was suffering from malignant lymphoma, since the origin of her fever was unknown, and laboratory data and the right cervical lymph node swelling were suspicious for this. Biopsy of the right cervical lymph nodes was performed, revealing sinus histiocytosis, a non-specific finding. After day 18, her symptoms began to subside. and she became more alert. She began oral intake of liquids and solid foods. However, alopecia developed suddenly on day 28. Liver needle biopsy was performed on day 29. The specimen showed normal portal tracts. Fat-laden Ito cells were seen in the space of Disse (Fig. 5). These clinical features were consistent 145
K. Nagai et al.
Fig. 6. Clinical parameters
in relation to the patient’s daily diet.
with vitamin A poisoning and hepatic injury secondary to an eating disorder. She was discharged on September 28. On October 7, we again reviewed her history. She had stopped her excessive intake of pumpkin more than 2 years previously but had substituted for it an excessive intake of carrots, beta-carotene-rich vegetables, liver, and laver, still concerned with weight reduction (Fig. 6). Thus, the final diagnosis was vitamin A poisoning due to excessive intake of these foods, and hepatic injury related to an eating disorder. Her symptoms resolved as her diet was changed. She was instructed about maintaining a normal diet. After discharge, her alopecia continued for about 6 months, but her general condition stabilized. Her body weight increased by 6 kg in 6 months. Just prior to discharge, her serum vitamin-A and beta-carotene levels were 681 ng/ml retinol (normal 410-1200 ng/ml) and 272 beta-carotene (normal 37.0 pg/dl). During follow-up, serum vitamin-A levels showed almost no change and beta-carotene levels declined gradually to within normal limits. AST, ALT, hemo-
146
globin, TG, and CRP reached normal limits by the end of December. The patient has remained healthy, and menstruation resumed in January 1998 (Fig. 7).
Discussion Excessive intake of the yellow-green vegetables can lead to vitamin A toxicity. This is because most of the yellow-green vegetables consumed are carrots, pumpkin, and other beta-carotene-rich vegetables, all containing vitamin A. Most cases of vitamin A poisoning are a result of excessive vitamin A supplementation, accidental ingestion of vitamin A, or improper vitamin A therapy (6-10). Vitamin A poisoning from excessive intake of yellow-green vegetables, liver, and laver is very rare indeed. In particular, vitamin A poisoning associated with an excessive intake of laver is extremely rare. Laver (Nori) is a seaweed consumed in Japan, which contains approximately 250 pg/g beta-carotene. Our patient ate about 10 to 20 g of Nori per day. The vitamin A content was about 1400 to 2800 IU per day. She ate other beta-carotene-rich vegetables daily as well.
Vitamin A toxicity
Fig. 7. Vitamin A (retinol) andj3-carotene levels September 22 to December 24. On September 22, the patient’s blood chemistry test showed retinol681 nglml (normal 41&1200 nglml), B-carotene 272 pgldl (normal 687.0 pgidl). Retino1 levels were nearly unchanged, but p-carotene levels gradually declined to within normal limits with decreased intake of yellow-green vegetables, liver, and laver.
Hypercarotenemia causes yellow-orange pigmentation of the skin. This pigmentation has earlier been described under the names “aurantiasis” and “carotenosis” cutis. It is primarily a result of elevation of vitamin A active carotenoids, especially beta-carotene (11). In this case, although the serum beta-carotene level was high, serum retinol levels were almost within normal limits. In other severe cases reported, serum retinol levels were also normal (6). This may be partly due to impaired synthesis of the transport proteins, retinol binding protein, and transthyretin, and possibly also to impaired hepatic release of vitamin A (12). Additionally, although some 60-70% of dietary beta-carotene is converted into retinol in the human gut, excess beta-carotene intake does not cause hypervitaminosis A. This is mainly due to the inhibition of vitamin A production from beta-carotene when dietary intake of betacarotene is high. When beta-carotene is not converted into retinol, it is taken up unchanged by the intestine. As a result, beta-carotene is generally recognized as a safe nutrient and dietary supplement for humans (13). In this case, the final diagnosis was vitamin A poisoning due to excessive intake of these foods with resultant hepatic injury associated with the eating disorder. However, two important questions remain. The first is why the patient’s symptoms developed acutely under the condition of chronic toxicity. The toxic potential of retinoids may be dramatically affected by simultaneous exposure to other toxic substances. Examples of conditions enhancing vitamin A toxicity are the consumption of alcohol, a low protein intake and possibly a high intake of other fat-soluble vitamins such as E and perhaps D. The threshold for vitamin A toxicity may also be lowered by liver diseases such as
viral hepatitis (9,13). Another factor involved in vitamin A toxicity is age. Elderly persons may have quite a tolerance for high retinoid intake, whereas children can be intoxicated by low amounts (13). Therefore, a partial explanation for our patient’s acute onset might have been her age, secondary to the eating disorder. Another explanation might be an unknown virus, which did not seem to affect the liver, since there was no liver failure. We ruled out only HAV, HBV, HCV, EBV, CMV, Herpes simplex, measles, and mumps. The second issue was whether her hepatic injury was caused directly by vitamin A or by her eating disorder. Ascites and hepatomegaly developed acutely within just a few days. Liver needle biopsy showed fat-laden Ito cells in the space of Disse. These clinical features suggest hepatic injury caused by vitamin A. In vitamin A poisoning, liver function test abnormalities are nonspecific, and there are minor elevations of AST and ALT as well as a slight increase in ALP (13). Moreover, common effects of vitamin A poisoning in the human liver include hepatomegaly due to numerous, enlarged fat-storing cells, resulting in portal hypertension, with obstruction of blood flow in the sinusoids and obliteration of the space of Disse (13-15). There are also minor elevations of AST and ALT with eating disorders. Therefore, there is evidence that her hepatic injury was caused by vitamin A and possibly by other aspects of her eating disorder. The patient has remained healthy. But a strict follow-up will be necessary, because vitamin A overdose can also give rise to an insidious development of cirrhosis, which does not regress after withdrawal of vitamin A (16). Our experience with this patient was instructive from both a clinical and a public health perspective. The excessive intake of vitamin A-rich foods and juices should be addressed publicly and recognized as potentially hepatotoxic. This case highlights the need for greater educational efforts to prevent the consumption of excessive amounts of these foods.
References
K. Nagai et al. 7. Kransinki SD, Russel RM, Otradovec CL, Sadowski JA, Hartz SC, Jacob RA, et al. Relationship of vitamin A and vitamin E intake to fasting plasma retinol, retinolbinding protein, retinyl esters, carotene, alpha-tocopherol, and cholesterol among elderly people and young adults: increased plasma retinyl ester among vitamin A supplement users. Am J Clin Nutr 1989; 49: 112-20. 8. Herbert V Toxicity of 25.000 ILJ vitamin A supplements in health food users. Am J Clin Nutr 1982; 36: 185-6. 9. Hathcock JN, Hattan DG, Jenkins MY, McDonald JT, Ramnathan Sundaresan P Wilkening VL. Evaluation of vitamin A toxicity. Am J Clin Nutr 1990; 52: 183-202. 10. A de Francisco. K Zaman, HR Chowdhury, Waked MA, Chakraborty J, Yunus Mohamed. Accidental ingestion of vitamin A. Tropical Doctor 1995; 25: 187. 11. Curran CJ, Erdman JW, Nelson RA. Alteration in vitamin A and thyroid hormone status in anorexia nervosa and associated disorders. Am J Clin Nutr 1985; 42: 1183-91.
148
12. Geoffrey CF. Hypervitaminosis A. In: Drug-induced hepatic tibrosis and cirrhosis. Drug-induced Liver Disease 1994; 19: 44552. 13. Hendriks HFJ, Bosma A, Brouwer A. Fat-storing cells: hyperand hypovitaminosis A and the relationships with liver fibrosis. Semin Liver Dis 1993; 13: 72-80. 14. Russell RM, Boyer JL, Bagheri SA, Hruban Z. Hepatic injury from chronic hypervitaminosis A resulting in portal hypertension and ascites. N Engl J Med 1974; 291: 435-40. 15. Hruban Z, Russell RM, Boyer JL, Glagov S, Bagheri SA. Ultrastructural changes in livers of two patients with hypervitaminosis A. Am J Path01 1974; 76: 451-66. 16. Geubel AR Galogcy C. Dive C, Rahier J, Alves N. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology 1991; 100: 1701-9.