Rare Coexistence of Acute Intermittent Porphyria With Systemic Lupus Erythematous: Case Report and Literature Review

Abstract

Porphyrias, particularly acute intermittent porphyria (AIP), are rare, inherited disorders of heme synthesis. On the other hand, systemic lupus erythematosus (SLE) is an uncommon autoimmune disease that affects women predominantly. The coexistence of AIP and SLE is rare. We report a case of concomitant diagnosis of AIP and SLE in a 21-year-old woman who presented with recurrent acute abdominal, chest, and back pain associated with nausea and vomiting, followed by arthralgia, multiple joint pain, and rash. Investigations revealed severe hyponatremia related to SIADH (syndrome of inappropriate antidiuretic hormone secretion) with a positive SLE antibody panel and a positive urine screen for porphobilinogen. Molecular test confirmed the diagnosis of AIP with a pathogenic mutation in the HMBS gene.

Introduction

Acute intermittent porphyria (AIP) is a rare genetic disorder that affects the heme biosynthesis pathway, leading to the accumulation of porphyrins and their precursors in the body as a consequence of a partial deficiency of the heme biosynthetic enzyme porphobilinogen deaminase (PBGD), also called hydroxymethylbilane synthase (HMBS). ¹ On the other hand, systemic lupus erythematosus (SLE) is a chronic autoimmune disease that has involvement of multiple organ systems, including the skin, joints, and kidneys. ² While SLE is relatively uncommon and AIP is relatively rare, the coexistence of AIP and SLE is an exceptionally rare with only few cases reported in the literature.^3-5 The age-standardized prevalence of SLE among emirates was estimated to be 103/100 000 population (95% confidence interval: 84.5-124.4). ⁶ However, there is no available local data on AIP prevalence. The presence of the two conditions together presents a unique diagnostic and management challenge, as both have different spectrums of signs and symptoms and variable in their presentations that might not be specific for a particular disease.

In this report, we describe a young Emirati woman who presented with acute abdominal pain, nausea, vomiting, rash, and multiple joints pain with laboratory finding of severe SIADH (syndrome of inappropriate antidiuretic hormone secretion)–related hyponatremia. Further investigations confirmed diagnosis of SLE and AIP. This case adds to the previously published 15 cases of this rare coexistence of AIP and SLE. ⁵ It also highlights the importance of taking detailed clinical presentation and family history to reach the diagnosis as well as the need of a multidisciplinary approach in the care of these complex patients.

Case

A 21-year-old woman presented to the emergency department with 6-day history of intermittent moderate-to-severe dull-like abdominal pain associated with frequent episodes of vomiting. The pain was mildly relieved by oral paracetamol. In addition, she reported change in urine color to dark (Cola-like). Over few days, she developed a skin rash over both elbows and knees with mild arthralgia. The rest of the systemic review was unremarkable at that point. She had no significant past medical history and not on regular medications. She denied sick contacts, eating from outside, recent travel, and she completed her immunizations.

On physical examination, she was oriented, alert but slightly drowsy and anxious. Her vital signs were pulse rate of 104 beat/min, tympanic temperature of 37.1°C, and blood pressure of 124/48 mm Hg. Clinically she had dry oral mucosa and abdominal examination revealed mild epigastric area tenderness. The skin examination revealed a well-demarcated hyperpigmented rounded skin lesions with scaly surface involving the dorsal surfaces of the elbows and knees. The rest of the systemic examination was unremarkable.

Initial investigations showed severe hypoosmolar hyponatremia with serum sodium level of 115 mmol/L. The rest of the laboratory findings are listed in Table 1. Thyroid function test, morning cortisol, amylase, lipase, bilirubin (both total and direct), aspartate aminotransferase, and alanine transaminase were all within the normal limits. The diagnoses of severe dehydration with suspected concomitant SIADH was made.

Table 1.

Initial Laboratory Results.

	Result	Normal range
Serum tests
Sodium level (Na), mmol/L	115	135-145
Potassium level (K), mmol/L	3.1	3.6-5.2
Chloride level (Cl), mmol/L	76	96-106
S creatinine level, micromole/L	66	52-110
Urea level, mmol/L	2.6	2.1-8.5
Serum osmolality, mOsmol/kg	253	275-295
White blood cell (WBC) ×10/L	9.5	4-11
Hemoglobin, g/L	126	117-155
Platelets (PLT) ×109/L	216	150-450
Urine tests
U sodium level, mmol/L	139	Up to 20
U potassium level, mmol/L	13.6	Up to 20
U chloride level, mmol/L	129	98-106
U osmolality level, mOsmol/kg	372	50-1200
U ketones	+2	0

She was managed with 3 L of normal saline with no improvement in sodium level and she started to be confused. Therefore, normal saline was stopped and fluid restriction was initiated and a total of 300 mL of hypertonic saline (3% NaCl) was administered intermittently in the high dependency unit. This was followed by continuous infusion of 1.8% sodium chloride. Serum sodium levels and patient’s mental status were fluctuating over the following four days for which she required multiple intravenous boluses of hypertonic saline and changes in the infusion rate of the 1.8% sodium chloride until she achieved a serum sodium level of 131 mmol/L. Before workup completion and dermatology review, the patient left the hospital against medical advice.

Two days later, she presented to the emergency department with severe abdominal pain, nausea, and vomiting. Repeated laboratory investigations showed serum sodium level of 118 mmol/L, chloride level of 81 mmol/L, potassium level of 2.8 mmol/L. Clinically she was confused, but the rest of the neurological examination was intact. Treatment with 3% hypertonic saline was initiated as a bolus then switched to continuous infusion of 1.8% NaCl. At this point, the mother reported that the patient’s sister had an episode of severe hyponatremia requiring intensive care unit admission two years ago. Additionally, the father, and a cousin had episodes of recurrent abdominal pain and vomiting years ago. Based on that, acute porphyria was suspected and workup was initiated. Since the neurovisceral manifestations can be the presenting clinical features in all types of acute hepatic porphyrias, the differential diagnosis included AIP, delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP), hereditary coproporphyria (HCP), and variegate porphyria (VP). However, since AIP is the commonest type among them and giving the autosomal dominant inheritance pattern in this family, AIP was highly suspected in our patient. The absence of blistering and pain with sun exposure makes cutaneous porphyria unlikely.

On the fifth day of her second admission, serum sodium level was corrected to 131 mmol/L. At this time, she developed backache with sever arthralgia involving bilateral elbows, bilateral wrist joints, and proximal interphalangeal joints. In addition, the skin lesions described earlier spread further to involve her upper limbs, central chest, and forehead, and photosensitivity was reported.

The autoimmune screen (Table 2) showed positive antinuclear antibodies (indirect immunofluorescence assay) of 1:320 and positive DNA ab (DS) of 67.4 IU/mL, cardiolipin IgG of 22.3 CU, and cardiolipin IgM of 42.6 CU. Also, she was found to have hypocomplementemia with C3 and C4 of 0.64 and 0.08 g/L, respectively. The liver function test remains within normal limit and serology for hepatitis B, hepatitis C, and HIV was negative. Skin biopsy via direct immunofluorescence revealed some granular staining for IgG, C3, and fibrin as well as cytoid bodies staining with paucicellular vacuolar/lichenoid interface dermatitis that were strongly suggestive of subacute lupus erythematosus (Figure 1). Following the diagnostic criteria, SLE diagnosis was made and parenteral steroid was initiated (0.5 mg/kg intravenous methylprednisolone). The patient had dramatic clinical improvement and was discharged home on oral prednisolone.

Table 2.

Further Investigations.

	Serum tests	Normal range
Immunology
Antinuclear antibodies (ANA), titer IIF	1:320	>1:40
DNA ab (DS), IU/mL	67.4	<=26.9
Cardiolipin IgG, CU	22.3	<=20.0
Cardiolipin IgM, CU N	42.6	<=20.0
Complement C3, g/L	0.64	0.9-1.8
Complement C4, g/L	0.08	0.1-0.4
Porphyria screen
Urine delta-aminolevulinic acid, μmol/mmol	114	1.2-24
Urine porphobilinogen, μmol/mmol	266	<1.3
Urine porphyrins total, nmol/L	1086	<250

IIF = indirect immunofluorescence assay.

Figure 1.

Skin biopsy indicates subacute lupus erythematosus: (A) sporadic lymphocytes seen in the lower epidermis with some pigment incontinence indicating subtle interface dermatitis, (B) alcian blue-PAS (periodic acid-Schiff) stain highlights increased dermal mucin, mainly superficially, (C) IgM direct immunofluorescence highlights an apoptotic keratinocyte in the papillary dermis center field, (D) C3 focal granular staining at the dermo-epidermal junction upper center field.

At outpatient follow-up, the porphyria workup came back positive (Table 2). However, no additional samples to differentiate the type of acute porphyria (spot urine porphyrins, plasma porphyrins, stool porphyrins) were performed in our patient. Further genetic analysis revealed a heterozygous pathogenic nonsense mutation c.594G>A (p.W198X) in hydroxymethylbilane synthase (HMBS) gene confirming the diagnosis of autosomal dominant AIP. Her sister and cousin were tested positive for the same variant. Other family members were offered screening as well.

Currently, she is on tapering prednisolone dose and azathioprine 100 mg daily. Hydroxychloroquine (HCQ) 200 mg daily was added for the first few months and stopped later after improvement of the condition to avoid the possibility of precipitating further porphyria attacks. She was educated about the symptoms and the provoking factors of AIP. In addition, alert card was provided and standby medication (Hemin) was arranged in case needed during future attacks. She did not have any further attacks till the time of writing this report.

Discussion

Acute attacks in porphyrias can occur in four disorders including AIP, ALA dehydratase porphyria, VP, and HCP.

Although abdominal pain and neurological manifestations can occur in all types, AIP is the only disorder that does not have cutaneous manifestation. ⁷ In our patient, the cutaneous manifestation was SLE related as proven by the biopsy.

Acute intermittent porphyria, the most frequent form, is an autosomal dominant condition due to partial deficiency of the third enzyme of heme synthesis, PBGD (or HMBS). In Western population, the prevalence of the mutations is around 1 carrier per 2000 persons. However, the acute attack prevalence is around 5 per 100 000 and occurs in less than 10% of at-risk population.^8,9 This indicates that other factors such as hormones, drugs, infection, or dietary changes could play a role as triggering factors. ⁴ In addition, it highlights the importance of biochemical confirmation of elevated porphyrins (porphobilinogen, total porphyrins, and fractionated porphyrins) before proceeding to genetic testing as identifying pathogenic variants in HMBS gene may or may not explain the patient’s clinical presentation. To date, there is no correlation between genotype and phenotype in AIP, though some studies reported higher penetrance and/or more severe clinical manifestations in patients harboring certain mutations such as c.593G>A (p.Trp198Ter), c.1073delA, and c.76C>T (p.Arg26Cys).^9,10 On the contrary, other studies reported conflicting penetrance pattern with specific variant (P.R173W) suggesting that other factors such as modifying genes and environment play a role.^11,12

The coexistence of SLE and AIP is extremely rare with up to 15 published cases to date.^4,5Table 3 summarizes them here. Most reported patients are women aged between 13 and 57 years. The SLE diagnosis preceded the AIP diagnosis in all patients except four, including ours. The time difference between the two diagnoses is highly variable ranging from 2 days to 20 years. Genetic confirmation was reported in 2 AIP patients including ours and 1 HCP patient.

Table 3.

All Reported Cases of Coexistence of SLE and Acute Porphyria Including the Current Case.

Case	References	Sex	Age	Disease sequence	Lapsed time	SLE treatment	Family history of AIP	Genetic test
1	Wolfram 13	F	30	SLE>AIP	4 mo	NA	NA	NA
2	Marsden 14	F	57	SLE>AIP	2 d	Chloroquine	NA	NA
3	Passaron et al 15	F	13	SLE>AIP	2 y	Chloroquine	NA	NA
4	Filiotou et al 16	F	31	SLE>AIP	1 y	Barbiturates	NA	NA
5	Quilichini and Guerder 17	F	22	SLE>AIP	6 y	Steroids, analgesics	NA	NA
6	Rosemarin et al 18	F	39	SLE>AIP	2 y	Steroids, phenobarbital, and propranolol	Absent	NA
7	Allard and Scott 19	F	47	SLE>AIP	15 y	Steroids	Absent	NA
8	Andersson and Lithner 20	F	37	AIP>SLE	NA	NA	NA	NA
9	Alioua et al 21	F	24	SLE>HCP	6 mo	Steroids	Present	NA
10	Alioua 16	F	43	AIP>SLE	20 y	Thalidomide	Present	NA
11	Korkmaz 22	F	31	SLE>HCP	5 y	Steroids, methotrexate	na	NA
12	Bharati et al 23	M	49	AIP>SLE	2 y	Steroids, MMF	Present	Heterozygous mutation of HMBS: IVS14+1G→T in intron 14
13	Patil et al 24	NA	NA	SLE>AIP	NA	NA	NA	NA
14	Esteve-Valverde et al 4	M	51	SLE>AIP	10 d	Steroids, HCQ, azathioprine	Absent	NA
15	Liu et al 5	F	30	SLE>HCP	6 y	Steroids, HCQ	Absent	Heterogeneous splicing mutation of CPOX:c.700+2 T > C (intron 2)
16	Current patient	F	21	AIP>SLE	12 d	Steroid, HCQ, azathioprine	Present	Heterogeneous nonsense mutation of HMBS: c.594G>A (p.W198X)

Abbreviations: SLE, systemic lupus erythematosus; AIP, acute intermittent porphyria; NA, not available; HCP, hereditary coproporphyria; MMF, mycophenolate mofetil; HMBS, hydroxymethylbilane synthase gene; HCQ, hydroxychloroquine.

The pathophysiological explanation for the association between SLE and porphyria is unknown. Some theories include shared genetic component, autoimmunity triggered by the porphyria toxins, and a common metabolic defect leading from one condition to another.^17,25,26

It is considered a diagnostic challenge as many clinical signs such as abdominal pain, malaise, fever, neurological, and psychiatric manifestations do overlap between the two conditions. Furthermore, porphyria symptoms may mimic other common conditions and this could explain the delay of the diagnosis in such cases. In addition, as stated earlier, many of the AIP patients may not have history of acute attacks and absent family history does not rule out the diagnosis.

In addition, both AIP and SLE acute attacks can be triggered by similar precipitating factors such as infection, hormonal changes, stress, and drugs. More than 100 drugs can provoke acute attacks in AIP patients and medications are the main triggers in 37% of patients.^27,28 Examples of these mediations include nonsteroidal anti-inflammatory drugs (NSAIDs), antimicrobials, antiepileptics, antihypertensives, sedatives, and hormonal therapies.^28,29 Some drugs can trigger both SLE and AIP such as hydralazine, nifedipine, nitrofurantoin, carbamazepine, sulfasalazine, tamoxifen, and estrogen.^30,31

Some of these drugs are used in SLE treatment, and as highlighted in Table 3. Two patients used chloroquine as SLE treatment and possibly was the trigger, two patients were using HCQ but trigger factor attributed to HCQ in one patient only. In other five patients, the culprit medications included steroids along with other AIP-triggering drugs—phenobarbital, NSAIDs, and propranolol. Giving the long lapsed time between the two conditions in some of these patients, it is not clear whether the provoking factor was absolutely related to the drug only or there was an additional trigger. It is worth to mention that chloroquine and HCQ are effective treatment for porphyria cutanea tarda (PCT), though the medium-high doses may lead to hepatic toxicity in PCT patients. ³²

After establishing the diagnosis, education regarding the triggering factors is very important for the patient and family members who carry pathologic variants. The prognosis of acute attacks is good, with most patients with AIP fully recover; however, 5% to 20% of patients might have morbidity and mortality, especially in undiagnosed, delayed, or inappropriate treatment. ³³ The long-term sequelae of AIP can be hepatocellular carcinoma, hypertension, and chronic kidney disease. ³³ The detailed discussion of AIP is beyond the scope of this report.

Conclusion

The association between AIP and SLE is extremely rare. In patients with SLE, attacks of severe abdominal pain, vomiting, SIADH-related hyponatremia, and neuropsychiatric manifestations should alert to the possible concomitant AIP. Careful review of all patients’ medications is very important as many are involved in provoking both AIP and SLE. Prompt diagnosis can ensure patient full recovery from acute AIP attack and prevent long-term complications of undiagnosis.