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

Abstract

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.

RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice

“…Although hemin is effective, it is slow to take effect and is associated with various side effects such as phlebitis, thrombosis, and iron overload (15). Recently, orthotopic liver transplantation has successfully treated several acute hepatic porphyria patients with recurrent and uncontrollable attacks (18)(19)(20), but it is associated with high morbidity and limited organ availability and should be reserved as a last-resort treatment. Thus, there is a clear need for a more effective, fasteracting, and safer therapy.…”

“…and incapacitating attacks resulted in the rapid normalization of ALA and PBG levels and the abrupt remission of attacks (18)(19)(20). Thus, the liver is the primary site of pathology in the acute hepatic porphyrias, and therapies designed to inhibit the induced overexpression of ALAS1 and the resulting elevation of ALA and PBG would prevent or treat the acute attacks in all four acute hepatic porphyrias.…”

Liver Fibrosis Associated with Iron Accumulation Due to Long-Term Heme-Arginate Treatment in Acute Intermittent Porphyria: A Case Series

“…The intravenously administrated heme inhibits the upregulation of ALA synthase in the liver resulting in a dramatic reduction of urinary and plasma ALA and PBG (Puy et al 2010). Liver transplantation has become a valid treatment option in selected patients with recurrent attacks and significant disabling symptoms with poor quality of life (Seth et al 2007;Singal et al 2014).…”

Hepatic Artery Thrombosis

“…Only 5 of these patients were previously reported in the literature, and the follow-up was shorter. [4][5][6] Nine patients (90%) were female, and this reflects the increased prevalence of symptomatic acute porphyria in women. The median age at transplantation (31 years, range ¼ 18-50 years) was much lower than the median age of the traditional LT population.…”

“…Only a small number of cases of LT for AIP have been reported so far. [4][5][6] Using data from the UK Transplant Registry (which is maintained by National Health Service Blood and Transplant on behalf of transplant services in the United Kingdom and Ireland), we describe a larger national series with longer follow-up (median followup time ¼ 23.4 months), and we include the indications and outcomes for all 10 LT procedures performed for AIP in the United Kingdom and Ireland since the first transplant in 2002.…”