Treatment with Haematin in Acute Hepatic Porphyria

Transcription

1 Quarterly Journal of edicine, New Series L, No. 198, pp , Spring 1981 Treatment with Haematin in Acute Hepatic Porphyria K. E. L. ccqll,. R. OORE, G. G. THOPSON AND A. GOLDBERG rom the University Department of edicine, Gardiner Institute, Western Infirmary, Glasgow Gil 6NT Accepted 2 October 1980 SUARY We report our experience with intravenous haematin in the treatment of 1 attacks of acute porphyria In eight patients. Seven patients had acute intermittent porphyria and one variegate porphyria. Peripheral neuropathy was a feature of nine of the attacks and in two the neuropathy necessitated assisted ventilation. The haematin lowered the urinary excretion of porphyrins and precursors in all patients by approximately 50 per cent of the pre-haematin values. It also repressed the activity of delta-ammolaevullnlc acid synthase, the rate-controlling enzyme of haem biosynthesis, in peripheral leucocytes in seven of the nine patients in whom it was monitored. The clinical response was less consistent,' with clinical Improvement accompanying only half of the courses. The two patients with respiratory paralysis died. There was localized phlebitis at the injection site following five of the courses but no other side-effects were noted. Previously published reports of haematin therapy for acute porphyria are reviewed. These consist of 5 courses in 2 patients. Biochemical improvement was a consistent finding. Clinical response has been less consistent Twenty-four of the courses were associated with sustained improvement, ten with temporary improvement relapse occurring within two to 1 days (three fatal). In eleven there was no improvement and three died. INTRODUCTION The acute porphyrias, namely acute intermittent porphyria (), porphyria variegata () and hereditary coproporphyria (HCP), are the result of hereditary abnormalities in the pathway of haem biosynthesis and present clinically with attacks of systemic illness. Abdominal pain, vomiting and constipation are the commonest features of these acute attacks. ental disturbance may also occur and in severe cases there is peripheral neuropathy which may progress to quadriplegia with bulbar and respiratory paralysis. All the clinical manifestations of acute porphyric attacks can be explained by neurogenic dysfunction within the central and peripheral nervous systems (ig. 1). Various factors may precipitate attacks in Correspondence to Dr. Kenneth E. L. ccoll, University Department of edicine, Gardiner Institute, Western Infirmary, Glasgow Gl 1 6NT.

2 162 K. E. L. ccoll and others Neurogenic Dysfunction CENTRAL PERIPHERAL ental disturbance Convulsions Hypothalamic dysfunction Extrapyramidal dysfunction otor Neuropathy Sensory neuropathy Autonomic neuropathy Gastrointestinal Cardiovascular Genitourinary IG. 1. The clinical features of the acute attack of porphyria are all explained by neurogenic dysfunction. patients with acute porphyria and these include exposure to certain drugs (oore, 1980) including alcohol, starvation, hormonal factors and stress (ccoll, oore, and Goldberg, 1980). Attacks of acute porphyria still carry a significant mortality. Each of the acute hepatic porphyrias is characterized by hereditary partial deficiency of one of the intermediate enzymes in the pathway of haem biosynthesis (Brodie, oore, and Goldberg, 1977). This biochemical pathway is present in all mitochondrial-containing cells in the body, and most active in haematopoietic and hepatic tissue. Haem biosynthesis commences within the mitochondrion with the condensation of glycine and succinyl CoA by the enzyme delta-aminolaevulinic V/////////77. fr^^~a ERROCHELATASE CTTOPIASU Excrmtktn Product* UROPOflPHYWNOGEN IE (S-COOH) uawonmvninogen DECARSOXVlAStt I1TROCCI- iphltrwi COPROPOflPHYRWOOEN H (-COOH) *"^_-.. COP«O«WPHV1<»( I IG. 2. Diagramatic representation of the pathway of haem biosynthesis. The rate of the pathway is controlled by the initial enzyme, ALA synthase, which is under negative feedback control by haem.

3 Treatment with Haematin in A cute Hepatic Porphyria 16 acid (ALA) synthase to form ALA (ig. 2). This passes out into the cytoplasm where it is converted to porphobilinogen (PBG) by ALA dehydratase. PBG is then converted by the concerted actions of uroporphyrinogen-1 -synthase and uroporphyrinogen cosynthase to uroporphyrinogen. This is then decarboxylated by uroporphyrinogen decarboxylase to coproporphyrinogen which re-enters the mitochondrion. Here coproporphyrinogen oxidase converts coproporphyrinogen to protoporphyrinogen and this is then oxidized by protoporphyrinogen oxidase. inally, iron is inserted into protoporphyrin by the enzyme ferrochelatase to form haem. The rate of the pathway is regulated by the initial enzyme, ALA synthase, which is under feedback repression and inhibition by haem at both transcriptional and translational cellular levels. In the acute hepatic porphyrias, the inherited enzyme deficiency results in a partial block in the pathway, and consequently, increased activity of ALA synthase, to maintain haem production. This increased activity of the initial enzyme results in accumulation of porphyrins and precursors formed prior to the enzymatic block and these appear in blood, urine and faeces. In, the block is at the level of uroporphyrinogen-1-synthase and there is overproduction of ALA and PBG which appears in blood and urine. In HCP and the block is more distal and there is overproduction of formed porphyrins as well as ALA and PBG. This hereditary enzymatic deficiency is present in most and probably all body tissues, though most of the excess porphyrins and precursors produced are of hepatic origin. The various factors which can precipitate acute attacks of porphyria share the ability to induce hepatic ALA synthase in experimental animals. The relationship between the abnormality of haem biosynthesis and the neurogenic dysfunction which characterizes the acute attacks is not known. In spite of the advancing knowledge of the nature of the biochemical disorder in the acute hepatic porphyrias, the management of the conditions remains unsatisfactory. Attacks can, to a large extent, be prevented by screening relatives and advising them to avoid precipitating factors. Patients who develop acute attacks are still largely treated symptomatically and supportatively until the attack remits spontaneously. Over the past ten years, however, two forms of treatment have become available which appear to bring about some biochemical and clinical improvement. The administration of calories in the form of sugar appears to repress the activity of ALA synthase and lower porphyrin and precursor production (Brodie, oore, Thompson, and Goldberg, 1977). The mechanism of this 'glucose effect' is not known. Another therapeutic development has been the intravenous administration of haematin. It has been known for 'some time from animal experiments that exogenous haem in the form of intravenous haematin is capable of suppressing chemically-induced hepatic ALA synthase (Granick, 1966). The haematin has been shown to be incorporated into functioning haemoproteins such as cytochrome P50 and tryptophan pyrrolase (Correia, arrell, Schmid, Ortiz de ontellano, Yost, and ico, 1979). Review of haematin therapy The literature contains reports of the administration of haematin in 5 attacks of

4 16 K. E. L. ccoll and others acute hepatic porphyria in 2 patients (Bonkowsky, Tschudy, Collins, Doherty, Bossenmaier, Cardinal, and Watson, 1971; Watson, Dhar, Bossenmaier, Cardinal, and Petryka, 197; Dhar, Bossenmaier, Petryka, Cardinal, and Watson, 1975; Peterson, Bossenmaier, Cardinal, and Watson, 1976; Watson, Pierach, Bossenmaier, and Cardinal, 1978; Brezis, Ghanem, Weiler-Ravell, Epstein, and orris, 1979; Lamon, rykholm, Hess, and Tschudy, 1979). Nearly all patients had a trial of glucose administration before the haematin therapy. In all attacks the haematin was associated with biochemical improvement in the form of reduction of plasma concentrations and/or urinary excretion of ALA, PBG and uroporphyrins. The plasma concentrations of the porphyrin precursors fell by per cent of pre-haematin values and this occurred within 2 hours of the first injection. On completion of the haematin infusions the concentrations generally rose again to plateau a few days later at a level between per cent of the pre-haematin concentrations. Critical analysis of the published reports shows that the clinical response has not been as consistent as the biochemical response. Twenty-four (5 per cent) courses have been associated with sustained clinical improvement, ten (22 per cent) with temporary improvement then relapsing within two and 1 days (three TABLE 1. Clinical response to haematin in 26 Class A attacks in 17 patients Age f ( \ 1 ( (2\ \21 f 1 1 I 1 I 1 [1 Sex Type of porphyria Clinical response Reference Brackets on left side of table group attacks in individual patients. Watson et al, 197 Dhar etal., 1975 Watson et al, 1978 Dhar et al, 1975 Dhar et al, 1975 Watson era/., 1978 Watson era/., 1978 Watson etal., 1978 Lamon etal., 1979 Lamon etal, 1979 Lamon et al, 1979 Lamon etal, 1979 Lamon etal, 1979 Lamon et al, 1979 Lamon etal, 1979 Lamon etal, 1979 Lamon etal, 1979 Lamon et al, 1979 Lamon et al, 1979 Lamon et al, 1979 Lamon et al, 1979

5 Treatment with Haematin in A cute Hepatic Porphyria 165 fatal) and in eleven (2 per cent) there was no apparent benefit. Three of these patients died during attack. The clinical response to the haematin in these patients must be viewed in association with the severity of attack. Twenty-six of these attacks in 17 patients can be classified as Class A (Watson et ai, 1978) as there was a combination of gastrointestinal symptoms, mental disturbance, hypertension and tachycardia but no significant peripheral neuropathy. In these attacks the haematin resulted in sustained improvement in fifteen (58 per cent), temporary improvement in seven (27 per cent) and no change in four (15 per cent) (Table 1). Ten attacks in eight patients were of Class B severity there being, in addition, severe peripheral neuropathy. The haematin therapy was associated with improvement of the neuropathy in six (60 per cent) but no change in four (0 per cent) (Table 2). Nine attacks in seven patients were of Class C severity there being severe generalized neuropathy resulting in respiratory embarrassment. In three ( per cent) of these attacks treatment with haematin was associated with maintained improvement of the neuropathy, in three temporary improvement occurred but the patients later died, and in three there was no improvement and death (Table ). In most cases where there was improvement in the neuropathy this began about the final day of the haematin infusion and continued slowly for several months. No T A B L E 2. Clinical response to haematin in ten Class B attacks in eight patients /6 \ Sex Type of porphyria Abdominal pain No data No data No data No data Neuropathy Reference Watson etal., 1978 Watson etal., 1978 Lamon etal., 1979 Lamon et al., 1979 Lamon etal., 1979 Lamon et al., 1979 Lamon et al., 1979 Brackets on left side of table group attacks in individual patients. T A B L E. Clinical response to haematin in nine Class C attacks in seven patients Age Sex Type of porphyria Neuropathy Reference (9 9 U9 No improvement died Early improvement died Early improvement died Early improvement 1 No improvement >died No improvement J Bonkowsky et al., 1971 Dhare/a/., 1975 Peterson et al., 1976 Brezis et al., 1979 Lamon et al., 1979 Lamon et al., 1979 Lamon et al., 1979 Brackets on left side of table group attacks in individual patients.

6 166 K.E.L. ccoll and others significant side-effects have been experienced with the dose of haematin administered to humans for treatment of acute porphyria (up to mg/kg/12 hours). In a small number of cases in which it has been injected into a small peripheral vein, phlebitis has been noted. One 0-year-old man with acute intermittent porphyria in remission developed transitory acute renal failure following the bolus intravenous infusion of haematin in a dose of 12 mg/kg (Dhar etal., 1978). We wish to report our biochemical and clinical assessment of haematin therapy of 1 attacks in eight patients with acute hepatic porphyria. PATIENTS Six of the patients were female and two were male with a mean age of 27 years (range years). All had except Case 5 who had. The diagnosis was established by measuring the urinary and faecal excretion of porphyrins and precursors and in the six patients treated in our own unit the activities of the enzymes of haem biosynthesis in peripheral blood cells were also measured. Two patients {Cases 5 and 6) received the haematin in their local hospitals as they were not fit for transfer. All patients had biochemical and clinical evidence of an attack of acute porphyria at the time of haematin administration. ETHODS Urinary coproporphyrin and uroporphyrin were measured by the method of Rimington (1971) and urinary ALA and PBG by the method of auzerall and Granick (1956). All analyses were performed using 2-hour collections. Normal ranges for our laboratory are as follows: 0 0 ixmo\ ALA/2 h, 0-16 /rniol PBG/2 h, 0-9 nmol uroporphyrin/2 h and 0 nmol coproporphyrin/2 h. Thirty ml of heparinized venous blood was required for the measurement of leucocyte ALA synthase activity as described by oore, Thompson, Goldberg, Ippen, Seubert, and Seubert (1978). This was placed immediately on withdrawal into ice and delivered to the laboratory within 15 min. It was centrifuged (000 g) at C for 0 min. The leucocytes were then separated from the red cells using a Pasteur pipette, washed four times in isotonic saline (150 mmol/1) at C and finally lysed in an equal volume of isotonic saline with an ultrasonic homogenizer (Polytron, Kinematica, Lucerne). 100/il of the homogenate was then used for assay of ALA synthase by measurement of uptake of U C glycine into ALA which was quantitated with respect to the protein content of the homogenate as assayed by the method of Lowry, Rosebrough, arr, and Randall (1951). The normal range for ALA synthase activity ( nmol ALA/g protein/h) was found by examining 50 healthy volunteers (1 females, 29 males) ranging in age from 1 to 72 years. The haematin was produced from expired HbsAg negative packed cells as kindly communicated by Professor C. J. Watson (inneapolis). Haemin was first prepared as described by isher (1955) and then dissolved in 1 per cent sodium carbonate solution. The ph was adjusted to 8 with 1 mol/1 HC1. The final solution was confirmed to be sterile, non-pyrogenic to rabbits and free of proteinaceous contamination using electrophoresis. The haematin was stored in solution at C

7 Treatment with Haematin in Acute Hepatic Porphyria 167 for up to ten days before use. Immediately before administration the haematin solution was drawn up through a 5 fim aspiration needle filter and then injected via a 0-22 /um filter (illex illipore), in doses of mg/kg body weight over 20 min into the rubber bung of a slowly running intravenous infusion of physiological saline. Patients received either 12 hourly or daily doses and courses lasted three to five days. RESULTS Haematin and urinary porphyrin and precursor excretion Before haematin administration, urinary excretion of ALA and uroporphyrin was increased in all cases and the urinary PBG in all but two cases. Haematin reduced the urinary ALA excretion in all but one case (mean reduction = 1 per cent) the urinary PBG in all but two cases (mean reduction = 7 per cent) and also the uroporphyrin in all but two cases (mean reduction = per cent) (Table ). After completion of the haematin therapy, excretion rose over the following three days to plateau at levels of per cent of the pre-haematin values (Table 5). There was no significant difference in the depression of urinary porphyrin and precursor excretion between the two dose schedules employed (Table 6). Urinary coproporphyrin excretion was only slightly increased before haematin administration. TABLE. Percentage change in leucocyte ALA synthase activity and urinary excretion of porphyrins and precursors following commencement of haematin therapy in patients in attack of acute porphyria. In each case the mean values during haematin therapy have been compared with mean values over the three days immediately preceding therapy Patient Haematin dose (mg/kg/2 h) Duration of therapy (days) Percentage change in leucocyte ALA synthase activity Percentage change in urinary excretion of ALA PBG URO COPRO Case 1 course i course ii course iii course iv course v Case 2 Case course i course ii Case Case 5 Case 6 Case 7 Case ean

8 168 K.E.L. ccoll and others TABLE 5. ean urinary excretion of porphyrins and precursors before, during and following haematin therapy. All 1 course in eight subjects are included ean urinary excretion of ALA (//mol/2 h) PBG O/mol/2 h) URO (nmol/2 h) COPRO (nmol/2 h) Three days pre-haematin During haematin Three days post-haematin TABLE 6. Effect of haematin dosage on change in urinary porphyrin and precursor excretion No. of courses ean percentage: change in urinary excretion during haematin treatment ALA PBG URO COPRO Haematin mg/kg/2 h Haematin 8 mg/kg/2 h - -HAEATIN-* Uucocyta AlA ynthoie (nmolala/) (gprotaiiy'h ) 00- Time(Doyi) Poit Commencement of Hoematin IG.. Effect of haematin therapy on the activity of leucocyte ALA synthase in seven uncomplicated courses in five patients. Patient case number indicated by arabic numeral and, where appropriate, course number by roman numeral in parenthesis.

9 Treatment with Haematin in Acute Hepatic Porphyria 169 Haematin and leucocyte ALA synthase activity Activity of leucocyte ALA synthase was monitored during nine courses of haematin to six patients. Prior to haematin administration this was increased in each case studied with a mean activity of 61 nmol ALA/g protein/h (range ). Seven of the courses repressed the activity of ALA synthase, in four of these to within the normal range (ig. ). Blood for the enzyme assays was withdrawn immediately before the haematin injections. On one occasion a further sample was obtained one hour after injection and the leucocyte ALA synthase activity was found to be only 5 nmol ALA/g protein/h, which is below our lower limit for normal subjects. In most cases activity of ALA synthase rose again within 8 hours of completion of therapy to levels similar or slightly lower than the pre-treatment values. There was no evidence of rebound phenomenon. Two courses in separate subjects were not associated with depression of activity of ALA synthase (ig. ) and these were the two courses complicated by severe phlebitis. Clinical response Abdominal pain was the major symptom of the 11 attacks in which the patients remained conscious. ollowing haematin administration, pain was reduced in seven, unaltered jn two and increased in two attacks (Table 7). Reduction in pain usually occurred on the third day of haematin administration and often lasted only one to three days. Neuropathy was the major clinical sign in nine attacks and in seven of these it objectively improved following the j haematin. Neurological improvement was. usually noted within seven days of commencing haematin and continued slowly over the ensuing months. No neurological improvement occurred in the two patients (Cases 5 and 6) who were completely paralysed and --HAEATIN Uucocyts ALA * 0 synthow (nmol ALA/) (g protni/h) Pr«-Ho«motm Tura(Dori) foit Commencanwit of Hoemotin IG.. Leucocyte ALA synthase activity, during two courses of haematin therapy complicated by severe phlebitis.

10 170 K. E. L. ccoll and others T A B L E 7. Clinical response to haematin therapy of acute hepatic porphyria Age (years) Sex Class of attack* Response to haematin Abdominal pain Neuropathy Outcome Case 1 course i course ii course iii course iv course v Case 2 Case course i course ii Case Case 5 Case 6 Case 7 Case B A B B C B A A A C C B A Worse Worse Comatose Comatose Died Died * Classification is as described by Watson el al., 1978, i.e. Class A = Includes gastrointestinal symptoms and signs, hypertension and tachycardia, psychiatric manifestations but absent or mild peripheral neuropathy Class B = As above but severe peripheral neuropathy Class C = Life threatening generalized neuropathy with respiratory failure. TABLE 8. Effect of haematin therapy on analgesic requirement. Table shows the analgesia administered over the seven days before and seven days after the commencement of haematin, and also the percentage change in analgesic requirement Pre-haematin analgesic requirement (mg pethidine/2 h) Post-haematin analgesic requirement (mg pethidine/2 h) Change in analgesic requirement (as % of pre-haematin dose) Case 1 course i course ii course iii course iv course v Case 2 Case course i course ii Case Case 7 Case (+ diamorphine 8-5mg/2h) (+ diamorphine 8-5mg/2h) (+ diamorphine 17mg/2h) 07-10% -20% -6% +6% + 2% 0-5% % Increase -8%

11 Treatment with Haematin in A cute Hepatic Porphyria 171 unconscious before receiving haematin and both died within three weeks of therapy from complications of intermittent positive pressure ventilation. All other patients survived the attacks. In an attempt to obtain a more objective and accurate assessment of the clinical response the analgesic requirement was monitored in the 11 courses administered to conscious patients. This was reduced following five of the 11 courses, unchanged in two and increased in four (Table 8). There was no discernible difference in clinical response between the two dose schedules employed. Two courses {Case course i, and Case ) led to severe phlebitis of the arm following injection of the haematin into antecubital veins. There was associated leucocytosis and mild pyrexia in both cases. The severe pain associated with the phlebitis explains the increased analgesic requirement in spite of unchanged abdominal pain in Case. ild phlebitis occurred following three other courses. No other side-effects were observed. In particular, there was no deterioration in renal function related to haematin administration. DISCUSSION Our results confirm that intravenous haematin lowers the urinary excretion of ALA, PBG and uroporphyrin in patients during an attack of acute hepatic porphyria. It has been assumed by previous workers that this is the result of the haematin entering hepatocyte mitochondria and there repressing ALA synthase activity. Our ability to demonstrate effective repression by haematin of this enzyme in peripheral leucocytes supports this hypothesis. In two courses of haematin, leucocyte ALA synthase was not repressed though reduction of urinary porphyrin excretion would suggest that hepatic ALA synthase was repressed. Both of these courses were complicated by severe phlebitis with pyrexia and this may have affected the leucocyte response. The clinical response was not as consistent as the biochemical response, since improvement accompanied only about half of the courses and in several of these was only temporary. The majority of acute attacks of porphyria resolve spontaneously and this makes it impossible to be certain that the clinical improvement was due to haematin. Because of the rarity and nature of the condition, a double blind controlled trial would be very difficult to mount. The consistent biochemical response but less marked clinical response raises the question of the association between the biochemical and clinical features of acute porphyria. All the clinical manifestations of the acute attack of porphyria can be explained by neurogenic dysfunction (ig. 1). Neurohistological changes, including demyelination and axonal degeneration, may be seen in patients who have died from severe attacks (Gibson and Goldberg, 1956). The relation of the defined disorder of haem biosynthesis to this neuropathy is unknown. The simplest explanation is that the excess circulating ALA or PBG or metabolites, which are mainly hepatic in origin, are neurotoxic. This initially appears plausible as excess ALA and PBG are a constant feature of attacks of acute porphyria. Neuropathy does not occur in the non-acute porphyrias (cutaneous hepatic porphyria, erythropoietic protoporphyria and congenital porphyria) which are also due to hereditary enzyme deficiencies in the pathway of haem biosynthesis but in which there is no overproduction of

12 172 K. E. L. ccoll and others porphyrin precursors. or the 'porphyrin precursor neurotoxicity' hypothesis to be tenable these substances must firstly be able to gain access to the nervous system. The few studies of CS concentrations in patients in acute attacks of porphyria (Percy and Shanley, 1977; Bonkowsky et al, 1971) have shown that both are present but at concentrations of less than 20 per cent of serum levels. oore and eredith (1976) studied, in rats, the tissue concentrations of I C labelled ALA injected intraperitoneally in a dosage of 0 //g/kg. They found brain concentrations of 5 to 10 per cent of blood levels. Tenability of the neurotoxicity theory also depends on the ability of these substances to cause neuropathy. Goldberg, Paton, and Thompson (195) were unable to demonstrate any pharmacological effects of PBG. arcus, Wetterberg, Yuwiler, and Winters (1970) administered high doses of ALA (- mmol/kg) to rats and noted no EEG or behavioural changes. Watson et al. (1978) reported that the administration of ALA and PBG to nephrectomized rats resulted in no alteration of blood pressure or nervous behaviour. In allylisopropylacetamide-induced chemical porphyria, in which high blood levels of porphyrin precursors occur, no neurological effects had been observed (Goldberg, Rimington, and enton, 1955; arcus et al, 1970). ore recently, however, Cutler, oore, and Ewart (1979) reported behavioural changes following the injection of ALA (1-6 mmol/kg) in rats. Several workers have reported a variety of effects of ALA on neuro-muscular function in a variety of in vitro preparations (cgillion, oore, and Goldberg, 1975; Loots, Becker, eyer, Goldstuck, and Kramer, 1975; Becker, Goldstuck, and Kramer, 1975; Cutler, Dick, and oore, 1978; Becker, Viljoen, and Kramer, 1971; Becker and Kramer, 1977). No studies in acute porphyria to date, however, have shown CS levels comparable with those required to produce neurological changes in these in vitro models (Percy and Shanley, 1977). ALA is structurally similar to the neurotransmitter gamma aminobutyric acid (GABA) and uller and Snyder (1977) have shown it to have GABA agonist effects in animals at concentrations similar to those occurring in acute porphyria. The relevance, however, of these conflicting reports of minor behavioural and neuropharmacological effects of ALA to the severe and widespread functional and structural neuronal changes seen in human acute porphyria must remain in doubt. Another obstacle for acceptance of the neurotoxicity theory is the poor correlation in clinical practice between the urinary excretion of ALA and PBG and the presence and severity of neuropathy (iyagi, Cardinal, Bossenmaier, and Watson, 1971; ). Variations in blood brain barrier permeability may be important. The other main theory explaining the neuropathy of acute porphyria is that it is the result of disordered haem biosynthesis within nerve cells. Since the characteristic abnormality of haem biosynthesis has been demonstrable in every extra-hepatic tissue studied including fibroblasts, erythrocytes and amniotic cells, it is likely that it will also be present in nervous tissue (Brodie et al, 1977). Impaired haem biosynthesis within nervous tissue could result in deficiency of essential haemoproteins such as mitochondrial cytochromes required for oxidative phosphorylation or microsomal cytochromes that catalyse mixed function oxidation (eyer and Schmid, 197). It has been shown in rat liver that partial

13 Treatment with Haematin in Acute Hepatic Porphyria 17 blockade of haem biosynthesis results in impaired drug-mediated induction of cytochrome P50 (axwell and eyer, : 197). If the neuropathy of acute porphyria is due to impaired intra-neuronal haem biosynthesis then the precipitating factors of acute attacks must be capable of modifying neuronal haem biosynthesis. Little is known of the regulation of neuronal haem biosynthesis. Paterniti, Simone, and Beattie (1978) were unable to induce rat brain ALA synthase with fasting or intraperitoneal injections of alcohol, ALA or,5- dicarbethoxy-l,-dihydrocollidine, Percy and Shanley (1979) were unable to detect any alteration in rat brain ALA synthase activity, total haem or cytochrome P50 levels following intraperitoneal injections of allyl-isopropylacetamide and/or phenobarbitone. At the present time there is insufficient knowledge of neuronal haem biosynthesis to be able to know whether disorder of this could result in the neuropathy of acute porphyria. Haematin therapy may allow further understanding of the aetiology of porphyric neuropathy. Haematin has been shown to lower circulating levels of ALA and PBG and if these are responsible for the clinical syndrome improvement would be expected. Haematin, however, might also be able to correct intra-neuronal haem deficiency. Little is known about uptake of administered haematin by nervous tissue. Lamon et al. (1979) were unable to detect haematin in CS of two patients with acute porphyric relapse being treated with intravenous haematin. As haematin in body fluids is predominantly protein bound, the CS concentration of haematin would be much less than in plasma as the CS/plasma protein concentrations is about 1:00. The spectrophotometric method used by Lamon et al. (1979) would be incapable of detecting such levels. Confirmation that haematin can produce neurological improvement without entering nervous tissue would disprove the neuronal haem deficiency theory for porphyric neuropathy. Our conclusion from our own studies and review of the literature is that haematin can cause clinical improvement, though it only occurs following 50 per cent of courses and is often temporary. It appears to be free of serious side effects when used in the recommended doses. Phlebitis around the injection site may be avoided by using a central venous line. The inconsistent clinical response to haematin makes it difficult to clearly define its place in clinical practice. We feel that haematin should be considered in the acute porphyric attack which is unresponsive to the removal of precipitating factors and laevulose infusions, especially where there are signs of developing neuropathy. It appears to have little place in the management of chronic attacks. urther research into the optimum dose schedule, rate of administration and timing of administration in relation to the onset of the attack is required, and should result in a more consistent clinical response. ACKNOWLEDGEENTS We wish to thank the departments of pharmacy at Stobhill General Hospital and the Western Infirmary, Glasgow for their assistance in the preparation of the haematin solution. We also thank Dr. Richards, Good Hope General Hospital, Sutton Coldfield and Dr. I. K. Brown, Walton Hospital, Liverpool, for permitting us to include their patients (Cases 5 and 6).

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