A Young Woman Presenting with Diffuse Abdominal Pain

A 41-year-old woman presents with diffuse abdominal pain, rated 10/10 in severity, described as “deep and cramping.” The pain began approximately 72 hours prior, with associated intermittent nausea. She had 1 episode of non-bloody, non-bilious vomiting 8 hours prior to arrival. She denies back pain, pelvic pain, or dysuria. There have been no recent changes in her bowel movements. She has had no associated sweats, chills, or fevers.

History

The patient was diagnosed 7 years ago with acute intermittent porphyria, with a course notable for many subsequent brief admissions to outside hospitals for exacerbations of abdominal pain, nausea, vomiting, and mental status alterations. Additionally, she has hypertension—which is suboptimally controlled due to poor compliance with her antihypertensive medication. She has a history of anxiety and depression and has been referred to psychiatry in the past, but has not followed up. 

Physical Examination

Physical examination reveals a normal temperature of 37°C and a blood pressure of 164/96 mm Hg. She is tachycardic to 110 beats per minute. Her head and neck examination is negative for any oral lesions; she has no thyromegaly and no palpable cervical nor supraclavicular adenopathy. Her cardiac exam is notable only for tachycardia. 

She has no abnormal findings on lung exam, and is mildly tachypneic at 18 breaths per min with no significant respiratory distress. Her abdominal exam reveals a diffusely nontender abdomen, with no rebound and no guarding. Bowel sounds are normal throughout. There is no bruising, no rashes, nor any other noted skin lesions.

Laboratory Tests

Complete blood count and metabolic panel are both within normal limits. Hepatic function tests are normal. A spot urine porphobilinogen (PBG) level is 0.3 (measured in mg/g creat, with ref range <2.0). A 24-hour urine delta-aminolevulinic acid (ALA) measurement is ordered and pending. Review of records from 7 years earlier reveals a porphobilinogen-deaminase (PBGD) level of 4.9 nmol/s/l (ref range 6.0-6.9 nmol/s/l).

Which of the following is the best next step in the management of this patient's condition?

A. Carbohydrate loading with 300 g daily, given as intravenous glucose.

B. Panhematin 4 mg/kg per day, given intravenously for 4 consecutive days.

C. Referral to hepatology for liver transplant evaluation.

D. Supportive treatment, with workup for other disorders—including a CT of the abdomen and pelvis with IV contrast.

(Answer and discussion on next page)

Correct Answer: D

This patient’s spot urine PBG level, which is well within the reference range, argues strongly against an attack of acute intermittent porphyria (AIP). AIP is a member of a family of inborn errors of heme synthesis, collectively known as the porphyrias. Each of these 8 diagnoses are characterized by a different enzymatic deficiency within the biosynthetic pathway. 

Classically divided into either hepatic or erythropoietic, based on the site of production and accumulation of the intermediary, these disorders may be further characterized into 3 groups¹: acute hepatic porphyrias, hepatic cutaneous porphyria (including only porphyria cutanea tarda), and erythropoietic cutaneous porphyrias.

Counted among the acute hepatic porphyrias, AIP is an autosomal dominant disorder resulting from an inherited deficiency of the catalyst PBGD. This results in interruption of heme biosynthesis at the third step in the pathway, wherein precursor porphobilinogen (PBG) molecules are unable to combine 4-fold for the formation of hydroxymethylbilane (HMB). This results in accumulation of PBG, as well as its immediate precursor ALA—often to levels giving rise to peripheral, autonomic, and CNS toxicities. 

Symptoms

Patients having an acute attack of AIP may present with a variety of neurological symptoms, predominantly due to autonomic neuropathy. The hallmark abdominal pain is thought to be secondary to splanchnic dysfunction, and vagal symptoms such as orthostatic hypotension and diarrhea have also been observed. Additionally, severe acute attacks are frequently associated with peripheral neuropathic symptoms such as sensory abnormalities, muscle weakness, and limb pain. Mild mental symptoms such as confusion are not infrequent, and seizures are also possible in extreme cases. 

The etiology of these symptoms in AIP is traced mainly to upregulation of ALAS1 by depletion of heme stores within the liver, with consequent overproduction of ALA—which has been demonstrated in vitro to have direct neurotoxicity.² 

Other potential contributors include the structural similarities between ALA and gamma-aminobutyric acid (parasympathetic effects), formation of free radicals by overproduced ALA, and deficiency of oxidative cytochromes (CYPs) within the liver due to a lack of the constituent heme molecule. Because there is no inflammatory component underlying acute attacks, described pain is usually out of proportion to that elicited on physical exam. 

Incidence and Precipitating Factors

Of the acute hepatic porphyrias, AIP is the most commonly diagnosed. The estimated prevalence of this autosomal dominant disorder is 5 per 100,000 people, occurring in all races but somewhat more common in northern Europe. There have been >200 different mutations identified within the PBGD gene³ in patients with AIP, all resulting in the characteristic partial deficiency of the enzyme. As many patients remain asymptomatic throughout life, the abovementioned prevalence is considered by many to be an underestimation of those harbouring the relevant PBGD mutations.

Due to partial (half normal) enzymatic levels, many patients remain free of acute episodes well into their second or third decades of life (time of symptomatic onset is often peri-pubertal⁴), although precipitating factors have been identified and make earlier acute episodes more likely to occur. These include medication exposures (most notably those inducing hepatic CYPs and ALAS1), such as anti-epileptics and rifampin, alcohol use, exposure to androgenic and high-progesterone states (eg, during the luteal phase of the menstrual cycle), and poor nutritional status. Cigarette smoking has also been implicated: A study of 356 Swedish patients demonstrated an association between tobacco use and repeated recurrent acute episodes of AIP.⁵ The common result of each of these precipitating factors is induction of ALAS1 or a member of the hepatic CY P450 gene family, thereby resulting in greater accumulation of the intermediate PBG (and its proximal precursor ALA). 

Diagnosis and Treatment

Patients in whom AIP is suspected should undergo appropriate workup for other likely etiologies for their symptoms; symptoms such as poorly-localized abdominal pain, motor weakness, paresthesias, and altered mental status have other potential causes which are of greater incidence than acute porphyria. 

If AIP is suspected, spot urine analysis for PBG is an excellent initial test given the marked elevation of urine PBG during acute attacks (often to levels as high as 50 mg/d to 200 mg/d).⁶ If the spot urine test for PBG is negative but clinical suspicion for AIP remains high, 24-hour urine collection for quantitative measurement of PBG, ALA, and total porphyrins may be more revealing. 

Studies of urinary levels of both PGB and ALA have been shown to remain elevated for years after an acute attack, with half-lives of 10.6 and 7.7 years for PBG and ALA, respectively.⁷ In this same study, urinary measurements within 7 days of the acute attack revealed a median PBG-to-creatinine ratio (mmol/µmol) of 57.1 (minimum of 19.6) and a median ALA-to-creatinine ratio (mmol/µmol) of 28.7 (minimum 11.0). To confirm underlying AIP following an acute attack, or to help distinguish AIP from the other acute hepatic porphyrias, more definitive testing involves measurement of HMB-synthase activity or analysis for mutations within the PBGD gene. 

Treatment of an AIP exacerbation typically begins with supportive measures, such as narcotic analgesics for severe abdominal pain, IV fluid and electrolyte repletion, and phenothiazines for symptoms of nausea and vomiting. Carbohydrate loading (typically 300 g/d to 400 g/d, given intravenously) is thought to be helpful especially in patients for whom poor nutritional status is identified as a potential precipitating factor. 

Additionally, carbohydrates may have some repressive effect on the activity of ALA synthase and have been shown to reduce urinary excretion of porphyrin precursors. Hemin is an iron-containing porphyrin, which is typically administered at an intravenous dose of 1 mg/kg to 4 mg/kg daily for 4 consecutive days, thought to exert its effect by negative feedback inhibition of ALA synthase. Importantly, a symptomatic profile resembling that of AIP in the absence of elevated urinary ALA or PBG secretion is not an indication for initiation of these directed therapies. 

Clinical Picture

The patient in this case did present with symptoms concerning for an attack of AIP, such as poorly-localized abdominal pain, nausea, and vomiting. However these symptoms are very nonspecific, emphasizing the importance of obtaining a spot urine PBG level and/or urine ALA levels. As these are markedly elevated in nearly all cases of true AIP exacerbation, and as the symptoms of AIP are thought to result from direct neurotoxicity of ALA and PBG, a normal or undetectable PBG level effectively rules out an attack and should prompt evaluation for other causes of the patient’s pain. 

Additional helpful testing includes 24-hour urine ALA test, which in this patient was later found to be within normal limits (5.5 mg/24, ref range <6.4). Her PBGD level, which is below the reference range per prior testing yet well above the approximate 50% activity level expected with heterozygosity, is likely due to variation which has been previously demonstrated among normal individuals.⁸ 

A 2002 Finnish study of 192 patients with AIP and their 293 healthy relatives used mutational analysis in combination with biochemical testing to evaluate the accuracy of common measures including PBGD activity; 23% of healthy relatives in whom AIP had been excluded were shown to have PBGD levels below the reference range (false positives).⁸ Additionally, activity can be altered by induction or inhibition of erythropoiesis, and by comorbid processes including anemias, liver disease, malignancy, uremia, and chronic polyarthritis. 

Other possible etiologies for poorly-localized, crampy abdominal pain which is out of proportion to that elicited on exam include mesenteric ischemia, especially given her history of poorly-controlled hypertension. The recognition of laboratory findings effectively excluding an attack of AIP allows for full attention to continued workup for other pathology.

Outcome of the Case

The patient was treated with narcotic analgesics, with resolution of her abdominal pain within 1 to 2 days. Further workup including a CT of the abdomen and pelvis revealed no acute intraabdominal or pelvic pathology. Her urine culture did not identify any bacterial pathogens. Her 24-hour urinary ALA level was found to be nonelevated. She was discharged on day 3, with follow-up appointments in place for her primary care provider and psychiatry for her history of anxiety and depression.

Take-Home Message

Drug-induced prolongation of acute intermittent porphyria (AIP) is an autosomal dominant disorder defined by deficiency of the enzyme hydroxymethylbilane-synthase. As symptoms of AIP are thought to result from direct neurotoxicity of accumulated aminolevulinic acid (ALA) and PBG, treatment of symptoms is best guided by measurement of the levels of these porphyrin precursors within the urine. 

A spot urine PBG is an excellent screening test as the level of this intermediate is markedly elevated during acute attacks, and can be followed by 24-hour testing for ALA and total porphyrins. Negative testing effectively makes an attack of AIP highly unlikely as the etiology of the presenting symptoms and, given the demonstrated long half-lives of both ALA and PBG, is also helpful for the retrospective interpretation of symptoms reported months or even years prior. 

Treatment with carbohydrate loading and hemin should be reserved for symptom constellations consistent with an attack of AIP, complete with concurrent elevation of measured intermediates within the heme biosynthetic pathway.

Philip Pancari, MD, is a fellow in hematology/oncology at Temple University Hospital and Fox-Chase Cancer Center in Philadelphia, PA.

Ronald Rubin, MD, is a professor of medicine at Temple University School of Medicine and chief of clinical hematology in the department of medicine at Temple University Hospital, both in Philadelphia, PA.

References:

1. Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012; 120(23):19-27.

2.  Pischik E. Neurological manifestations of acute intermittent porphyria. Cell Mol Biol. 2009;55(1):72-83.

3.  Anderson KE. Approaches to treatments and prevention of human porphyrias. In: Kadish KM, Smith KM, Guilard R, eds. The Porphyrin Handbook. Vol 14. San Diego, CA: Academic Press; 2003:247-275.

4.  Schuurmans MM, Schneider-Yin X, Rüfenacht UB, et al. Influence of age and gender on the clinical expression of acute intermittent porphyria based on molecular study of porphobilinogen deaminase gene among Swiss patients. Mol Med. 2001;7(8):535-542. 

5.  Bylesjö I, Wikberg A, Andersson C. Clinical aspects of acute intermittent porphyria in northern Sweden: a population-based study. Scand J Clin Lab Invest. 2009;69(5):612-618.

6. Trier H, Krishnasamy VP, Kasi PM. Clinical manifestations and diagnostic challenges in acute porphyrias. Case Rep Hematol. 2013;628602.

7.  Marsden JT. Urinary excretion of porphyrins, porphobilinogen, and delta-aminolaevulinic acid following an attack of acute intermittent porphyria. J Clin Pathol. 2014;67:60-65. 

8.  Raili K. Molecular and biochemical studies of acute intermittent porphyria in 196 patients and their families. Clin Chem. 2002; 48(11):1891-1900.