ERYTHROPOIETIC protoporphyria (EPP) is an inherited disorder of porphyrin metabolism. 1Common manifestations of EPP include photosensitivity and mild hepatic dysfunction. Occasionally, in patients with EPP, end-stage hepatic failure and, very rarely, neurologic dysfunction develop. 2–7We describe the perioperative treatment of a patient with EPP and end-stage liver disease, necessitating liver transplantation, whose care was complicated by photosensitivity and severe polyneuropathy.
A 54-yr-old man with a medical history of EPP associated with hepatic dysfunction and photosensitivity manifesting as painful swelling and skin discoloration during exposure to artificial or natural light was admitted to the hospital with increasing abdominal pain, low-grade fever, and increasing fatigue. Neurologic examination at admission revealed normal sensory motor, deep-tendon reflex and cranial nerve function and the absence of asterixis. During the patient's first 4 weeks of hospital admission, his liver function deteriorated and generalized weakness developed, with which he involuntarily dropped objects, such as cigarettes and cups, and complained that “his mouth and body felt paralyzed.” He was treated with four cycles of plasmapheresis, which reduced his total serum porphyrin level from an initial value of 2,792 μg/dl to a minimum of 448 μg/dl (normal range, 16–60 μg/dl), but his hepatic and neurologic function continued to worsen. By the fifth week, the patient was unable to raise his legs, his speech was unclear, he had difficulty swallowing, and he was intubated for respiratory failure. During his sixth week of hospital admission, a suitable donor liver became available.
In preparation for taking this photosensitive patient to the operating room, the intensities of the lights in the operating room were assessed using a detector and photometer (model numbers XRD140A and 1700, respectively; International Light, Newburyport, MA). The detector, which had a detection range of 350 nm to 500 nm, was placed on a table in the center of the operating room directly under the focused lights. Covering the overhead incandescent operating room lights with an amber TA-81 filter (Madico Inc., Woburn, MA) reduced their intensities in the 350–500 nm range by 97%. The addition of a clear filter (CLS-200-X; Madico Inc., Woburn, MA) further reduced the intensity to immeasurable levels. Similarly, the TA-81 and CLS-200-X filters together reduced the light intensity from a halogen head lamp to immeasurably low levels in the aforementioned wavelength range. The light intensity of the operating room's three fluorescent ceiling lights was only 5% of that produced by even a single overhead incandescent operating room light, and therefore we concluded that it was not necessary to filter this light during surgery.
The patient was transported to the operating room while intubated but awake. Anesthesia was induced with fentanyl and was maintained with nitrous oxide and isoflurane and small doses of muscle relaxant. The procedure proceeded smoothly, with an estimated blood loss of 4,000 ml, and the patient was transported in stable condition to a cubicle that was equipped with light filters in the intensive care unit. The patient was awake by the next morning and his new liver functioned well. Although still weak, the patient was oxygenated and was ventilating well with low levels of pressure support in the morning of postoperative day 3 and a trial extubation was performed. However, he was reintubated later that day secondary to tachypnea and respiratory fatigue with an arterial carbon dioxide tension of 99 mmHg. A neurologic evaluation showed profound, diffuse proximal muscle weakness with some distal sparing. Deep-tendon and gag reflexes were absent. Electromyography confirmed the presence of a profound axonal neuropathy, showing attenuated compound muscle action potentials and sensory nerve action potentials in the upper extremities, relatively preserved compound muscle action potentials and sensory nerve action potentials in the lower extremities, and active proximal denervation. A lumbar puncture revealed a normal level of protein in the cerebrospinal fluid. The patient was extubated again on postoperative day 9, but was reintubated 3 days later for increasing respiratory distress. He returned to the operating room on postoperative day 14 for placement of a tracheostomy and jejunostomy under filtered light. One month after the transplantation surgery, the patient was completely awake and alert but remained areflexic and completely unable to raise his arms or legs. He required mechanical ventilation until the ninth postoperative week. At that time, he recovered sufficient strength to lift his right arm several inches from his bed. After nearly a year of physical rehabilitation, he has recovered most of his strength and has resumed work.
Porphyrias are diseases resulting from either inherited or acquired enzymatic abnormalities in heme synthesis. 1First described by Magnus in 1961, EPP results from an inherited error of porphyrin metabolism caused by a partial deficiency of ferrochelatase, the terminal enzyme of the heme biosynthetic pathway that catalyzes the insertion of iron into protoporphyrin IX. 8The clinical manifestations of EPP result from the accumulation of free protoporphyrin in the skin, erythrocytes, plasma, bile, and feces. 9Although mild abnormalities in liver function test results are common, progression to hepatic failure may occur. It is believed that crystalline protoporphyrin deposits lead to hepatocyte injury. Transplantation is an effective treatment option for protoporphyrin-induced liver failure, but recurrent hepatic graft injury in patients with EPP has been reported. 10
Neurologic abnormalities are not uncommon in patients with hepatic porphyrias, such as acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, but have rarely been reported in patients with EPP. In our review of the English literature, we found reports of only 12 other cases of neurologic complications arising in patients with EPP. 2–6In all but one patient, neurologic dysfunction occurred in the setting of end-stage liver disease and high levels of protoporphyrins in erythrocytes or plasma, or both. In the one exception, the neuropathy was attributed to Guillain–Barre syndrome, suggesting that the polyneuropathy seen in patients with EPP may result from an accumulation of protoporphyrin within nerve tissue. 4Postoperatively, our patient exhibited profound, diffuse weakness and a normal cerebrospinal fluid protein, and electromyographic studies were indicative of active denervation without demyelination. These findings have been reported in the small number of other patients with EPP-associated neuropathy and are not consistent with the demyelinating syndrome of Guillain–Barre syndrome. 11Cyclosporin and tacrolimus have also been associated with neurologic dysfunction. 12,13Although these drugs may have contributed to the postoperative weakness exhibited by our patient, significant dysfunction was noted before the administration of immunosuppressive drugs. Finally, profound muscle weakness may be a manifestation of critical illness polyneuropathy. In our patient, the time of onset, the greater proximal involvement, the rapid progression of weakness, and the electromyography findings tend to argue against this diagnosis, although we cannot exclude the possibility that it contributed to his neuropathy, particularly in the immediate perioperative period.
In addition to polyneuropathy, our patient also experienced photosensitivity. This is not an uncommon complaint of patients with EPP who have high levels of protoporphyrin, and it presents a practical problem for medical providers in the operating room. 14Protoporphyrin absorbs light in the violet region, with a maximal absorption between 400–410 nm. This may lead to the formation of free radicals that can induce tissue damage, ultimately leading to the formation of biliary fistulas, intestinal perforation, and even death. 2,3,15
Two preventive measures were used in this patient to decrease the risk of light-induced injury. First, plasmapheresis was used preoperatively to decrease protoporphyrin levels. 16Exchange transfusion has also been suggested as a treatment before surgery, although it was not performed in this case. 17Second, the operating room lights and halogen head lamps were fitted with filters to minimize light output at the wavelengths absorbed by protoporphyrin. 18Filters were not placed over the fluorescent ceiling lights because we thought that the light output was not sufficient to cause tissue damage. In retrospect, it may have been prudent to filter these lights as well; after sitting on a table in the operating room for 2 hours following resection, the native liver developed a dark discoloration on fluorescent light–exposed surface, indicative of a phototoxic reaction.
The authors thank Saad Shafqat, M.D., Ph.D., for helpful comments during the preparation of this report.