Xanthoderma During Therapy for Falciparum Malaria

CASE REPORT

A 33-year-old liberian-born man returned from a trip to Liberia with fever, chills, headache, and an urticarial eruption over his flank and was noted to have intense yellowing of the palms of his hands and the soles of his feet. The patient presented to the Miriam Hospital Travel Clinic in Providence, Rhode Island. He had been seen in advance of travel for general advice regarding malaria prophylaxis and had received gamma globulin, yellow fever vaccine, diphtheria-tetanus, enhanced inactivated polio vaccine boosters, and oral typhoid vaccine. He took mefloquine, beginning one week prior to travel, and weekly for the duration of his one-month stay, but he did not use repellents and had received multiple insect bites.

The patient had discontinued use of mefloquine upon returning to the United States. He reported having no allergies or taking any additional medications other than ibuprofen. His symptom complex began within one week of discontinuing mefloquine. Malaria smears were positive for intraerythrocytic ring forms, consistent with P. falciparum. Admission for inpatient treatment was suggested but declined. While attempting to begin outpatient treatment with quinine and doxycycline, he developed worsening headaches, which prompted his admission.

The most notable part of his physical examination was the intense bright yellow discoloration of his palms and soles, out of proportion to his mildly icteric sclerae and mucous membranes. Some pruritic papules were located over the lower flank and buttock regions. The rest of his examination was normal. Significant laboratory values included a hemoglobin of 13.9 g/dL, platelet count of 89,000/mcL and serum creatinine 1.1 mg/dL, glucose 125 mg/dL, LDH 213 U/L, albumin 3.6 g/dL, total bilirubin 0.8 mg/dL (direct bilirubin 0.4), and mild G6PD deficiency. Other liver function tests were within normal limits.

He continued treatment for falciparum malaria with improvement of his symptoms and clearance of the parasitemia by day 3. Dietary history was explored regarding the possibility of hypercarotenemia, although he denied having an unusually large intake of carrots or any other foods associated with hypercarotenemia on preliminary review. However, his measured serum carotene level was 410 mcg/mL (normal, 50-200) during this admission.

Table

Causes for xanthoderma when hyperbilirubinemia is not present

1. Excessive dietary intake of carotene, lycopene, or riboflavin. Includes fruits, vegetables, and oils (red palm oil) and vitamins high in such constituents.

2. Serum lipid elevation causing binding of lipophilic carotinoids. Seen in some diabetics, hypothyroidism, hypopituitarism, and nephrotic syndrome.

3. Chemical exposure or pharmaceuticals including quinacrine (Atabrine), fluorescein (orange-red dye), saffron (food coloring and cooking spice), santonin (an anthelmintic derived from wormwood), dinitrophenol (a toxic dye), tetryl acid (yellow crystalline explosive primer) and picric acid (trinitrophenol), and acriflavine (formerly used as a topical and urinary antiseptic).

4. Multiple myeloma—possibly caused by IgG possessing anti-flavin activity binding to riboflavin.

5. Inborn errors of beta-carotene metabolism, male castration, liver disease, and anorexia nervosa are among the other possible causes of xanthoderma.

CASE REPORT AND COMMENT BY MARIA D. MILENO, MD, AND FRANK J. BIA, MD, MPH

Xanthoderma refers to yellow-orange discoloration of the skin. Once called "aurantiasis cutis," the term referred to the yellow pigmentation of the skin that resulted from the consumption of Japanese oranges. If jaundice is ruled out with normal serum bilirubin and absence of bilirubin in the urine, hypercarotenemia is likely. Excessive consumption of carotene-rich foods is by far the most common cause of carotenemia.1 Carotenes occur in all pigmented vegetables and fruits. Diet-induced carotenemia may be seen in food faddists,2 patients who attempt to lose weight by eating low-calorie food items such as carrots, and children on a homogenized diet. (It may be interesting to those who are currently immersed in the care of babies that carrots are now added to most strained commercial baby foods on the market because carrots are cheap and readily available.)

Lycopene is a physiologic inert structural isomer of beta-carotene that is found in tomatoes, beets, and rose hips. Other medical syndromes have been associated with xanthoderma, including diabetes mellitus, hypothyroidism,3 and nephrotic syndrome, which cause elevated levels of serum lipids that bind the lipophilic carotenes and result in prolonged yellow-orange skin discoloration. Bounin and Levinson reported carotenemia in a group of patients with chronic malaria who had been inadequately treated. Their results were presented in a report to the Therapeutic Society of the School of Medicine at Rostow-on-the-Don in 1934. It is not clear that dietary factors were recognized as potential contributing factors for malaria patients in that report.4 Bray reported hypercarotenemia in two young Biafran brothers with falciparum malaria who were being treated in London around 1970.5 He considered the possibility that their diet of cassava and yams might have caused the documented hypercarotenemia, and that it was not related to malaria per se.

There are also case reports of patients with xanthoderma as a manifestation of multiple myeloma.6 An inborn error of beta-carotene’s metabolism to vitamin A, without lipidemia or over-ingestion of carotene, has been described. Other conditions associated with carotenemia are listed in the table. Excess ingestion or percutaneous absorption of chemicals such as quinacrine, mepacrine, fluorescein, saffron, santonin, dinitrophenol, tetryl and picric acids, and canthaxanthine may produce a yellow pigmentation of the skin. Canthaxanthine is the principle coloring constituent in a number of commercial tanning capsules. Our patient had none of the above reasons for his hypercarotenemia.

Our review of the literature revealed yet another case of a Liberian patient with hypercarotenemia who was being evaluated for vivax malaria in Memphis, TN. In that case, carotenemia was due to the ingestion of red palm oil, which the patient consumed while living in Liberia.7 Further conversations with our patient revealed that he also consumed great quantities of red palm oil, as he usually does upon visiting Liberia. This particular vegetable oil contains yellow beta-carotene, and it is often used for cooking throughout west Africa.8 Xanthoderma, or more specifically carotenoderma, is endemic in west Africa where red palm oil is used for frying and added to soups or stews. It is rich in carotinoids (0.05-0.2% by weight). Pure palm oil is expensive but readily available in urban areas of North America. Consultants to patients returning from Liberia and other west African nations should be aware of this interesting skin finding and its etiology. Not jaundiced? Xanthoderma? Think carotene. Think red palm oil.

References

1. Leung AKC. Carotenemia. Adv Pediatr 1987;34:223-248.

2. Hashimoto H. Carotinoids pigmentation of the skin resulting from a vegetarian diet. JAMA 1922;78:1111-1113.

3. al-Jubouri MA, et al. Xanthoderma: An unusual presentation of hypothyroidism. J Clin Pathol 1994;47:850-851.

4. Bounin E, Lévinson M. Sur la clinique et la pathogénèse de la caroténémie. Z Vitaminforsch 1936;5:12-21.

5. Bray BV. Orange soles. Lancet 1970;1:1348.

6. Clegg KE, Schiffman FJ. Carrot juice xanthoderma: An orange patient with multiple myeloma. RI Med 1993;78:361-363.

7. Stack KM, et al. Xanthoderma: Case report and differential diagnosis. Cutis 1988;41:100-102.

8. Person JR. Red palms and orange palms. Arch Dermatol 1981;117:757.