Current and innovative emerging therapies for porphyrias with hepatic involvement.

Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway intermediates. The symptoms depend upon the chemical characteristics of these substances. Porphyrins are photoreactive and cause photocutaneous lesions on sunlight-exposed areas, whereas accumulation of porphyrin precursors is related to acute neurovisceral attacks. Current therapies are suboptimal and mostly address symptoms rather than underlying disease mechanisms. Advances in the understanding of the molecular bases and pathogenesis of porphyrias have paved the way for the development of new therapeutic strategies. In this Clinical Trial Watch we summarise the basic principles of these emerging approaches and what is currently known about their application to porphyrias of hepatic origin or with hepatic involvement.

Liver transplantation for acute intermittent porphyria: a viable treatment?

BACKGROUND: Acute intermittent porphyria (AIP) is the most common hepatic porphyria. Its clinical presentation includes severe disabling and life-threatening neurovisceral symptoms and acute psychiatric symptoms. These symptoms result from the overproduction and accumulation of porphyrin precursors, 5-aminoleuvulinic acid (ALA) and porphobilinogen (PBG). The effect of medical treatment is transient and is not effective once irreversible neurological damage has occurred. Liver transplantation (LT) replaces hepatic enzymes and can restore normal excretion of ALA and PBG and prevent acute attacks. METHOD: Two cases of LT for AIP were identified retrospectively from a prospectively maintained LT database. RESULT: LT was successful with resolution of AIP in two patients who suffered from repeated acute attacks. CONCLUSION: LT can correct the underlying metabolic abnormality in AIP and improves quality of life significantly.

Liver transplantation for porphyria: who, when, and how?

Porphyrias are a heterogenous group of diseases that may result in disabling or life threatening neurovisceral symptoms and/or cutaneous photosensitivity. In acute intermittent porphyria, the clinical features, particularly neurological symptoms, may be life-threatening and disabling. Conventional treatment with human hemin, though effective in reducing symptoms, does not reverse neuropathy when structural nerve damage has occurred and may cause intense phlebitis. Liver transplantation (LT) may be considered as treatment for those with repeated life-threatening acute attacks resulting in poor quality of life, requirement of ventilatory support, and progressive loss of venous access due to hemin infusion. Patients with variegate porphyria (VP) present after puberty with neurovisceral symptoms and skin manifestations. LT resolved VP in the 1 patient reported in the literature. Aminolaevulinic acid dehydratase deficient porphyria is a rare autosomal recessive disorder and a child who presented with failure to thrive and required transfusions and parenteral nutrition did not improve with LT. In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin in the bone marrow. Protoporphyrin is hepatotoxic and pigment loading of hepatocytes and bile canalicular sludging may result in progressive cholestasis and cirrhosis. LT is beneficial for such patients with end-stage liver disease. Perioperative management includes use of filters on operative lights to prevent skin burns and intestinal perforation. Other concerns include development of neuropathy, biliary complications, and recurrent liver disease. This review addresses the rationale, patient selection, evaluation, management issues, and technique of performing LT in various types of porphyria.

Hepatic protoporphyrin metabolism in patients with advanced protoporphyric liver disease.

Protoporphyria is a genetic disorder in which liver damage is caused by the toxic effect of protoporphyrin accumulation in the liver. In this study protoporphyrin was measured in the resected livers of 7 patients who had liver transplantation and an additional patient from whom liver tissue was obtained post mortem. Comparison of liver, erythrocyte and serum protoporphyrin levels demonstrated a marked gradient between these compartments: erythrocyte, 5781 +/- 655 micrograms/dl; serum, 384 +/- 102 micrograms/dl; liver 377,238 +/- 55,568 micrograms/100 gm wet weight, (mean +/- SE). Protoporphyrin levels in bile of 3 patients were 55,559, and 1,153 micrograms/dl, indicating a gradient between liver and bile as well. Examination of the livers by polarization microscopy and electron microscopy demonstrated protoporphyrin pigment crystals. In one patient who had recurrent liver disease after transplantation, the protoporphyrin concentration in the graft at the time of death was similar to that in the resected liver. These data indicate that liver protoporphyrin levels in patients with advanced protoporphyric liver disease are much higher than levels in blood and bile, in part because protoporphyrin forms crystalline deposits in liver tissue. Thus, progressive hepatic accumulation of protoporphyrin occurs in the face of impaired biliary excretion. An intrinsic defect in hepatic excretion of protoporphyrin is probably not necessary for this condition to develop because liver disease can occur in the graft following transplantation.

Liver transplantation in a boy with acute porphyria due to aminolaevulinate dehydratase deficiency.

The clinical and biochemical outcome of a liver transplantation in a seven-year-old boy with acute porphyria due to aminolaevulinate dehydratase deficiency is described. Before transplantation standard liver function tests were normal and the rationale for transplantation was that the new liver would reduce the metabolic disturbance and thus avert the porphyric symptoms. During the year after the transplantation, the functioning of the new liver has been excellent. Basal excretion of porphyrin and porphyrin precursors has remained unchanged but, with the new liver transplant the patient has been able to withstand several porphyrinogenic challenges without increasing the excretion. Episodes of neurological and respiratory crises may have been due to persistent porphyric vulnerability. Alternatively, two early attacks may have been caused by neurotoxic effects of cyclosporin in combination with the existing damage to nervous tissue.