Phototherapy: from ancient Egypt to the new millennium.

Phototherapy with ultraviolet light was widely and successfully used in the past for treatment of a variety of diseases. Phototherapy with visible light alone has no benefit except in the therapy and prophylaxis of unconjugated hyperbilirubinemia. For this purpose, radiation in the region of approximately 480 to 500 nm is most effective and radiation above approximately 550 nm is useless. The principle effect of the treatment is not photodegradation of bilirubin, but conversion of the pigment to structural isomers that are more polar and more readily excreted than the normal, more toxic "dark" form of the pigment. This, coupled with some photooxidation of bilirubin, diminishes the overall pool of bilirubin in the body and lowers plasma levels. In the future, phototherapy may be supplanted by pharmacologic treatment, but in the near future, the most likely advance will be the introduction of novel forms of light production and delivery.

Current therapy for Crigler-Najjar syndrome type 1: report of a world registry.

This study represents a multicenter survey on the management of patients with Crigler-Najjar syndrome (CNS) type 1. The aim of the survey was to find guiding principles for physicians in the care of these patients. Fifty-seven patients were included. At the time of inclusion, 21 patients had received a liver transplant (37%). The average age at transplantation was 9.1 +/- 6.9 years (range, 1-23 years); the age of the patients who had not been transplanted at the time of inclusion was 6.9 +/- 6.0 years (range, 0-23 years). Brain damage had developed in 15 patients (26%). Five patients died, and 10 are alive with some degree of mental or physical handicap. In 2 patients, ages 22 and 23 years, early signs of bilirubin encephalopathy could be reversed, in 1 by prompt medical intervention followed by liver transplantation and in the other by prompt liver transplantation. Seven patients underwent transplantation with some degree of brain damage at the time of the surgery; 1 of these died after retransplantation, 2 improved neurologically, and 4 remained neurologically impaired. The age of 8 patients with and 13 without brain damage at or before transplantation was 14.3 +/- 5.9 and 5.9 +/- 5.4 years (P < .01), respectively. Therapy of CNS type 1 consists of phototherapy (12 h/d), followed by liver transplantation. Phototherapy, although initially very effective, is socially inconvenient and becomes less efficient in the older age group, thus also decreasing compliance. Currently, liver transplantation is the only effective therapy. This survey shows that, in a significant number of patients, liver transplantation is performed after some form of brain damage has already occurred. From this, one must conclude that liver transplantation should be performed at a young age, particularly in situations in which reliable administration of phototherapy cannot be guaranteed.

Quantum yields for laser photocyclization of bilirubin in the presence of human serum albumin. Dependence of quantum yield on excitation wavelength.

The quantum yield for laser photocyclization of bilirubin to lumirubin in the presence of human serum albumin (phi LR) was measured at five monochromatic excitation wavelengths in the range 450-530 nm. Solutions used were optically thin throughout the wavelength range and precautions were taken to exclude contributions from photocyclization of bilirubin XIII alpha impurities. The values obtained (7.2-18 x 10(-4] were lower than those previously reported and showed the following wavelength dependence: 457.9 less than 488.0 less than 501.7 less than 514.5 approximately equal to 528.7. However, the rate of lumirubin formation, normalized to constant fluence, decreased with wavelength over the same wavelength range and no evidence was found that photoisomerization of bilirubin to lumirubin is faster with green (514.5 or 528.7 nm) than with blue (457.9 or 488.0 nm) light. The stereoselectivity of the configurational isomerization of bilirubin to 4Z,15E and 4E,15Z isomers also was studied. This reaction became less regioselective for the 4Z,15E isomer with increasing wavelength. The observed wavelength dependence of phi LR and of the [4E,15Z]: [4Z,15E] ratio at photoequilibrium are consistent with an exciton coupling model in which intramolecular energy transfer can occur between the two pyrromethenone chromophores of the bilirubin molecule in the excited state. Relative rates of lumirubin formation in vivo at different excitation wavelengths and constant fluence were estimated for different optical thicknesses and for different skin thicknesses. These estimates suggest that the recently reported clinical equivalence of blue and green phototherapy lights probably reflects the marked variation of skin transmittance with wavelength more than wavelength-dependent photochemistry. The calculations also indicated that the optimal wavelength for phototherapy is probably on the long wavelength side of the bilirubin absorption maximum.

Photophysical studies of tin(IV)-protoporphyrin: potential phototoxicity of a chemotherapeutic agent proposed for the prevention of neonatal jaundice.

The strongly light-absorbing metalloporphyrin tin(IV)-protoporphyrin IX (SnPP) is currently being considered as a chemotherapeutic agent for preventing severe hyperbilirubinemia in newborns, a condition usually treated by phototherapy with visible light. To assess the potential phototoxicity of SnPP we studied the photophysics of the drug in aqueous and nonaqueous solutions using laser flash photolysis and pulse radiolysis. Quantum yields for formation of triplet-state excited SnPP were measured, along with triplet lifetimes and extinction coefficients. In addition, we measured quantum yields for the SnPP-photosensitized formation of singlet oxygen in MeO2H and 2H2O containing cetyltrimethylammonium bromide, using a time-resolved luminescence technique. Quantum yields for formation of triplet SnPP from monomeric ground-state SnPP are high (approximately equal to 0.6-0.8), and triplet lifetimes are long (approximately equal to 0.1-0.2 ms). Efficient quenching of triplet SnPP by molecular oxygen was seen with rate constants greater than 10(9) M-1.s-1. SnPP-photosensitized formation of singlet oxygen in aqueous and nonaqueous solvents was confirmed by the detection of the characteristic luminescence at 1270 nm (phi delta = 0.58 in MeO2H). The photophysical parameters and singlet oxygen-sensitizing efficiency of SnPP are similar to those reported for hematoporphyrin and other metal-free porphyrins known to be phototoxic to humans. These observations suggest that cutaneous photosensitivity arising from singlet-oxygen damage is likely to be an undesirable side-effect of SnPP therapy.

'Like a shrivelled blood orange'--bilirubin, jaundice, and phototherapy.

The biochemistry of bilirubin is reviewed with particular reference to newborn infants. The formation, properties, and metabolism of bilirubin are summarized and the importance of molecular shape, hydrogen-bonding, and polarity on the biologic disposition of bilirubin is emphasized. The chemical basis for the subtle influence of visible (blue) light on bilirubin structure and metabolism is explained, and recent concepts of the mechanism of phototherapy are presented. A glossary of current jargon is appended.

Light effects on transport and excretion of bilirubin in newborns.

There is now firm evidence that phototherapy has the following effects on bilirubin metabolism in humans with unconjugated hyperbilirubinemia. It rather rapidly converts a substantial fraction of the normal toxic 4Z, 15Z form of bilirubin to the 4Z, 15E form, which probably is less toxic. Simultaneously it enhances the overall excretion of bilirubin by converting it to oxidation products and structural and configurational isomers that are excretable in bile and urine without the need for glucuronidation. We know that these reactions occur in vivo because we have synthesized the compounds involved and have identified them unambiguously in vivo in the tissues of jaundiced babies and rats undergoing phototherapy. It is unlikely that these photobiological effects on bilirubin metabolism and transport are restricted to babies undergoing purposeful phototherapy. All babies are exposed to visible light and all develop hyperbilirubinemia during early life, with many exhibiting jaundice. Because there is no lower intensity threshold for photochemical reactions, it seems probable that the photobiological effects described in this paper occur in most newborns to some degree. Furthermore, similar photoprocesses would be expected to occur in the approximately 2-5% of the population who have the benign condition known as Gilbert's syndrome, which is characterized by chronic mild unconjugated hyperbilirubinemia, particularly when they sunbathe. Clearly, in the particular instance of phototherapy of neonatal jaundice, blue light is therapeutic. In some respects it acts like a drug, almost like the ideal magic bullet, because it is specific for the target molecule and safe. The main limitation of phototherapy is that it is inefficient, a limitation that seems to be imposed by transport processes in the body and the optics of skin rather than by the photochemical reactions on which it depends.

Phototherapy for neonatal jaundice: in vitro comparison of light sources.

Phototherapy results in the conversion of bilirubin to more water-soluble isomers. Six clinically used phototherapy lamps which differ in their emission spectra have been compared in their ability to produce configurational and structural isomers of bilirubin in vitro. For all of the lamps, the initial rate of configurational isomerization was highly correlated (r = 0.969) with the intensity of irradiation falling within the bilirubin absorption band. The percentage of the total bilirubin converted to the configurational isomer at equilibrium was dependent upon the spectral distribution of the lamp, and was greatest (26.2 +/- 1.3%) with the special blue lamp, which has a narrow spectral output centered at 445 nm. The rate of formation of the structural isomer, lumirubin, was generally dependent upon the intensity of irradiation within the bilirubin absorption band.

Phototherapy for neonatal jaundice: optimal wavelengths of light.

Phototherapy results in transformation of bilirubin to more water-soluble isomers. The efficacy of monochromatic visible light from 350 to 550 nm in the fastest photoisomerization reaction was quantitated by high-pressure liquid chromatography. The most effective wavelengths in vitro (i.e., leading to greater than 25% photoisomer) were in the blue spectrum from approximately 390 to 470 nm. Green light (530 nm) was not only ineffective for production of photoisomer, but capable of reversing the reaction. The results indicate that any clinically useful phototherapy unit must include the blue portion of the visible spectrum, and suggest that the effectiveness of phototherapy may be increased by elimination of green light.

Hepatic excretion of circulating bilirubin photoproducts in the Gunn rat.

To investigate the origin and metabolism of the intermediates that occur in blood during phototherapy of neonatal jaundice, serum from irradiated homozygous Gunn rats was injected intravenously into other homozygous Gunn rats fitted with bile fistulas, and the excretion of pigment in the bile of the recipient rats was studied. In some experiments the donor rats were labeled with [14C]bilirubin; in others the recipient rats were labeled. Injection of donor serum from irradiated rats caused a transient burst of pigment excretion in the bile of the recipient rats. However, simultaneous bursts of pigment and 14C excretion were observed only when the donor rat was labeled and the recipient rat was not, and not when the donor rat was unlabeled and the recipient rat was labeled. In addition, there was simultaneous transient enhanced excretion of pigment and label when labeled recipient rats were exposed briefly to blue light. We conclude that (a) the phototherapy intermediates previously detected spectroscopically in serum are formed from bilirubin and are excreted in bile independently of bilirubin; (b) the enhanced excretion of pigment in bile during phototherapy is not caused by complex formation between bilirubin and photoproducts, or by liver damage produced by photoproducts or light.

Blue light and bilirubin excretion.

Blue light converts bilirubin in the skin of jaundiced rats to metastable geometric isomers that are transported in blood and excreted in bile. The same reaction probably occurs in jaundiced babies exposed to light, particularly during treatment with phototherapy. Excretion of unisomerized bilirubin is prevented by intramolecular hydrogen bonding, and the pigment has to be metabolized to more polar derivatives to be excreted efficiently.

Jaundice phototherapy: micro flow-cell photometry reveals rapid biliary response of Gunn rats to light.

Hepatic pigment clearance in rats can be followed continuously with photometric detectors designed for high-pressure liquid chromatography. This method showed that light has a fast effect on bilirubin metabolism in homozygous Gunn rats, even at low doses and intensities. This is consistent with geometric isomerization of bilirubin IXalpha as a primary step in phototherapy.

Photochemotherapy of glioma cells by visible light and hematoporphyrin.

Malignant tumors take up and retain hematoporphyrin to a much greater extent than do normal tissues. Porphyrins are photodynamic agents that sensitize cells so that they are damaged by exposure to light. Treatment with hematoporphyrin followed by irradiation with light can destroy glioma cells in culture in less than 8 min and gliomas growing s.c. in rats in about 40 min. Photochemotherapy may become useful in the management of malignant tumors that are resistant to current methods of treatment.