Recovery from a variegate porphyria by a liver transplantation.

The porphyrias are a group of inherited or acquired enzymatic defects of heme biosynthesis. Each type of porphyria has a characteristic pattern of overproduction and accumulation of heme precursors based on the location of dysfunctional enzyme in the heme synthetic pathway. Variegate porphyria, one of the acute hepatic porphyrias, is characterized by a partial reduction in protoporphyrinogen oxidase, the seventh enzyme of the heme biosynthetic pathway. A case of liver transplantation is described with a recovery from a variegate porphyria. Acute porphyria is commonly worsened by a wide variety of medications. We describe a step-by-step perioperative management protocol.     

A family with acute intermittent porphyria

Porphyrias are inherited defects in heme metabolism that result in excessive secretion of porphyrins and porphyrin precursors. Porphyrias can be classified into acute, (neuropsychiatric), cutaneous and mixed forms. There are seven main types of porphyrias; acute intermittent porphyria and plumboporphyria are predominantly neuropsychiatric; congenital erythropoietic porphyria, porphyria cutanea tarda and erythropoietic protoporphyria have predominantly cutaneous manifestations and hereditary coproporphyria and variegate porphyria are classified as mixed as they both have neuropsychiatric and cutaneous features. They cause life-threatening attacks of neurovisceral symptoms that mimic many other acute medical and psychiatric conditions. Lack of clinical recognition often delays effective treatment, and inappropriate diagnostic tests may lead to misdiagnosis and inappropriate treatment. Although the specific enzyme and gene defect have been identified, diagnosis and treatment of these disorders present formidable challenges because their signs and symptoms mimic other common conditions. We present a case report of a 13 years old girl who suffers from acute intermittent porphyria and the family tree showing all members who suffer from it.     

Porphyria in relation to surgery and anaesthesia.

A review is presented of the more recent biochemical findings in the hepatic porphyrias. The clinical aspects of acute porphyria are re-emphasized and illustrated with a case history. In particular the differentiation between porphyria and surgical causes of abdominal pain is stressed. The anaesthetic management is discussed and details of diagnostic and screening tests are given.     

Erythropoietic Protoporphyria: A Case Report and Literature Review

Erythropoietic protoporphyria is considered a rare disease overall, but in children is the most common form of porphyria, and certainly the most common type of erythropoietic porphyria. Despite this fact, erythropoietic protoporphyria is a disease that has been known to evade or at least delay diagnosis, leading to unnecessary suffering by the patient. Given the distress it may cause a patient and his or her family as well as the potential complications of this disease, the importance of maintaining a heightened awareness when presented with a child complaining of photosensitivity cannot be overstated. This case report will review the important clinical indicators, pathogenesis, histology, diagnosis, management, and treatment of this disease, so that affected children will no longer have to play “hide and seek” when diagnosed with this sun-sensitive disease.There are several types of cutaneous porphyrias that are grouped into one of two categories: hepatic porphyrias and erythropoietic porphyrias. In erythropoietic porphyrias, the excess of porphyrins is mainly found in the red cells.¹ Erythropoietic protoporphyria (EPP) is a type of erythropoietic porphyria and is the most common porphyria found in children.² EPP was first clearly defined in 1961 by I.A. Magnus et al³ and is clinically characterized by photosensitivity to visible light with subsequent physical cutaneous signs in the skin exposed to sun. Photosensitivity with cutaneous lesions usually presents in infancy or early childhood. However, there have been cases of delayed diagnosis resulting from either a late onset of symptoms, patients with only mild symptoms, or simply from a failure to diagnose. As a result, dermatologists must employ a keen awareness for EPP in children with subjective photosensitivity even without associated clinical cutaneous findings.     

Anesthesia and hepatic porphyria

Three of the acute hepatic porphyrias, acute intermittent porphyria, variegata porphyria and hereditary coproporphyria, are characterized by an idiosyncratic reaction to many common drugs; the resulting excessive excretion of porphyrin precursors is responsible for episodes of acute neurological dysfunction. This review aimed to focus the attention of the anaesthesiologist on the porphyrinogenic properties of all the drugs used in anaesthesia and intensive care. An outline of the chemistry of porphyrins and the enzymatic pathways were recalled, so as to place the acute porphyrias in their proper perspective. There follows a reminder of the clinical aspect of acute porphyric crises. The part played by drugs is then assessed from clinical and laboratory data concerning their porphyrinogenicity. Those drugs for which there is conflicting evidence regarding their safe use in porphyric patients are discussed: propofol, ketamine, benzodiazepines, etomidate, local anaesthetics. Recommendations supported by clinical and experimental data are given, especially the results obtained with the chick embryo liver model. Treatment of the acute crisis is provided, with particular emphasis on the use of haematin. The anaesthetic management of hepatic porphyric patients is described. Those drugs which are well-known porphyrinogenic compounds in the chick embryo liver must be excluded from use for anaesthesia in the porphyric patients, even if they have been observed to be innocuous in rare cases of asymptomatic patients. Finally, recommendations for anaesthesia in symptomatic cutanea porphyria are given.     

Peridural anesthesia with procaine and fentanyl in a parturient with acute intermittent porphyria

Acute intermittent porphyria is one of three severe hepatic porphyrias. Clinical manifestations include intermittent acute attacks of abdominal pain and neuropathy with an occasionally outcome. These attacks are often precipitated by endogenous (menstrual cycle and pregnancy in women) or exogenous factors (porphyrinogenic drugs). An epidural analgesia was performed during the labour of a pregnant woman with acute intermittent porphyria just after an acute attack of abdominal pain. Analgesia was obtained using procaine and fentanyl. The choice of drugs was based on available clinical reports and experimental studies of the porphyrinogenicity of drugs in animal models (rat in vivo and chick embryo in ovo).     

Fifty years of porphyria at the University of Cape Town

The porphyrias are a group of disorders resulting from defective haem biosynthesis. One form, variegate porphyria, is common in South Africa as a result of a founder effect. Over the past 50 years, the University of Cape Town Faculty of Health Sciences has built and maintained an international reputation for excellence in the field of porphyria. The porphyria group is respected for its research and for its accumulated experience in the management of these disorders. Equally important has been the comprehensive and holistic care offered to patients with porphyria, and to their families.     

Desfluran bei akute intermittierender Porphyrie

Despite the low incidence of the acute porphyrias, a profound knowledge of the disease is essential for anaesthesiologists, as a variety of perioperatively administered drugs are potential triggers of an acute attack. There is an ongoing discussion about the use of volatile anaesthetics in porphyrias, but halothane and isoflurane seem to be safe. There is no clinical data or case report about the use of desflurane in this specific patient group, but its fast and relatively unchanged elimination and the minimal induction of the cytochrome P 450 system seem to be favorable in this setting. We report the use of desflurane in a patient with acute intermittent porphyria, scheduled for hemihepatectomy. To minimize perioperative distress by pain or the need for postoperative mechanical ventilation, we chose a balanced anaesthesia technique with desflurane, sufentanil and atracurium in combination with a continuous epidural analgesia (bupivacain and fentanyl) for the postoperative period. Preoperatively the porphyrin precursors were analyzed in serum and urine and postoperatively the 24 h-urine was screened every 2 days until postoperative day 6 to monitor the porphyria activity. The preoperative data showed high concentrations of porphyrin precursor excretion, confirming the diagnosis of AIP. The postoperative data in the 24 h-urine were significantly lower than preoperative levels and reached normal levels at postoperative day 5. There were no clinical symptoms of a porphyric attack during the postoperative hospitalization. The patient was discharged on postoperative day 21 in excellent condition. We conclude that our perioperative management prevented an acute porphyric attack in this case. Desflurane might be a valuable alternative to other hypnotics in patients with AIP.     

Chemotherapy in porphyria

The clinical courses of 5 patients with hepatic porphyrias (4 with porphyria variegata) who required chemotherapy for disseminated malignant diseases are reviewed. Antineoplastic agents were employed without evidence that these drugs precipitated porphyric crises. It is concluded that the chemotherapeutic approach to these patients should be based on the appropriate treatment for the malignant condition.     

Resin Hemoperfusion in Hepatic Porphyrias

Abstract: In three types of hepatic porphyrias, 32 hemoperfusions over polyhema-coated Amberlite XAD-2 resin were performed. An attack of acute intermittent porphyria subsided after a 6-h hemoperfusion. During the procedure, 13 L of plasma was completely cleared of porphyrins. In a child with variegate porphyria, the laboratory changes were slight and no clinical effect of hemoperfusion was seen. In a patient suffering from porphyria cutanea tarda resistant to standard therapy, 30 hemoperfusions were performed during a period of 10 months. The total plasma porphyrin concentration increased sharply following the start of the treatment, and preceding the fifth procedure it reached a peak of four times the initial value. Since then, the plasma porphyrin level decreased, eventually to one-half the starting value. The mean drop in porphyrin level during each perfusion was 22%. Similar changes were observed in the amount of porphyrins excreted into the urine, which, following an early rise, decreased to 25% of the initial value. However, the patient's skin vulnerability improved only slightly. There were no untoward effects of the treatment.     

Past and future: porphyria and porphyrins

Porphyria is a compelling disease--disrupted enzyme pathways, heightened sensitivities, and a fascinating history tied in with tales of Dracula. This review discusses the history, pathophysiology, classification, and treatment of porphyria. It further discusses the way in which research on the etiologies of the various porphyrias has led to the development of porphyrin-based photodynamic therapy, which shows great promise in targeted therapy for a variety of serious pathologies.     

Acute intermittent porphyria after right hemi-colectomy

IntroductionAcute intermittent porphyria is a rare autosomal dominant metabolic disease. It is caused by a genetic mutation that results in deficiency of porphobilinogen deaminase enzyme, the third enzyme in heme biosynthesis. Acute intermittent porphyria precipitated by surgery is very rare.Case presentationWe present a 24 year-old woman who developed acute intermittent porphyria five days after right hemi-colectomy. Her presentation included neuro-visceral and psychiatric manifestations, and severe hyponatremia. She received critical care symptomatic management including mechanical ventilation. The diagnosis was based on a positive urine test for porphobilinogen and confirmed by the presence of a heterozygous mutation in the hydroxyrmethylbilane synthase (HMBS) gene (c.760delC p Leu254).DiscussionAcute intermittent porphyria is the most common and life threatining type of acute porphyrias. It is more common in women and usually presents after puberty with acute abdominal pain and diverse neuro-psychiatric manifestations that can be confused with several surgical and medical diseases. Acute intermittent porphyria after surgery is most likely due to postoperative pain and low-calorie intake. Once suspected, prompt ICU management including high calorie intake are necessary to avoid serious complications and mortality before starting definitive treatment with hematin.ConclusionAcute intermittent porphyria should be suspected in any patient, particularly young women, who develop diverse neuro-visceral and psychiatric manifestations and hyponatremia after surgery.     

Acute intermittent porphyria and chronic renal failure

Despite the little known association between renal damage and the acute porphyrias, limited information is available on the characteristics and pathogenesis of renal disease in this patient group. Previous reports have focused on hypertension as the principal etiological factor. We have studied a series of 9 patients with acute intermittent porphyria (AIP) attending the Porphyria Clinic at King's College Hospital, London, UK, who were referred to the Renal Unit for investigation and treatment of their renal disease. No evidence of a glomerular lesion was found in any of the patients. In contrast, renal histology showed features of a tubulointerstitial disease, and there was evidence of impaired erythropoietin production. Hypertension and nonsteroidal antiinflammatory drug use were present in about a half of the patients. It is postulated that the nephrotoxic effects of porphyrin precursors may contribute to the etiology of this clinical syndrome.     

Obstetrical anaesthesia and porphyrias

Acute hepatic porphyrias are genetic diseases, characterized by acute neurological symptoms, sometimes fatal, triggered by different factors, in particular by many anaesthetic drugs, and also by pregnancy. We report here the experience of three porphyric patients'deliveries, allowing us to consider a proposition of management in this context. After discussion between anaesthesiologist, obstetrician and porphyria specialist, two types of management of such patients can be foresee. Asymptomatic patients, or in long remission, can benefit from locoregional anesthesia techniques with bupivacaine for both labour analgesia and Caesarean section. Spinal anaesthesia is then the technique of choice, allowing using smaller quantity of local anaesthetic than epidural anaesthesia. For symptomatic patients, or in crisis, we have rather choose intravenous narcotics for labour analgesia, and general anaesthesia for Caesarean section. The hypnotic agent of choice for both induction and maintenance of such anaesthesia is then propofol.     

Combined liver and kidney transplantation in acute intermittent porphyria

We report two patients with acute intermittent porphyria (AIP) who were successfully treated with combined liver and kidney transplantation. Both had a very poor quality of life as a result of years of frequent acute porphyria symptoms, chronic peripheral neuropathy and renal failure requiring dialysis. After transplantation, clinical and biochemical signs of porphyria disappeared. The excretion pattern of porphyrin precursors normalized within the first day and plasma porphyrins returned to normal within a week. These and other recent cases have clarified previous concerns and have helped to formulate the indications for and the timing of transplantation in AIP.     

Pretransplant evaluation of a patient with acute intermittent porphyria

The pretransplant evaluation of a patient with a rare diagnosis requires knowledge of the pathophysiology and the transplant literature. A 55-year-old man presented with hypertensive kidney failure and the clinical diagnosis of acute intermittent porphyria. Complications of acute intermittent porphyria, which is a defect of heme production, are due to the accumulation of heme intermediates often precipitated by medications. Based on animal data, cyclosporine is considered unsafe in patients with acute intermittent porphyria. As part of the pretransplant evaluation, the patient received separate trials of tacrolimus and cyclosporine, which did not stimulate his acute intermittent porphyria. Four months after a kidney transplant, the patient still had no signs of rejection or symptoms of acute intermittent porphyria. This is the first documented patient with acute intermittent porphyria who successfully received a kidney transplant using tacrolimus. Because of individual variations, pretransplant testing of calcineurin inhibitors should be continued in patients with acute intermittent porphyria.     

Clinical relevance of hemochromatosis-related HFE C282Y/H63D gene mutations in patients on chronic dialysis

BACKGROUND: The actual prevalence and the clinical relevance of gene mutations of HFE (which are linked to hemochromatosis) have not yet been established in patients on chronic dialysis. On the basis of theoretical premises, it could be hypothesized that these genetic determinants might influence the response to iron intake and the susceptibility for iron overload in patients in parenteral iron therapy. Furthermore, carriers for these mutations might be prone to develop sporadic porphyria cutanea tarda and cardiovascular events. METHODS: C282Y/H63D mutations of HFE gene were evaluated in 132 patients (34 in peritoneal dialysis, 98 in HD) and correlated with biochemical parameters of iron status (ferritin (FER) concentration and transferrin saturation (TSAT)), red cell parameters (red cell size and hemoglobin content), erythropoietin (EPO) dosage, major cardiovascular events and C-reactive protein as marker of chronic inflammation, in patients without iron therapy and after i.v. iron supplementation (< or = 60 mg/week) and with the presence of biopsy-proven porphyria. RESULTS: C282Y heterozygous mutation was found in 8/132 (6.6%); H63D homozygous and heterozygous mutations were found in 3/132 (2.3%) and 22/132 (16%) patients, respectively. Two patients (1.5%) showed double heterozygosis. No differences in baseline serum FER and TSAT and the other biochemical and clinical parameters were found in patients bearing mutations alleles nor after continuous iron therapy at low dosages. However, the prevalence of patients capable of maintaining normal hemoglobin (Hb) level without EPO therapy is increased in the C282Y-mutated patients. Only 1 patient out of the 4 with biopsy-proven porphyria cutanea tarda was bearing gene mutations (H63D heterozygosis). CONCLUSION: C282Y/H63D HFE gene mutations do not seem to be related to major abnormalities in biochemical parameters of iron status in dialysis patients without iron therapy or after i.v. iron supplementation, granted that low dosages are employed. Obviously, as our patients were exposed to a relatively uniform iron regimen in our clinical center (< or = 60 mg/week), it is unclear if other dosing regimens will unmask clinically significant differences between the heterozygotes and normals. The fact that the C282Y-mutated patients more frequently maintain high Hb values without EPO is interesting as could suggest a better use of available iron for erythopoiesis, but needs to be confirmed in larger samples. No clear association is demonstrated with porphyria cutanea tarda and major cardiovascular events.     

Hypertension and renal impairment as complications of acute porphyria.

Chronic hypertension with renal failure is the most common cause of death in a large family (10 children, 40 grandchildren, 109 great-grandchildren) with acute porphyria. A prospective study of 26 porphyric (19 latent) and 26 nonporphyric subjects shows a significant difference between mean systolic (141 versus 123 mmHg, P < 0.05) and diastolic (88 versus 74 mmHg, P < 0.05) blood pressures and plasma creatinines (geometric mean 99 versus 79 mmol/l, P < 0.02). Five of the 19 porphyric grandchildren have died of the complications of chronic hypertension, with renal failure in three. When the results of the retrospective and prospective studies in these 19 subjects are combined, 10 of the 16 tested (62%) had hypertension and seven of the 14 tested (50%) had renal impairment. Neither hypertension nor renal failure are known to affect the 21 grandchildren who were either not porphyric or of unknown status. This family provides a unique opportunity to study these common but little reported sequelae of acute porphyria. These complications affect subjects with latent porphyria as well as those who have experienced clinical attacks.     

Neurochemical aspects of porphyria. Studies on the possible neurotoxicity of delta-aminolaevulinic acid.

It has been proposed that delta-aminolaevulinic acid (ALA), which is overproduced in the inherited hepatic porphyrias, may be responsible for the neurological manifestations of the acute attacks seen in these disorders. Studies were conducted in rats to test the neurotoxicity of ALA. It was found that, after intraperitoneal or subcutaneous injections, ALA is rapidly eliminated via the kidneys. In nephrectomised animals sustained elevation of blood ALA concentration was demonstrated, but despite this, brain uptake was extremely low. Experiments on incorporation of [4-14-C]-ALA into brain haem yielded similar information. After intraventricular injection of [4-14-C]-ALA, significant uptake by brain tissue occurred. The subsequent disappearance of ALA was moderately rapid and was virtually complete within 24 hours. Uptake of [4-14-C]-ALA was apparently significantly greater in the hypothalamus than in other brain areas. The subcellular distribution of radioactivity did not reveal any preferential uptake by nerve endings. Intraventricular injection of unlabelled ALA revealed definite but transitory neurotoxic effects in doses of 3 micromoles and greater. These include involuntary movements and ataxia. No effect of ALA administration on brain protein synthesis could be demonstrated. It is concluded that ALA does have effects on the nervous system in vivo, but the significance of these effects in relation to the pathogenesis of the neurological manifestations of acute porphyria is questionable.     

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.