Diagnostic and Therapeutic Challenges in an Acute Variegate Porphyric Crisis Complicated by Anuric Renal Failure and Multiorgan Dysfunction: A Case Report

Introduction

Acute hepatic porphyrias arise from genetic defects affecting heme synthesis [1–3]. This results in the accumulation of porphyrin precursors, which can cause multiorgan dysfunction or “acute porphyric attacks” [1–3]. Neurological manifestations of the disease vary, including acute peripheral neuropathy, dysautonomia, neuropsychiatric symptoms, seizures, and encephalopathy [4,5], accompanied by multiorgan failure. Porphyric attacks are triggered by fasting, alcohol, medications (especially cytochrome P450 inducers), and metabolic stress caused by infections (including Staphylococcus aureus) [6,7]. Autonomic dysfunction may include fever and hemodynamic instability, mimicking sepsis [6,7]. Neurological improvement can take weeks to months [4,5], necessitating the early identification of an acute porphyric crisis and aggressive institution of appropriate therapies.

Aminolaevulinic acid (ALA) and porphobilinogen (PBG) porphyrin precursor accumulation can drive the neurotoxicity seen in acute hepatic porphyrias [1–3]. Variegate porphyria (VP) can cause acute neurovisceral attacks and photocutaneous lesions [1–3]. It results from a defect in protoporphyrinogen oxidase, which is inherited through an autosomal dominant mechanism [1–3]. South Africa has the highest incidence of porphyria internationally, with VP being the most prevalent [8].

Urinary porphobilinogens (urinary PBG) and ALA, in addition to serum, fecal, and urinary porphyrins, are elevated during acute porphyric attacks [1–3]; identification of their elevated levels is diagnostic. Porphyrins are photosensitive and biode-graded by exposure to ultraviolet light; a protected, freshly voided urine sample is therefore required for diagnostic processing by spectrophotometric or chromatographic analyses. Further porphyria subtyping is undertaken by plasma fluorescence, with ∼626 nm being diagnostic of VP [1]. Plasma fluorescence, however, does not confirm an acute attack. Urinary assessments are favored for diagnostic purposes due to the rapid turnaround times in obtaining a diagnostic result [1–5], but are of limited value in anuric renal failure states. Reliance on fecal porphyrins, in particular, coproporphyrin III and protoporphyrin, is required in anuric patients and can help confirm the diagnosis of VP. However, fecal testing is not readily available in all centers, nor is the assay as robust and timely as the diagnostic analyses of its urinary counterparts [1–5].

Treatment of acute neurovisceral porphyric crises relies on inhibition of 5’-aminolevulinate synthase 1 (ALAS1) activity in the liver [1–5]. This in turn reduces the production of toxic heme precursors, especially ALA. Treatment of precipitating factors, modulating the cytochrome-P450 (CYP450) system, and decreasing metabolic stressors, are also recommended [1–5]. Carbohydrate loading during acute attacks to upregulate hepatic ALAS1 expression is central to treating acute porphyric attacks [1–5]; intravenous heme infusions downregulate ALAS1 expression and typically normalizes ALA and PBG levels within four days [1–5,8]. Its prompt initiation therefore reduces the severity and duration of attacks [1–5,8].

Extracorporeal circuits such as therapeutic plasma exchange (TPE) and intermittent hemodialysis can assist removal of toxic heme precursors and have been used as adjunctive therapies during acute porphyric attacks [9–12]. TPE has limited evidence for use in acute intermittent porphyrias [10,11] and erythropoietic protoporphyria [12], but to the best of our knowledge, has not been trialed in VP patients, including those with neurological manifestations of the disease. Continuous renal replacement therapy (CRRT) has not previously been described as a modality of porphyrin removal.

This report describes a 77-year-old woman with a delayed acute variegate porphyria diagnosis, manifesting with a neurovisceral crisis and multiorgan failure secondary to methicillin-sensitive Staphylococcus aureus (MSSA) sepsis. The diagnostic and treatment challenges of an acute neurovisceral VP crisis are considered, particularly in the setting of anuric renal failure and multiorgan dysfunction. Novel diagnostic insights are provided through effluent dialysate testing of PBGs in this anuric porphyria patient. Difficulties surrounding the biochemical monitoring of heme-arginate replacement therapy and treatment responses during concurrent TPE and CRRT are also explored.

Case Report

A 77-year-old South African woman residing in South Africa and visiting family in Perth, Western Australia, presented to our center with a three-day history of atraumatic and progressive abdominal, right-arm and lumbar pain. Her past medical history included insulin-dependent type 2 diabetes mellitus, stage 4 chronic kidney disease (baseline creatinine 170 μmol/L) secondary to longstanding hypertension and diabetes, hyperlipidemia, osteoarthritis, hypothyroidism, a left below-knee amputation secondary to previous trauma, and a prior cholecystectomy. She had an existing diagnosis of cutaneous porphyria. Her long-term medications included levothyroxine 75 μg daily, indapamide 25 mg daily, pregabalin 25 mg at night, etorocoxib 75 mg at night, valsartan 160 mg daily, and insulin degludec/aspart (Ryzodeg®). She was a non-smoker and did not drink alcohol. She had no allergies. She had been clinically well within the preceding six months prior to her admission.

On admission to our unit, her temperature was 35.5–36.0°C with a heart rate of 95 bpm and respiratory rate of 18 breaths/ minute. Her oxygen saturation was 94% on room air. She was hypotensive with a blood pressure of 80/40 mmHg, which improved to 106/63 mmHg with an intravenous 500 mL bolus of 0.9% normal saline. Her blood glucose was 9.9 mmol/L, with ketones of 1.3 mmol/L. She did not develop a fever of >38°C within the first 24 hours of her hospitalization. Her cardiorespiratory and abdominal examination results were unremarkable, with no discernible tenderness or organomegaly. Assessment of her right shoulder elicited pain on palpation of the pectoral muscles and acromioclavicular joint. Her Hawkins impingement test result was negative. Crepitus or swelling over the shoulder joint was not observed. She had widespread scarring and superficial ulceration of the skin with no signs of cellulitis. No other autoimmune, infectious, or malignant stigmata were identified.

Her initial blood investigations (Table 1) revealed marked leukocytosis with associated neutrophilia and left shift, mild thrombocytopenia, acute-on-chronic renal failure, hyponatremia secondary to SIADH, with serum osmolality 285 mmol/kg (reference range: 275–295 mmol/kg), urinary sodium 11 mmol/L (reference range: 40–210 mmol/L), urine osmolality 335 mmol/ kg (reference range: 75–300 mmol/kg), biochemical liver dys-function, and mild coagulopathy (INR 1.5 (reference range: 0.9–1.3), fibrinogen 5.4 g/L (reference range: 2.0–4.0g/L), APTT 33 seconds (reference range: 27.5–38.5 seconds), and PT 17.8 seconds (reference range: 12–16.5 seconds). Her C-reactive protein (CRP) was elevated at 352 mg/L (reference range <5 mg/L) with a lactate of 3.6 mmol/L (reference range <1.3 mmol/L) and procalcitonin of 22.10μg/L (reference range <0.05 μg/L). Peripheral aerobic and anerobic blood cultures identified the presence of MSSA, which were thought to account for her blood and biochemical abnormalities. Comprehensive septic screening was undertaken and did not identify a specific nidus for her MSSA infection; chest X-ray imaging did not isolate a consolidative process. X-ray and ultrasound imaging of her right shoulder revealed a supraspinatus tendinopathy with no abscesses. Abdominal ultrasonography revealed a heterogenous liver without hepatosplenomegaly and small kidneys with chronic cortical thinning. A urine culture revealed contaminant mixed growth, from which MSSA could not be isolated. Computed tomography (CT) imaging of the brain showed no intracranial pathology, while spinal views revealed chronic facet joint osteoarthropathies. Subsequent whole-body positron emission tomography/computed tomography (PET/CT) imaging did not identify a focal source for her MSSA bacteremia. Transthoracic and transesophageal echocardiograms did not isolate any mobile echodensities, valvular vegetations, or paravalvular abscesses. The MSSA infection was deemed to be cutaneous in origin.

Intravenous piperacillin/tazobactam 4.5 g bid was empirically commenced, which was later rationalized to cefazolin 2 g tds for her MSSA sepsis following consultation with our Infectious Diseases Department. On day 4 of her hospital admission, she developed progressive multiorgan dysfunction, presumed to be solely secondary to her MSSA sepsis, prompting an urgent transfer to Intensive Care. Severe hypotension refractory to initial intravenous fluid resuscitation was noted to be consistent with distributive shock, requiring intravenous noradrenaline (0.02–0.2 μg/kg/h) titrated to target a mean arterial pressure of >65 mmHg. Concurrent autonomic failure with a syndrome of inappropriate ADH (SIADH) secretion resulting in hyponatremia with a serum sodium nadir of 126 mmol/L were also identified, in conjunction with worsening anuric renal failure (peak urea 41.4 μmol/L, creatinine 537 μmol/L, eGFR 6 mL/ min/1.73 m2); CRRT was subsequently commenced. Moderate thrombocytopenia (platelet nadir 71×109/L) was also noted in the setting of acute-on-chronic biochemical hepatic dysfunction (bilirubin 181 μmol/L, albumin 22 g/L) and MSSA sepsis. Serial blood cultures revealed persistence of the original MSSA isolate despite cefazolin therapy. Her intravenous antibiotics were changed to piperacillin/tazobactam 4.5 g tds for several days, and later rationalized to cephazolin 2 g qid on CRRT. She improved clinically, enabling vasopressor support to be weaned.

Nine days following admission, and despite initial clinical and biochemical improvements, she developed a new, progressive encephalopathy (GCS6: E3V2M1) with flaccid tetraparesis, facial dyskinesia, and peripheral areflexia. Her brain stem reflexes remained intact. Repeat blood cultures had shown clearance of the MSSA from the blood and the CRP had decreased to 63 mg/L. Her neurological presentation was atypical for resolving MSSA sepsis; therefore, alternative diagnoses, including an acute porphyric attack, were explored. Magnetic resonance imaging (MRI) results of the brain and spinal cord were un-remarkable. An electroencephalogram showed a non-specific encephalopathy with no epileptiform activity. A lumbar puncture was performed and abnormal xanthochromic cerebrospinal fluid (CSF) was obtained (Figure 1A). Biochemical analyses showed a markedly elevated protein 25.84 g/L (reference range: 0.15–0.45 g/L), reduced glucose at 1.9 mmol/L (reference range: 2.8–4.4 mmol/L), with leukocytes 24/μL (differential: 80% lymphocytes, 20% polymorphonuclear leukocytes), and erythrocytes 14/μL. The CSF bilirubin and oxyhemoglobin were elevated (0.8125 AU, reference range <0.0071 AU; and 1.2940, respectively). CSF porphyrins were not assessed. Extensive CSF microbiological and autoimmune investigations for viruses, bacteria, and Mycobacterium tuberculosis, including atypical autoimmune encephalitides, were negative. Despite objective evidence noting the resolution of her MSSA bacteremia and absence of other causes (eg, infarction, other infections, autoimmune diseases, neoplasms), we suspected the presence of an inherited disorder contributing to her neurological compromise and reliance on CRRT. An acute porphyric crisis manifesting with multiorgan dysfunction, encephalopathy, and diffuse polyradiculoneuropathy, triggered by MSSA bacteremia, was considered as the primary differential.

Diagnostic challenges were encountered in confirming an acute porphyria neurovisceral crisis in this patient with anuric renal failure. Urinary PBGs were retrospectively quantified using a commercially available kit (PM Separations) using a resin exchange method on samples collected >72 hours earlier; unfortunately, these urine specimens had been exposed to light and returned negative results. Fecal coproporphyrin III and protoporphyrin analyzes are no longer undertaken in our region and have an approximately two-week processing time from interstate centers; samples were therefore not collected. Plasma porphyrin levels (assessed via fluorometry [Varian Eclipse Fluorimeter] against a reference standard following their extraction from plasma using an ether-acetic acid mixture) were moderately elevated at 4.9 μmol/L (reference range: <1.5 μmol/L); however, this result is difficult to interpret in the setting of MSSA sepsis and multiorgan dysfunction. Plasma fluorescence showed a pathognomonic peak wavelength at 628 nm, which although diagnostic for VP, does not confirm an acute attack.

We subsequently developed a novel diagnostic assay of dialysis effluent PBG (using the same resin exchange protocol as detailed above for urinary PBGs, PM Separations), to confirm that the patients’ neurological sequelae were in keeping with an acute porphyric neurovisceral attack. Reference values for measuring and reporting dialysis effluent PBGs are not available. Therefore, we constructed a novel “pseudo-normal” reference range. We measured PBGs in dialysate bags (pre-CRRT) to provide a negative control (undetectable <0.1 μmol/L), in addition to the dialysate effluent from another patient without porphyria (a 72-year-old Australian woman admitted with septic shock complicated by anuric renal failure, with dialy-sate PBG 0.3939 μmol/L) to establish a “pseudo-normal” reference range. The resultant effluent PBG in our patient’s sample was very high (1.91 μmol/L) compared to controls, confirming that her presentation was consistent with an acute neurovisceral attack in the setting of VP. Her diagnosis was later corroborated with repeat, light-protected urinary PBG testing (U-porphyrin/creatinine ratio 328 μmol/mmol consisting mostly of coproporphyrin; reference range <35 μmol/mmol) and subsequent retrospective review of correspondence from her retired South African physician, who was uncontactable at the time of her hospital admission.

While awaiting diagnostic confirmation from these investigations, we initiated empiric treatment for a suspected acute neurovisceral porphyric attack. Metabolic stress and CYP450 induction were reduced by medication rationalization and avoidance of porphyrinogenic medications [1–5]. Three hundred grams of carbohydrates were given daily via total parenteral nutrition and 50% dextrose. Intravenous cimetidine 400 mg bid was initiated due to its down-regulating effects on ALA and CYP450 [4,5]. Her pain was managed with intravenous fentanyl at 20 μg/h. Intravenous cefazolin 2 g qid and CRRT were continued. TPE was also empirically commenced; four cycles of 4 L TPE achieving a 1–1.5 plasma volume exchange utilizing albumin 4% replacement was undertaken. Multiple TPE and CRRT circuits were lost due to activation of the blood leak detector clamp of the Prismaflex CRRT system used in our center. This safety feature uses infrared spectrophotometry on the efferent limb of the circuit, detecting and preventing blood from entering the effluent bag in rare cases of filter fracture [13]. We speculate that inappropriate clamping occurred due to high levels of porphyrins present in the pigmented effluent (Figure 1B), which have a similar absorption wavelength as blood, thereby activating the safety clamp. We bypassed this mechanism by attaching and infusing two 3-mL syringes filled with 0.9% normal saline via a plastic connector (Figure 2); this permitted TPE and CRRT to proceed without further circuit interruptions. Mean PBG measurements in the TPE effluent were greater (∼4.095 μmol/L) than the CRRT effluent (∼1.537 μmol/L), suggesting that the former was more effective in removing porphyrins from the circulation. Intravenous heme-arginate dosed at 4 mg/kg daily was initiated on day 10 of admission for 8–10 hours daily, followed by 12 hours of high-volume CRRT (40 mL/kg/hour effluent) using Hemosol® predilution and dialysate bags. This enabled fluid balance and metabolic control given the persisting anuric renal failure, while optimizing IV heme therapy efficacy, given the unclear pharmacodynamics and potential removal via the CRRT circuit.

Despite the above measures and prior to her fifth TPE session, she continued to deteriorate neurologically, developing an acute decline in GCS 6 (E4, M1, V1) with right-sided gaze deviation and loss of airway reflexes. A seizure was presumed, and she was given 5 mg intravenous midazolam with good effect. She was subsequently intubated. Repeat CT imaging of her brain revealed a new, 6-mm subdural hemorrhage (SDH) posterior to the clivus, with no midline shift. This was likely precipitated by a progressive, multifactorial coagulopathy arising from her MSSA sepsis, consumptive thrombocytopenia, synthetic hepatic dysfunction, and post-TPE coagulopathy. Before TPE, her coagulation studies showed INR 1.1, fibrinogen 4.5g/L, and APTT 35 seconds, with platelets of 130×109/L. After TPE, her coagulation profile showed INR 1.4, APTT 69 seconds, and fibrinogen 1.5 g/L. Rotational thromboelastometry (ROTEM) showed prolonged clotting times, low clot amplitude at 5 and 10 minutes, and low MCF. She was given two units of fresh frozen plasma, which normalized her coagulopathy on repeat testing. TPE was subsequently discontinued and her SDH improved to 3 mm in diameter on serial CT imaging. Additional whole-body CT imaging revealed a new nosocomial pneumonia and low-volume, bilateral pulmonary emboli. Microbiological evaluations of her sputum and blood cultures isolated Enterobacter and Candida albicans species, respectively, resulting in escalation of her intravenous antimicrobials to meropenem 1 g bid and anidulafungin 100 mg daily. An unfractionated heparin infusion targeting a low therapeutic APTT level was started for her provoked pulmonary emboli. No neurological improvements were observed despite administration of heme-arginate for four days, and following the best available evidence [8], treatment was continued for a further four days. Early percutaneous guided tracheostomy was undertaken one day after intubation to facilitate neuro-prognostication. Despite the above aggressive interventions with intensive care level support for one month, the patient failed to improve, with persisting severe encephalopathy, tetraparesis, and oligoanuric renal failure. Recovery and rehabilitation to return to independent living and an acceptable quality of life were deemed impossible. Following discussions with her family, she was transitioned to palliative care measures. She died from her illness on day 33 of her admission.

Discussion

Neurological manifestations of acute hepatic porphyrias, including VP, are heterogenous in presentation and are associated with high mortality rates [4,5]. Early diagnostic confirmation of elevated urinary or fecal PBG and ALA are central to commencing supportive therapies, including intravenous heme and glucose/carbohydrate loading, and, occasionally, TPE and hemodialysis [1–12]. We have reported a challenging case of an acute VP crisis in an elderly woman triggered by MSSA sepsis, likely arising from cutaneous origins, manifesting with progressive encephalopathy and multiorgan failure, which required innovative diagnostic extracorporeal effluent assays to confirm an acute VP attack. Elevated effluent PBGs from TPE and CRRT dialysates may be of diagnostic value in acute porphyrias.

Diagnostic assays for VP, especially during acute attacks, include the detection of elevated urinary PBGs [1–3]. Serum, fecal, and urinary porphyrins can also be diagnostic [1–3]. In patients with anuric renal failure during an acute porphyric crisis, the diagnosis often relies upon serum and fecal porphyrins. Expert consensus guidelines recommend reliance on the plasma porphyrin level, but acknowledge that these levels are typically high in patients with renal failure [14,15] and may not be diagnostic of an acute porphyric attack. Fecal porphyrin assays are not commonly performed and were not available at our institution. To the best of our knowledge, we are the first to report a novel approach of assessing TPE and CRRT effluent dialysates to detect raised PBGs to confirm an acute VP crisis in a patient with anuric renal failure. Combined with a high index of clinical suspicion, effluent testing from extracorporeal circuits in anuric patients can facilitate timely diagnosis of VP, enabling early initiation of targeted therapies. However, further research is needed to establish clear effluent reference ranges for PBGs that constitute an acute porphyric crisis in VP and other acute porphyrias.

Some studies support the use of TPE or intermittent hemodialysis in acute intermittent porphyria with neurovisceral compromise [9–11,16]. Extracorporeal circuits that remove plasma porphyrins frequently function as adjuncts to bridge patients to commencing intravenous heme [9] or when patients have failed such therapies [10]. To the best of our knowledge, no reports exist documenting the combined use of TPE with hemodialysis, let alone in a CRRT fashion, in an acute VP crisis with concurrent intravenous heme-arginate therapy. The molecular weight of heme-arginate is 792.7 Daltons [17]. Hemearginate would be freely filtered through the CRRT circuit using a Prismaflex ST150 membrane filter unless there is significant protein binding [13,18]. Unfortunately, the pharmacokinetics underpinning heme-arginate and its protein binding are poorly characterized, with some reports suggesting it is bound to albumin and hemopexin [19]. In our case, to optimize the presence of heme-arginate to downregulate hepatic ALAS1 expression in vivo and to minimize its removal by CRRT, we employed a high-volume effluent CRRT protocol involving 12-hours of hemodiafiltration, followed by an intravenous dose of heme-arginate. We observed that PBG effluent measurements were higher in the TPE circuit compared to CRRT, suggesting that the former is more effective in clearing excess plasma porphyrins. We postulate that this variation is due to porphyrin protein binding and the different sieving coefficients of extracorporeal membranes utilized [18].

Our case report also highlights novel technical issues in a VP patient with multiorgan failure requiring extracorporeal filtration. We observed the loss of multiple circuits due to inappropriate activation of the blood leak detector circuit clamp. Other authors have reported similar observations arising from high-dose hydroxocobalamin infusions used in cyanide toxicity [20,21]; hydroxocobalamin induces a red-orange discoloration of the effluent fluid, which has a spectral wavelength similar to that of blood, and inappropriately halted hemodialysis in these patients. We suspect that the filtered porphyrins in the effluent of our patient (Figure 1B) induced a similar effect, inadvertently activating the circuit clamp. We developed a bypassing solution utilizing two 3-mL syringes filled with 0.9% normal saline (Figure 2), enabling TPE and CRRT to proceed unhindered. Therefore, in patients with undifferentiated anuric renal failure and other multiorgan sequelae, repeated cross-clamping circuit failures during extracorporeal filtration should prompt consideration of acute porphyria as part of the differential diagnosis.

Neurovisceral sequelae arising from acute porphyric crises are frequently severe and show limited resolution with intravenous heme replacement [8]. The pathophysiology unpinning the heterogenous neurological manifestations of VP and other acute porphyrias are poorly understood, although several theories have been proposed. Approximately 1–10% of plasma ALA levels cross the blood–brain barrier and exert direct neurotoxic effects [4,5,22]; ALA recruits free oxygen radicals, which results in direct mitochondrial damage, loss of the action potential, and axonal degeneration. In rat models, ALA crosses the blood–brain barrier and exerts these degenerative effects by binding to GABA-receptors [23], mimicking the neuropsychiatric manifestations seen in neurovisceral porphyrias. However, few CSF porphyrin assessments have been obtained from acute porphyria patients with neuroencephalopathies. One study has shown that these levels are negligible in comparison to the serum and have normal CSF appearances, suggesting that ALA accumulation within the nervous system does not play an important role [24]. This was not observed in our patient, with xanthochromic CSF appearances (Figure 1A) mimicking that of the CRRT effluent (Figure 1B); this is strongly suggestive of the presence of CSF porphyrins, although this was not formally tested in our patient. Further, our patient’s CSF bilirubin and oxyhemoglobin were markedly elevated, suggesting there was significant disruption of the blood–brain barrier, which could have contributed to her neurological decline.

Central nervous system (CNS) heme deficiency is an alternative theory explaining porphyric neuropathies [4,5]. This impairs the production of mitochondrial cytochromes, tryptophan dioxygenase, and nitric oxide synthase, all of which are central to normal neuronal and autonomic functions [4,5]. CNS cells express ALAS1 [25]. Failure of intravenous heme to cross the blood–brain barrier may explain the lack of efficacy in porphyric neuroencephalopathies, as unopposed ALAS1 expression can drive central porphyrin accumulation [4,26]. The xanthochromic appearances of our patient’s CSF, in addition to her failed neurological recovery despite prolonged intravenous heme-arginate therapy, lends further support to this theory. It stands to reason then that the intrathecal delivery of heme may have beneficial CNS effects by targeted suppression of ALAS1, although such drug formulations are not available and need further research. Serial CSF porphyrin assessments in porphyria patients who fail to improve neurologically with treatment may also be of prognostic value, but should be confirmed with future prospective studies.

Conclusions

Progressive neurological sequelae and multiorgan failure that arise in the absence of a clear etiology should prompt the early consideration of an underlying acute porphyric crisis as a diagnosis of exclusion. In patients with anuric renal failure requiring renal replacement therapy, effluent porphyrin assays can serve as an adjunctive diagnostic tool to confirm the presence of an acute porphyric attack. Effluent porphyrin byproducts can also interfere with extracorporeal circuits, which can provide further diagnostic clues of an acute porphyria in un-differentiated clinical presentations. TPE and hemodialysis appear to effectively remove plasma porphyrins, solidifying their value as adjunctive treatments alongside intravenous hemearginate replacement in acute porphyric crises.