Journal of the Royal Society of Medicine Volume 71 October 1978
775
Case reports Deficiency of hepatic coproporphyrinogen oxidase in hereditary coproporphyria' J L M Hawk BSC FRACP I A Magnus MD FRCP G H Elder MD MRcpath A Parkes PhD M Doyle Institute of Dermatology, London E9 6BX
Hereditary coproporphyria (HC) was first proposed by Berger & Goldberg (1955) to describe a type of porphyria in a Swiss family and seems to have been originally described by Watson et al. (1949). It is the least common of the three autosomal dominant hepatic porphyrias associated with acute systemic attacks (i.e. acute intermittent porphyria (AIP), variegate porphyria (VP) and HC). It is characterized most commonly by intermittent attacks of acute abdominal pain, sometimes accompanied by neurological or psychiatric symptoms and, in about a third of cases, by skin lesions. Drugs such as barbiturates and possibly certain tranquillizers and anticonvulsants may precipitate acute systemic attacks (Goldberg et al. 1967). Impairment of hepatobiliary excretion may be associated with the appearance of skin lesions (Brodie et al. 1977). The biochemical abnormality is the excretion of large amounts of coproporphyrin III in the faeces and to a lesser extent in the urine. During acute attacks, urinary porphobilinogen (PBG), a precursor of the porphyrins (Figure 1), is also excreted in large amounts (Goldberg et al. 1967, Brodie et al. 1977). It has previously been shown that in AIP, VP and HC there is an increase in the liver of 5aminolaevulinate synthase. This has been attributed to a compensatory change secondary to the primary inherited enzyme defect further on in the haem biosynthetic pathway, resulting in specific excretion patterns for each condition (Kaufman & Marver 1970, McIntyre et al. 1971). In AIP reduced activity of uroporphyrinogen-I-synthase, responsible for cyclization of PBG, has been shown in liver, fibroblasts and erythrocytes (Meyer & Schmid 1978). In HC, a reduction in activity of coproporphyrinogen (CPG) oxidase has been demonstrated in fibroblasts (Elder et al. 1976), leukocytes (Brodie et al. 1977) and lymphocytes (Grandchamp & Nordmann 1977). The interesting feature of this case is that the predicted decrease in CPG oxidase in the liver has been demonstrated. Case report In June 1977 the patient (female, aged 20) developed anorexia, fatigue, malaise, pruritus and jaundice, followed 1-2 days later by the appearance of multiple small variably-sized blisters and erosions on the face, backs of the hands and extensor surfaces of the arms (Figure 2). She had had petit mal epilepsy for some years, controlled by ethosuximide 500 mg twice daily. She was also taking an oral contraceptive (Ovranette - ethinyloestradiol 30 jig, levonorgestrel 150 pg). Alcohol intake was minimal. The jaundice settled gradually over two months, but crops of blisters recurred on the light-exposed areas on several occasions, most severely after 1 Case presented to Section of Dermatology, 20 April 1978 0 141-0768/78/100775-03/$O 1.00/0
,..
1978 The
Royal Society of Medicine
776
Journal of the Royal Society of Medicine Volume 71 October 1978
5 - Aminolaevulinate (ALA) ALA dehydrase
Porphobi inoqen Uroporphyrinogen T syrithase | - - and Uroporphyrinogen m cosynthase
Uroporphyrinogen m Uroporphyrin m j. - - Uroporphyrinogen decarboxylase
Coproporphyrinogen m C oproporphyrin m
I
forp-y-C__oproporphyrinogen oxi Protoporphyrinogen 2 - Ferrochelatase
Figure 1. Main features of porphyrin biosynthetic pathway. Boxed enzymes are mitochondrial
Haem
"W; -~~~~~~~~~~~~~~~~~~~~~4 '
'
"
_
Figure 2. Skin lesions during most phase of eruption (June 1977)
severe
ethosuximide, which had been stopped for some weeks, was restarted. By November 1977 she felt well again on no medication and total alcohol abstention. Investigations in June 1977 revealed raised values of serum bilirubin (196 jimol/1), aspartate transaminase (66 iu/1), alanine transaminase (124 iu/1) and alkaline phosphatase (150 iu/1). These values returned to normal by the end of August 1977. The clinical picture was one of viral hepatitis. Faecal coproporphyrin rose to a maximum of 323 nmol/g dry wt. (normal 0-76 nmol/g dry wt.) on 5 September 1977. Faecal protoporphyrin was never higher than 82 nmol/g dry wt.
Journal of the Royal Society of Medicine Volume 71 October 1978
777
(normal 0-200 nmol/g dry wt.) and always much lower than coproporphyrin. Urinary coproporphyrin levels were raised initially to 10 361 nmol/day (normal 1.5-432 nmol/day) and the urinary uroporphyrin was 1024 nmol/day (normal 0-49 nmol/day). Urinary PBG, measured a month after symptoms began, was normal. Skin biopsy in June 1977 revealed a subepidermal blister suggestive of porphyria. Liver biopsy in March 1978 showed normal histological features. Faecal porphyrin screening of the parents and all six siblings showed the abnormalities of HC in two siblings. The above evidence confirms the diagnosis of HC, although the normal faecal coproporphyrin values in the parents are unexpected and will be discussed later. Hepatic CPG oxidase activity was measured using a previously described technique (Elder & Evans 1978) and was found to be lowered at 0.44 nmol C02/h/mg liver protein. Values in 16 nonporphyric patients were 0.91-3.93 (mean 1.80) nmol C02/h/mg. CPG oxidase activity was also decreased in lymphocytes from the patient, being 0.14 nmol C02/h/mg protein (normal 0.19-0.71 (mean 0.43) nmol C02/h/mg). After transformation with phytohaemagglutinin and poke-weed mitogen, the activity increased to 0.37 nmol C02/h/mg, but remained lower than in controls (0.70-2.18 (mean 1.19) nmol C02/h/mg). Discussion
If the primary defect in HC is an inherited deficiency of CPG oxidase, low activity of this enzyme would be expected in the liver. Such reduced activity has been demonstrated here for the first time. Thus both HC and AIP have been shown to be associated with specific hepatic enzyme defects, and now VP is the only autosomal dominant hepatic porphyria associated with acute systemic attacks which is not yet fully investigated in this respect. The present case of HC apparently demonstrates skin lesions induced by cholestasis and consequent diversion to the skin of porphyrin normally excreted in the bile, similar to a previous report (Roberts et al. 1977). There is no evidence of an acute systemic attack of porphyria. Since acute systemic attacks of HC may occur, however, and be of severe consequence, a clinically convenient and biochemically sensitive screening test is necessary to reveal latent cases among relatives, thus enabling appropriate counselling. The current method of porphyrin screening of faeces is unsatisfactory. Specimen collection may be unpleasant for patients; also the test seems unreliable, especially in that both parents in this instance were apparently normal on faecal screening. Such normality is impossible in this autosomal dominant condition, the mode of inheritance being confirmed here by abnormalities in two siblings. Examination of blood lymphocyte CPG oxidase therefore seems likely to supersede faecal porphyrin screening as the method of choice (Grandchamp & Nordmann 1977).
Acknowledgment: We are grateful to Dr D C Nicholson for his very helpful advice. References Berger H & Goldberg A (1955) British Medical Journal ii, 85-88 Brodie M J, Thompson G G, Moore M R, Beattie A D & Goldberg A (1977) Quarterly Journal of Medicine 182, 229-241 Elder G H & Evans J 0 (1978) Biochemical Journal 169, 205-214 Elder G H, Evans J 0, Thomas N, Cox R, Brodie M J, Moore M R, Goldberg A & Nicholson D C (1976) Lancet ii, 1217-1219 Goldberg A, Rimington C & Lochhead A C (1967) Lancet i, 632-636 Grandchamp B & Nordmann Y (1977) Biochemical and Biophysical Research Communications 74, 1089-1095 Kaufman L & Marver H S (1970) New England Journal of Medicine 283, 954-958 McIntyre N, Pearson A J G, Allan D J, Craske S, West G M L, Moore M R, Paxton J, Beattie A D & Goldberg A (1971) Lancet i, 560-564 Meyer U A & Schmid R (1978) In: The Metabolic Basis of Inherited Disease. 4th edn. Ed. J B Stanbury, J B Wyngaarden & D S Fredrickson. McGraw Hill, New York; p 1166-1220. Roberts D T, Brodie M J, Moore M R, Thompson G G, Goldberg A & MacSween R N M (1977) British Journal of Dermatology 96, 549-554 Watson C J, Schwartz S, Schulze W, Jacobson L 0 & Zagaria R (1949) Journal of Clinical Investigation 28, 465-468
775
Case reports Deficiency of hepatic coproporphyrinogen oxidase in hereditary coproporphyria' J L M Hawk BSC FRACP I A Magnus MD FRCP G H Elder MD MRcpath A Parkes PhD M Doyle Institute of Dermatology, London E9 6BX
Hereditary coproporphyria (HC) was first proposed by Berger & Goldberg (1955) to describe a type of porphyria in a Swiss family and seems to have been originally described by Watson et al. (1949). It is the least common of the three autosomal dominant hepatic porphyrias associated with acute systemic attacks (i.e. acute intermittent porphyria (AIP), variegate porphyria (VP) and HC). It is characterized most commonly by intermittent attacks of acute abdominal pain, sometimes accompanied by neurological or psychiatric symptoms and, in about a third of cases, by skin lesions. Drugs such as barbiturates and possibly certain tranquillizers and anticonvulsants may precipitate acute systemic attacks (Goldberg et al. 1967). Impairment of hepatobiliary excretion may be associated with the appearance of skin lesions (Brodie et al. 1977). The biochemical abnormality is the excretion of large amounts of coproporphyrin III in the faeces and to a lesser extent in the urine. During acute attacks, urinary porphobilinogen (PBG), a precursor of the porphyrins (Figure 1), is also excreted in large amounts (Goldberg et al. 1967, Brodie et al. 1977). It has previously been shown that in AIP, VP and HC there is an increase in the liver of 5aminolaevulinate synthase. This has been attributed to a compensatory change secondary to the primary inherited enzyme defect further on in the haem biosynthetic pathway, resulting in specific excretion patterns for each condition (Kaufman & Marver 1970, McIntyre et al. 1971). In AIP reduced activity of uroporphyrinogen-I-synthase, responsible for cyclization of PBG, has been shown in liver, fibroblasts and erythrocytes (Meyer & Schmid 1978). In HC, a reduction in activity of coproporphyrinogen (CPG) oxidase has been demonstrated in fibroblasts (Elder et al. 1976), leukocytes (Brodie et al. 1977) and lymphocytes (Grandchamp & Nordmann 1977). The interesting feature of this case is that the predicted decrease in CPG oxidase in the liver has been demonstrated. Case report In June 1977 the patient (female, aged 20) developed anorexia, fatigue, malaise, pruritus and jaundice, followed 1-2 days later by the appearance of multiple small variably-sized blisters and erosions on the face, backs of the hands and extensor surfaces of the arms (Figure 2). She had had petit mal epilepsy for some years, controlled by ethosuximide 500 mg twice daily. She was also taking an oral contraceptive (Ovranette - ethinyloestradiol 30 jig, levonorgestrel 150 pg). Alcohol intake was minimal. The jaundice settled gradually over two months, but crops of blisters recurred on the light-exposed areas on several occasions, most severely after 1 Case presented to Section of Dermatology, 20 April 1978 0 141-0768/78/100775-03/$O 1.00/0
,..
1978 The
Royal Society of Medicine
776
Journal of the Royal Society of Medicine Volume 71 October 1978
5 - Aminolaevulinate (ALA) ALA dehydrase
Porphobi inoqen Uroporphyrinogen T syrithase | - - and Uroporphyrinogen m cosynthase
Uroporphyrinogen m Uroporphyrin m j. - - Uroporphyrinogen decarboxylase
Coproporphyrinogen m C oproporphyrin m
I
forp-y-C__oproporphyrinogen oxi Protoporphyrinogen 2 - Ferrochelatase
Figure 1. Main features of porphyrin biosynthetic pathway. Boxed enzymes are mitochondrial
Haem
"W; -~~~~~~~~~~~~~~~~~~~~~4 '
'
"
_
Figure 2. Skin lesions during most phase of eruption (June 1977)
severe
ethosuximide, which had been stopped for some weeks, was restarted. By November 1977 she felt well again on no medication and total alcohol abstention. Investigations in June 1977 revealed raised values of serum bilirubin (196 jimol/1), aspartate transaminase (66 iu/1), alanine transaminase (124 iu/1) and alkaline phosphatase (150 iu/1). These values returned to normal by the end of August 1977. The clinical picture was one of viral hepatitis. Faecal coproporphyrin rose to a maximum of 323 nmol/g dry wt. (normal 0-76 nmol/g dry wt.) on 5 September 1977. Faecal protoporphyrin was never higher than 82 nmol/g dry wt.
Journal of the Royal Society of Medicine Volume 71 October 1978
777
(normal 0-200 nmol/g dry wt.) and always much lower than coproporphyrin. Urinary coproporphyrin levels were raised initially to 10 361 nmol/day (normal 1.5-432 nmol/day) and the urinary uroporphyrin was 1024 nmol/day (normal 0-49 nmol/day). Urinary PBG, measured a month after symptoms began, was normal. Skin biopsy in June 1977 revealed a subepidermal blister suggestive of porphyria. Liver biopsy in March 1978 showed normal histological features. Faecal porphyrin screening of the parents and all six siblings showed the abnormalities of HC in two siblings. The above evidence confirms the diagnosis of HC, although the normal faecal coproporphyrin values in the parents are unexpected and will be discussed later. Hepatic CPG oxidase activity was measured using a previously described technique (Elder & Evans 1978) and was found to be lowered at 0.44 nmol C02/h/mg liver protein. Values in 16 nonporphyric patients were 0.91-3.93 (mean 1.80) nmol C02/h/mg. CPG oxidase activity was also decreased in lymphocytes from the patient, being 0.14 nmol C02/h/mg protein (normal 0.19-0.71 (mean 0.43) nmol C02/h/mg). After transformation with phytohaemagglutinin and poke-weed mitogen, the activity increased to 0.37 nmol C02/h/mg, but remained lower than in controls (0.70-2.18 (mean 1.19) nmol C02/h/mg). Discussion
If the primary defect in HC is an inherited deficiency of CPG oxidase, low activity of this enzyme would be expected in the liver. Such reduced activity has been demonstrated here for the first time. Thus both HC and AIP have been shown to be associated with specific hepatic enzyme defects, and now VP is the only autosomal dominant hepatic porphyria associated with acute systemic attacks which is not yet fully investigated in this respect. The present case of HC apparently demonstrates skin lesions induced by cholestasis and consequent diversion to the skin of porphyrin normally excreted in the bile, similar to a previous report (Roberts et al. 1977). There is no evidence of an acute systemic attack of porphyria. Since acute systemic attacks of HC may occur, however, and be of severe consequence, a clinically convenient and biochemically sensitive screening test is necessary to reveal latent cases among relatives, thus enabling appropriate counselling. The current method of porphyrin screening of faeces is unsatisfactory. Specimen collection may be unpleasant for patients; also the test seems unreliable, especially in that both parents in this instance were apparently normal on faecal screening. Such normality is impossible in this autosomal dominant condition, the mode of inheritance being confirmed here by abnormalities in two siblings. Examination of blood lymphocyte CPG oxidase therefore seems likely to supersede faecal porphyrin screening as the method of choice (Grandchamp & Nordmann 1977).
Acknowledgment: We are grateful to Dr D C Nicholson for his very helpful advice. References Berger H & Goldberg A (1955) British Medical Journal ii, 85-88 Brodie M J, Thompson G G, Moore M R, Beattie A D & Goldberg A (1977) Quarterly Journal of Medicine 182, 229-241 Elder G H & Evans J 0 (1978) Biochemical Journal 169, 205-214 Elder G H, Evans J 0, Thomas N, Cox R, Brodie M J, Moore M R, Goldberg A & Nicholson D C (1976) Lancet ii, 1217-1219 Goldberg A, Rimington C & Lochhead A C (1967) Lancet i, 632-636 Grandchamp B & Nordmann Y (1977) Biochemical and Biophysical Research Communications 74, 1089-1095 Kaufman L & Marver H S (1970) New England Journal of Medicine 283, 954-958 McIntyre N, Pearson A J G, Allan D J, Craske S, West G M L, Moore M R, Paxton J, Beattie A D & Goldberg A (1971) Lancet i, 560-564 Meyer U A & Schmid R (1978) In: The Metabolic Basis of Inherited Disease. 4th edn. Ed. J B Stanbury, J B Wyngaarden & D S Fredrickson. McGraw Hill, New York; p 1166-1220. Roberts D T, Brodie M J, Moore M R, Thompson G G, Goldberg A & MacSween R N M (1977) British Journal of Dermatology 96, 549-554 Watson C J, Schwartz S, Schulze W, Jacobson L 0 & Zagaria R (1949) Journal of Clinical Investigation 28, 465-468
