Off Target But Hitting the Mark

Additional laboratory studies were sent. Serum osmolality was 269 mosm/kg with a corresponding urine osmolality of 699 mosm/kg. A random urine sodium was 145 mEq/L. Thyroid stimulating hormone and cosyntropin stimulating testing were normal. IgM and IgG antibodies to Borrelia burgdorferi were negative. Urine porphobilinogen was sent. An electroencephalogram did not reveal epileptiform discharges. Magnetic resonance imaging (MRI) of the brain was significant for T2/FLAIR hyperintensity in the cortex and subcortical white matter of the occipital lobes bilaterally. Hypertonic saline and fluid restriction were initiated.

The patient’s labs are consistent with SIADH. Excessive ADH release because of volume depletion and consequent hyponatremia should have improved rapidly with the administration of saline. The high urine sodium suggests that she is now volume replete, while the high urine osmolality is consistent with the presence of excessive ADH in the absence of appropriate stimuli. In the context of normal thyroid and adrenal function, the hyponatremia is likely due to the SIADH.

Negative serologic testing for Lyme disease, 3 months after the onset of rash, excludes this diagnosis.

The MRI findings are consistent with posterior reversible encephalopathy syndrome (PRES), a clinicoradiographic syndrome of headache, altered mental status, seizure, and/or vision loss with associated white matter abnormalities of the posterior cerebral hemispheres. PRES has been reported with AIP as well as other disorders, most commonly hypertensive encephalopathy, eclampsia, and immunosuppressive drug use.

The patient’s sodium improved with fluid restriction and the administration of hypertonic saline. There was no recurrence of seizure activity. Amlodipine was initiated for blood pressure readings as high as 156/106 mmHg. A hepatobiliary scan revealed a gallbladder ejection fraction of 13%. Biopsies from her endoscopy revealed nonspecific inflammation without the presence of Helicobacter pylori. The patient was discharged home 7 days after admission after stabilization of serum sodium, improvement in her abdominal pain, and tolerance of oral intake. A plan was made for outpatient cholecystectomy.

Many causes of abdominal pain have been excluded and the remaining diagnostic possibility, porphyria, is rare. The clinicians have revisited their differential and considered other causes of abdominal pain, including functional gallbladder disorders. However, chronic cholecystitis (or functional gallbladder disorder) is not this patient’s primary problem. The diffuse, severe, and constant abdominal pain prior to admission is not typical of biliary pain, and many medical conditions and drugs, including amlodipine, can lead to a positive hepatobiliary scan. Chronic cholecystitis would not explain her seizure.

AIP remains at the top of the differential for this young woman. A urine porphobilinogen has been sent and must be followed up prior to any further workup or surgery.

One week after discharge, the patient’s urine porphobilinogen resulted at 172.8 mCmol/ (upper limits of normal 8.8). Sequencing analysis for genes coding the enzymes involved in the synthetic pathway for heme were sent. Hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase mutation assays were all normal. Despite the normal genetic assays, the diagnosis of AIP was made on the basis of the clinical presentation and elevated urine porphobilinogen. The patient was referred to a hematologist and initiated on oral glucose supplements and hematin infusions.

Although abdominal pain has a broad differential, the combination of abdominal pain and neurologic or psychiatric symptoms should suggest the possibility of porphyria, especially if symptoms are recurrent or unexplained. The porphyrias are a group of disorders caused by defects in the synthetic pathway of heme, leading to an overproduction and accumulation of precursors. Heme is a component of multiple proteins, including hemoglobin, myoglobin, and the cytochrome P450 enzymes. Although it is synthesized in all tissues, the bone marrow and liver are the organs most actively involved. The porphyrias can be classified according to the primary site of the overproduction and accumulation of heme precursors (liver vs bone marrow). Although there is overlap between the 2 groups, hepatic porphyrias often present with acute neurovisceral symptoms, while the erythropoietic porphyrias often cause cutaneous photosensitivity.¹

AIP is the most common hepatic porphyria with a prevalence of 1 in 20,000 in Caucasians of Western European descent.¹ AIP is caused by a defect in the gene that encodes porphobilinogen deaminase, leading to the accumulation of porphobilinogen.¹ The cardinal manifestation is an acute porphyric attack. While the precise mechanisms underlying the symptoms are unknown, the accumulating metabolites may be directly neurotoxic.² Attacks are precipitated by factors that induce heme synthesis, including caloric restriction, alcohol, and certain medications, particularly those that upregulate cyP450. The most commonly implicated drugs are anesthetics, antiepileptics, sulfonamides, rifampin, and estrogen and progesterone. Attacks can also be precipitated by changes in endogenous sex hormone levels, like the increase in progesterone seen in the luteal phase of the menstrual cycle, which may account for the higher incidence of symptomatic attacks in women.³

Acute attacks of AIP may have a wide variety of presentations; the disease was referred to as the “little imitator” in the early 20th century.⁴ The most common symptom is acute, severe abdominal pain, which may mimic an acute abdomen. Because the pain is neuropathic rather than inflammatory, abdominal tenderness, rebound, fever, and leukocytosis are usually absent, as they were in this patient. Abdominal pain is often accompanied by neuropsychiatric symptoms, including sensory and motor neuropathy, anxiety, hallucinations, delirium, and altered level of consciousness. Seizure occurs in 20% of cases. Involvement of the autonomic nervous system causes tachycardia and new onset hypertension in the majority of patients as well as restlessness and tremor. Hyponatremia, mediated by the syndrome of inappropriate ADH secretion, occurs in nearly a third of patients.^5,6 MRI findings consistent with PRES have also been described in AIP.⁷

The diagnosis of AIP is often delayed; diagnosis later in the disease course is associated with a poorer prognosis.⁸ Reported intervals between presentation and diagnosis range from several months to as long as 20 years.⁹ Associating the use of medications, caloric restriction, or the menstrual cycle with the exacerbation of symptoms or darkening of urine can help prompt an earlier diagnosis.⁶

AIP can be diagnosed by detecting a greater than 5-fold elevation of urinary porphobilinogen excretion in conjunction with the typical symptoms of an acute attack.⁵ Renal dysfunction causes urinary excretion of PBG to fall and serum levels to rise.¹⁰ Serum PBG levels should therefore be sent when AIP is suspected in the setting of renal dysfunction. The primary role of genetic testing in a patient who has AIP confirmed clinically and biochemically is to assist in genetic counseling and to identify asymptomatic family members.¹¹ Genetic testing is not required to confirm the diagnosis and does not help prognosticate. It is unusual that a mutation was not detected in this case, as the current sensitivity of genetic testing is 97% to 100%.¹¹

There are 4 principles of management of an acute porphyric attack. First, any precipitating factors such as medications should be stopped. Second, abdominal pain should be treated appropriately with opioids, if necessary. Third, if autonomic dysfunction is present, beta-blockers or clonidine should be given to treat hypertension.⁵ Finally, glucose and/or hemin should be administered to downregulate aminolevulinic acid (ALA) synthase by negative feedback. Downregulation of ALA synthase decreases the accumulation of the neurotoxic porphyrin precursors ALA and PBG.5 For patients with mild symptoms, glucose alone (300-500 g/d) may be enough to abort the attack.¹² This can be achieved via a high-carbohydrate diet in those able to tolerate oral intake or via continuous infusions of dextrose containing fluids.⁵ For more severe attacks with associated polyneuropathy, respiratory muscle weakness, or seizures, or for attacks that are not resolving, heme preparations dosed at 3 to 4 mg/kg/d for 3 to 4 days are indicated.⁵

The recent diagnosis of acute Lyme disease was a distractor in this presentation. In Lyme endemic areas, patients with erythema migrans are treated based on the clinical presentation rather than serologic testing.¹³ Although this patient took only 1 week of doxycycline, testing during this hospitalization showed that she had either been cured early or had not had Lyme disease in the first place. There is no known association between Lyme disease and the porphyrias, and doxycycline is not a common precipitant of AIP attacks.¹⁴ However, the GI side effects of doxycycline may have decreased caloric intake and ultimately provoked the patient’s first attack of AIP. The clinicians in this case appropriately avoided the “target” but hit the mark by correctly diagnosing AIP.