Roles and pitfalls of transplantation in human porphyria

In this issue of Liver Transplantation, the publication reporting “Liver Transplantation for Erythropoietic Protoporphyria (EPP) Liver Disease” provides important new information. The human porphyrias can be classified by the defective step in heme biosynthesis, by the clinical syndrome such as acute neurovisceral hepatic porphyria, or by the main organ manifesting defective heme biosynthesis.1, 2 Using the latter approach, of the seven human porphyrias, two are bone marrow or erythropoietic in origin and the other five, the hepatic porphyrias, reflect the metabolic defect in the liver. Four of the latter can present as acute porphyria and three as photocutaneous diseases. Only Porphyria Cutanea Tarda, often associated with liver damage, e.g., hepatitis C, and iron overload, is purely a cutaneous porphyria with no propensity for an acute attack. Epp, erythropoietic protoporphyria; ALA, delta-aminolevulinic acid; PBG, porphobilinogen. Erythropoietic Porphyrias mainly manifest as moderate to severe photocutaneous diseases, and in EPP, hepatobiliary complications, while a particular feature of this porphyria, occur only in a minority of patients. Thus, it is not surprising that the first report of hepatobiliary manifestations came from a dermatologist, Magnus et al. (1961). His group recognized EPP with solar urticaria as a new porphyria syndrome in a 35-year-old restaurateur who had a cholecystectomy 5 years previously for a solitary gallstone.3 Several other investigators reported biliary calculi in EPP at an age younger than expected in cholelithiasis. Protoporphyrin-containing stones were described by Cripps and Scheuer in 1965.4 This demonstrated that protoporphyrin in sufficient concentrations derived from the bone marrow but, cleared by the liver, might exceed the ability to be solubilized in biliary micelles to form calculi. If this occurred in bile, what might happen in the liver? The first evidence of hepatic involvement in EPP was reported in 1963 by Redeker et al. (International Porphyria Conference 1963) and confirmed by Cripps and Scheuer in 1965.4 Hepatocyte protoporphyrin in the cytoplasm was confirmed by microfluorospectrophotometry, by dense and irregularly scattered foci of dark brown pigment corresponding to protoporphyrin by fluorescent microscopy,4 and by birefringence in polarized light microscopy.5 Protoporphyrin is hepatotoxic.6-8 Between 1968 and 1980, there were reports of serious hepatic disease with abdominal pain simulating biliary colic and the development of jaundice heralding a relentless downhill fatal course in months.9-11 At laparotomy or autopsy, the livers were black (from protoporphyrin pigment), firm, and nodular. Familial portal fibrosis or cirrhosis has been reported. The metabolic basis for the liver disease in EPP is still an open question. The enzyme defect in EPP is diminished activity of the dimeric inner mitochondrial enzyme, ferrochelatase. This enzyme catalyzes the ultimate stage in heme biosynthesis, which is the insertion of iron into protoporphyrin IX.1 It is an autosomal dominant disease, but with one mutant allele, EPP patients have only 10 to 25% of normal activity.12, 13 The mutant enzyme may interfere with the catalytic activity of normal enzyme in the ferrochelatase dimer or the interaction maybe more complex. Ferrochelatase activity is deficient in many tissues studied, including the liver, which may also overproduce protoporphyrin, and the intrahepatic trafficking of protoporphyrin is not known. However, the 65% recurrence of disease post liver transplantation, as reported in this journal, suggests that pigment loading the hepatocytes from the bone marrow protoporphyrin overproduction is the main pathogenetic basis of EPP liver disease. All porphyrins absorb light energy with a major band near 400 nm (the Soret band) and four smaller bands between 500 and 630 nm. Excitation of this pigment by light energy is the basis of photocutaneous porphyria, and longer wave bands have been used therapeutically in photodynamic therapy of cancer and Barrett's esophagitis, following priming of abnormal cells with a porphyrin derivative, Liver transplantation in EPP cirrhosis has unique complications. The diseased liver and intraabdominal tissues are loaded with porphyrin pigment. Thus, during surgery, operative lights can cause harm by provoking photocutaneous and photo visceral damage. For this reason, special filters were placed over the operating room lights to minimize tissue burns. Another unique complication, pre- and peri-operatively, was neuropathy. Severe motor neuropathy occurred in six patients, four of whom required prolonged ventilation. Thus the authors recommend I.V. hematin and plasmapheresis, for EPP cirrhosis requiring orthotopic liver transplantation to minimize these crises. Post surgical recurrence of EPP liver disease occurred in 11 of the 17 patients (65%) who survived more than 2 months after liver transplantation. The overall graft survival rates vs. the UNOS data base of all primary liver transplants were comparable: 85% at 1 year, 69% at 5 years, and 47% at 10 years. However, six graft losses were caused by recurrent EPP liver disease. Should bone marrow transplantation, to correct the deficiency of ferrochelatase activity of hemopoietic tissues, be offered? Bone marrow transplantation has reversed the porphyria in one patient with EPP in whom the transplant was indicated for myelogenous leukemia14 and in experimental mouse models of EPP.15, 16 In matched sibling donors, the 3-year survival in bone marrow transplantation is 70–90%.17 The authors recommend consideration of bone marrow transplantation, if a matched sibling is available, early after liver transplantation. The use of liver and bone marrow transplantation raises interesting therapeutic possibilities in other human porphyrias. A candidate bone marrow porphyria is Congenital Erythropoietic Porphyria, also known as Gunther's disease.18 This is a rare autosomal recessive defect of the fourth enzyme of heme biosynthesis, uroporphyrinogen III synthase, and it is associated with dyserythropoiesis and normoblastic hyperactivity. This leads to overproduction of non-physiological hemoglobin heme precursors uroporphyrin I and coproporphyrin I. These accumulate in the skin, bones, and teeth. Exposure to sunlight usually leads to disabling photo mutilation with the loss of facial features such as the nose, ears, and lips. The teeth are brown, and fluoresce and the hands exhibit contractures and loss of fingers. The quality of life is dismal, requiring life-long avoidance of sunlight. Splenectomy, blood transfusions, sorbent therapy to adsorb intestinal porphyrins, I.V hematin, and sunscreens are minimally effective. Four case reports of curative allogenic or stem cell bone marrow transplant have been reported.19-22 The grafted bone marrow was associated with a substantial fall in porphyrin levels and photocutaneous sensitivity. The hepatic porphyrias are important hepatotogic clinical entities. The reader is encouraged to refer to the recent review article in the Annals of Internal Medicine in March 2005.2 The four acute hepatic porphyrias reflect defects in the enzymes catalyzing the second, third, fifth, and sixth steps in the hepatic heme biosynthetic pathway. Acute Intermittent Porphyria (AIP) and Variegate Porphyria are the most common. Several retrospective Scandinavian studies show a 60–70-fold increased prevalence of hepatocellular carcinoma compared to national age and sex matched controls.23-26 None of these patients had cirrhosis, chronic hepatitis, or steatohepatitis (Porphyrins and Porphyria Conference, Cape Town South Africa, 2005). This data strongly suggests hepatoma surveillance in this patient population. Induction of hepatic hemoprotein drug metabolizing enzymes can precipitate an acute neurovisceral attack, most commonly acute abdominal pain, vomiting, tachycardia, mild hypertension, polyneuropathy, hyponatremia, and mental symptoms. Diagnosis still depends on raised urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels above baseline. The treatment of acute porphyria with supportive measures includes carbohydrate loading, but the hallmark of therapy is I.V hemin given as Panhematin (Ovation Pharmaceuticals), which is the only FDA approved hemin therapy in the United States, or Heme-Arginate. This repletes hepatic heme depletion and thereby diminishes heme precursor overproduction including ALA and PBG. Panhematin, when given early in acute prophyria, usually aborts the acute attack. There is a small recalcitrant group of patients with recurrent acute porphyria, almost exclusively women, related to ovulation. Panhematin given in mid menstrual cycle usually helps as does hormonal manipulation of sex steroids. Some patients become refractory to these therapies and develop dependency to narcotics and frequent hospitalization for control of pain. Their quality of life is miserable and suicides have been reported in this porphyric subset. Are acute attacks the result of the neurotoxic effects of ALA and PBG or tissue heme depletion. An intriguing possibility is deficiency of nitric oxide synthase hemoproteins. These play an important role in the regulation of gastrointestinal motility and renal blood flow, and pathophysiologically may contribute to the abdominal pain, vomiting, and hypertension so common in the acute attack. Liver transplantation has been reported to resolve these recurrent attacks. Two recent reports published in 200427, 28 show liver transplantation in AIP and VP to result in both biochemical and clinical remission. This would favor ALA and PBG overproduced by the liver rather than extrahepatic tissue heme depletion as the pathogenetic mechanism for the acute symptoms. Transplantation of hepatocytes or specific gene replacement therapy is future therapeutic options. Orthotopic liver transplantation has been shown in the publication in this journal to have an important role in decompensated EPP cirrhotic. However this paper has broader implications as to the utility of liver or bone marrow transplantation or both in human porphyria.