Introduction

Acute intermittent porphyria (AIP) is an autosomal dominant disorder of the third enzyme in the heme biosynthetic pathway, resulting from a partial deficiency of hydroxymethyl-bilane synthase (HMB synthase)/porphobilinogen (PBG) deaminase.^[1] It is the most common hepatic porphyria, with a frequency of 1 in 20 000, but only a small proportion of patients (<10%) present with clinical disease.^{[1, 2]}

The major manifestations of the disease are severe neurovisceral symptoms and are often accompanied by nausea, vomiting, constipation, and diarrhea. Sudden death, presumably from cardiac arrhythmia, may also occur during an acute attack.^[3-5] Peripheral neuropathy, which is primarily a motor neuropathy, usually develops in the setting of abdominal pain and other features of a severe acute attack.^[6] Long-term complications include chronic arterial hypertension, renal impairment, and hepatocellular carcinoma. The overproduction and accumulation of porphyrin precursors, 5-aminoleuvulinic acid (ALA) and PBG coupled with a decreased free heme pool can adversely affect cytochrome P450 and important antioxidative enzymes, leading to an impaired detoxification mechanism in the liver. The intrinsic aberrations in AIP and endogenous oxidative damage to DNA have been postulated to incite carcinogenic mutations in the genome of liver cells.^{[7, 8]}

AIP is diagnosed by increased urinary PBG and 5-ALA excretion during a symptomatic relapse, with normal concentrations of fecal porphyrin. Treatment of acute episodes includes intravenous dextrose, correction of electrolytes, analgesia and intravenous hem arginate or suppression of ovulation in female patients.^[9-13]

Avoidance of precipitating factors is important in the management of AIP. Endogenous hormones, particularly progesterone, play a role and may account for the increased frequency of attacks in women. Therefore, many women with AIP receive prophylaxis by monthly hemin infusions. However, the effect of this treatment is transient or ineffective once irreversible neurological damage has occurred. In addition, it cannot be given orally as it is catabolized by heme-oxygenase during intestinal absorption. Patients who receive frequent hemin infusions are at risk of side-effects such as hemochromatosis, acute renal tubular damage, and phlebitis. Intense phlebitis is a major issue, and may compromise venous access. Frequent administration, therefore, requires long-term placement of central venous catheters. Patients with severe AIP have a very poor quality of life, and a standard 4-day hemin treatment costs approximately $8000.^[1]

Liver transplantation (LT) has been reported by Soonawalla et al as a treatment for AIP with improved quality of life.^{[14, 15]} The literature on transplantation for AIP is scarce. Here we report two cases of LT for AIP.

Case reports

Case 1

A 31-year-old woman with AIP was referred for LT. Her mother and two sisters were affected by AIP but to a lesser extent. Her symptoms began at the age of 12 and included a prolonged hospital admission with abdominal pain which resulted in appendectomy. At 25 years of age, she developed abdominal pain related to menstruation and was diagnosed with polycystic ovaries and endometriosis. She received antiandrogens (goserelin) without improvement. At this time, she developed pain in both arms and legs. At the age of 30 she had an abdominal hysterectomy and bilateral salpingo-oophorectomy, but continued to have nausea, recurrent abdominal and leg pain and frequent admissions to hospital. She received weekly hemin infusion for 3 years. Her left internal jugular and left subclavian veins had occluded. She had episodes of bacterial and candida line sepsis. Her quality of life was poor with recurrent acute attacks every 2 weeks.

Laboratory tests showed an increase in ALA in the urine to 17.2 µmol/mmol creatinine (normal: <3.8 µmol/mmol creatinine), PBG 47.7 µmol/mmol creatinine (normal: <1.5 µmol/mmol creatinine) and total porphyrin excretion (TPE) was 91 µmol/mmol creatinine (normal: <35 µmol/mmol creatinine). During an attack there was an increase in ALA: 17.7 µmol/mmol creatinine, PBG: 83 µmol/mmol creatinine, and TPE: 111 µmol/mmol creatinine. Her liver function and ultrasound remained normal.

She was transplanted with a size and blood group matched liver. The macroscopic appearance of the native liver was normal, and microscopic examination revealed mild portal fibrosis and non-specific inflammation. The postoperative period was uneventful. Immunosuppression included tacrolimus and prednisolone. The concentration of urinary heme precursor rapidly returned to normal (Fig. A). She developed late hepatic artery thrombosis at 8 months after LT with good collateral circulation and normal liver function. Twenty months after LT no manifestation of AIP relapse was noted.

Case 2

A 28-year-old woman with a 10-year history of AIP was referred for LT. She had frequent attacks with monthly hospital admissions with progressive polyneuropathy and myopathy. Hemin infusions and cimetidine were given. Her condition deteriorated with respiratory failure secondary to respiratory muscle weakness and sepsis with quadriparesis secondary to severe neuropathy and myopathy requiring invasive ventilation. She gradually improved over 2 months with return of muscle power and resolution of the right lower lobe collapse. She was able to stand and move her arms. Laboratory tests showed urinary ALA level 18 µmol/mmol creatinine, PBG level 65 µmol/mmol creatinine, and TPE 36 µmol/mmol creatinine. Her liver function and ultrasound of the liver remained normal.

Three months later, she was transplanted with an ABO identical whole liver graft. The macroscopic and microscopic appearance of the native liver was normal. The postoperative period was uneventful with standard immunosuppression. The concentration of urinary heme precursor rapidly returned to normal (Fig. B). Eighteen months after LT, she had normal nerve conduction and was enjoying a good quality of life.

Discussion

Porphyrias are a varied group of inborn errors of metabolism that develop from either inherited or acquired disturbances of heme biosynthesis. They are inherited as either autosomal dominant or recessive depending on the enzyme defects in heme biosynthesis. Most enzyme defects represent partial deficiencies because a complete enzyme deficiency along the heme pathway is not compatible with life.^[16-18] These enzymatic deficiencies result in overproduction of intermediate compounds, porphyrins, and lead to characteristic systemic and neurological manifestations. Porphyrias are classified either as hepatic or erythro-poietic types according to the primary site of over-production of porphyrins or their precursors. To date, 7 human porphyrias have been described, 5 hepatic and 2 erythropoietic types.

Erythropoietic porphyria (EPP) is caused by the deficiency of ferrochelatase. EPP is complicated by protoporphyrin-induced hepatotoxicity, leading to progressive hepatic failure in 10% of patients.^{[17, 18]} Pigment loading of hepatocytes and bile canalicular sludging results in inadequate biliary excretion of protoporphyrin and toxic effects on hepatobiliary structure and function with the development of subsequent liver fibrosis. Liver function can be rescued in some patients by suppressing erythropoiesis with hypertransfusion and/or hemin infusion and measures to increase excretion by plasmapheresis, administration of activated charcoal or bile acid sequestrants.^[18] There are several reports of successful LT for patients with EPP and end-stage liver disease. Since the majority of protoporphyrin originates from bone marrow, LT fails to correct the underlying metabolic deficiency, and protoporphyrin damage to the transplanted liver is likely. Sequential LT and bone marrow transplantation has also been reported as treatment of EPP with liver failure without disease recurrence.^{[9, 18]}

AIP is different from EPP in that there is no protoporphyrin accumulation. The disease process depends on the reduction of hepatic HMB synthase following heme depletion. The result is over-production of ALA and PBG in the liver which accumulates in neuronal tissue to cause neurological damage. Soonawalla et al^{[14, 15]} reported the first successful LT with resolution of AIP in a patient who suffered from repeated acute attacks and had a poor quality of life. The rationale for LT in AIP is that the replacement of hepatic enzymes can restore normal excretion of ALA and PBG and prevent acute attacks. In our patients undergoing LT for AIP, the postoperative period was uneventful, and they had no respiratory complications. Patient 2 had respiratory muscle weakness but improved significantly after respiratory rehabilitation before LT. Both patients remained free of porphyria symptoms after 20 and 18 months of follow-up.

The favorable outcome in our cases suggests that LT should be considered a satisfactory treatment for severe forms of AIP. The optimal timing and patient selection for LT has to be established. Frequent acute attacks requiring admissions to hospital with early signs of neuropathy can be considered as an indication for LT. Patients with AIP have normal liver function and do not meet minimum listing criteria should be listed as an exception. The optimum timing of transplantation may merit priority on the waiting list.

In summary, LT corrects the underlying metabolic abnormality in AIP and improves quality of life significantly.

Funding: None.

Ethical approval: Not needed.

Contributors: DFS wrote the first draft of this commentary. All authors contributed to the intellectual context and approved the final version. HN is the guarantor.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received July 9, 2009

Accepted after revision November 4, 2009