1 Division of Nephrology and 2 Division of Hematology, Cook County Hospital, Chicago, IL60612 and 3 University of Illinois College of Medicine at Chicago and 4 The Hektoen Institute for Medical Research, Chicago, Illinois, USA
Correspondence and offprint requests to: Professor Asad A. Bakir, Cook County Hospital, Division of Nephrology, 1835 West Harrison Street, Chicago, IL 60612, USA.
Keywords: systemic lupus erythematosus; nephritis; porphyria
Introduction
The rare co-existence of lupus erythematosus and porphyria may raise difficult diagnostic and therapeutic problems. The two diseases have many clinical signs in common, and treatment for lupus erythematosus with hydroxychloroquine, for example, may trigger porphyria in susceptible patients. The association between the two diseases may simply be coincidental, or may reflect a hitherto undiscovered link.
Case
A 24-year-old African American woman was admitted because of a week's history of severe intermittent cramping pain in the epigastrium and lower abdomen. The pain was followed 4 days later by fever, chills, nausea, vomiting and diarrhoea. Six months earlier she saw a doctor because of fever, malar rash and arthralgia of the hands and knees. He found antinuclear antibodies in her serum, made a diagnosis of systemic lupus erythematosus and gave her a course of prednisone which caused her symptoms to subside. She had no family history of systemic lupus erythematosus, but a brother of hers had reportedly died of `porphyria'. She herself, however, had not had any attacks suggestive of porphyria.
On admission, she looked very ill. Her temperature was 38°C and blood pressure 144/100 mmHg. She had a malar rash, and tenderness in the right and left upper abdominal quadrants. Stool, urine and blood cultures showed no pathogens. The renal service was consulted because of microhaematuria and deteriorating renal function. Urinalysis showed protein 2+, and 1012 red blood cells (RBC) per high power field. BUN was 15 mM/l and serum creatinine 247 µM/l, up from 11 mM/l and 133 µM/l, respectively, 2 months earlier; Na 135 mM/l, Cl 107 mM/l, K 5.2 mM/l, and HCO3 21 mM/l. Twenty-four hour urine protein was 1522 mg. Blood glucose was 6.6 mM/l, serum albumin 14 g/l, calcium 2.07 mM/l, phosphorous 1.1 mM/l, magnesium 0.82 mM/l, SGPT 20 IU/l, SGOT 20 IU/l, and alkaline phosphatase 102 IU/l. Haemoglobin was 88 g/l, haematocrit 27%, white blood cell count 3.6x109/l and platelets 15.1x109/l. Serum ANA was positive (>1/80 dilutions, speckled pattern); anti-double-stranded DNA antibody by enzyme-linked immunosorbent assay (ELISA) was 280 IU (normal <40) and anti-Sm antibody by ELISA 1402 U (normal <89); C3 was 440 g/l (normal 8802010) and C4 <100 g/l (normal 160470). Computerized tomography of the abdomen was not remarkable.
She was treated with 1 g of methyl prednisolone intravenously daily for 3 days, followed by prednisone 60 mg orally daily; and was also given one dose of cyclophosphamide, 750 mg intravenously. Renal function improved, with serum creatinine declining to 141 µM/l. Two weeks later, the patient developed acute psychosis, aggressive behaviour and flaccid paraplegia. Her sensory system was largely intact, but motor paralysis progressed to include the upper extremities and the muscles of respiration, necessitating mechanical ventilation. Twenty-four urinary porphyrin values are shown in Table 1. Porphobilinogen deaminase was 8.6 nM/s of uroporphyrinogen I/l RBC (normal >7); coproporphyrinogen oxidase, 0.06 nM/s of protoporphyrinogen/l RBC (normal: 0.10.3) and aminolaevulinic acid dehydratase 6.9 nM/s of porphobilinogen/l of RBC (normal: >4). Serum CPK was 28 IU/l. The cerebrospinal fluid had glucose of 5.5 mM/l, protein of 40 g/l; white blood cell count of 3x103/l, and cultures of the fluid yielded no microorganisms. A muscle biopsy was normal. Electromyography revealed severe axonal polyneuropathy with mild demyelinization. The patient was treated with intravenous haematin and 10% dextrose. Twenty-four hour urine and stool porphyrins 2 weeks after treatment are shown in Table 1
. She improved, and ventilatory support was discontinued. Hereditary coporphyria was thought to be the most likely diagnosis. She was discharged to a rehabilitation facility, but later died there from a severe pneumonia.
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This patient had systemic lupus erythematosus, with malar rash, arthralgia, anaemia, anti-native DNA antibodies in the serum, profound hypocomplementaemia and nephritis, which improved upon treatment with corticosteroids and cyclophosphamide. The abdominal pain was attributed initially to lupus serositis, until the patient developed profound neurological symptoms that raised the spectre of co-existing hepatic porphyria. Studies of the urine, stool and RBC did not pinpoint the type of hepatic porphyria in question, but were quite suggestive of hereditary coproporphyria.
Wolfram et al. first reported in 1952 the case of a patient who had systemic lupus erythematosus and who later developed acute intermittent porphyria [1]. Some 47 cases of lupus erythematosus have since been described in association with various types of porphyria [125]. Of these 47 cases, there were only seven cases (15%) of acute intermittent porphyria associated with systemic lupus erythematosus in six instances [16] and with discoid lupus erythematosus in only one instance [16]. Fully 38 of the 47 cases (81%) were porphyria cutanea tarda, associated with systemic lupus erythematosus in 18 instances [7,8,915], with discoid lupus erythematosus in 17 instances [10,15,17,20] and with subacute cutaneous lupus erythematosus in three instances [15,23,24]. There was only one case of porphyria variegata [21] and another of erythropoietic porphyria [22], each associated with discoid lupus erythematosus.
It is not known whether the association between porphyria and lupus erythematosus is purely coincidental, or whether it represents some common link. In studies on porphyria cutanea tarda, Clemmensen et al. found that none of their 55 patients fulfilled the diagnostic criteria for systemic lupus erythematosus [25] and Tio et al. failed to note excessive prevalence of autoantibodies in their patients [26]. Griso et al. attributed the finding of serum antinuclear antibodies in 14 of their 158 patients (12%) to old age or liver disease [27]. In a study of 38 patients with various types of porphyria, serum antinuclear antibodies were found in eight of 15 patients with acute intermittent porphyria, but only one patient had clinical evidence of systemic lupus erythematosus [28].
On the other hand, lupus erythematosus was present in 15 of 676 patients with porphyria (2.2%) seen at the Mayo Clinic over a 20-year period [15]. All these 15 patients had porphyria cutanea tarda, and in six of them (40%) lupus erythematosus was diagnosed either at the same time or within 1 year of the detection of porphyria. It is interesting that the gene for uroporphyrinogen decarboxylase, the deficient enzyme in porphyria cutanea tarda, is located on chromosome 1 [29], and that the 1q41q42 region of that chromosome is probably linked to systemic lupus erythematosus [30]. Lastly, porphyria cutanea tarda has been described in association with such autoimmune diseases as thymoma [31], scleroderma [32] and autoimmune haemolytic anaemia [30].
Harris et al. proposed the hypothesis, amongst others that porphyria elicits an autoimmune response that gives rise to lupus erythematosus [4]. The accumulation in porphyria of various porphyrins, especially uroporphyrin, causes complement activation and neutrophil chemotaxis upon exposure to UV light [34], increases collagen synthesis by human skin fibroblasts [35] and causes cell damage that may incite the formation of autoantibodies in genetically predisposed individuals [12]. On the other hand, chloroquine in doses used to treat systemic lupus erythematosus may trigger porphyria by releasing tissue-bound hepatic porphyrin [36].
In summary, clinicians should entertain the possibility of co-existing porphyria in patients with lupus erythematosus who develop severe neurovisceral signs. The occasional association of these two diseases is interesting, and is compatible with the notion that these two conditions are somehow connected.
Acknowledgments
We are indebted to Mrs Jewel Wallace for preparing the manuscript.
References