A wild case of abdominal pain

The Case

You are called to see a 17-year-old Hispanic girl in the pediatric emergency department (ED) complaining of abdominal pain for 1 week. She describes a “stabbing” pain in the epigastrium and flanks that radiates to the lower back. She says that the pain comes intermittently in attacks that occur throughout the day and may last up to several hours. She feels pain most of the day, but it is worse at night and frequently causes her to awaken from sleep.

She has not been able to attend school because of the discomfort. There is no association with eating, position, or movement. She had a few episodes of nonbloody, nonbilious vomiting on the first day of the pain, but has not vomited since. She denies having had a bowel movement in the past week, although usually she is quite regular. She has a mildly decreased appetite and also complains of feeling tired.

Her father agrees that she seems particularly fatigued, especially emotional, and at times disoriented. The pain began a day before the beginning of her menses, which occur at regular intervals. Her menses completed the day before she came here; she describes it as of normal duration and flow. On further history, the patient admits to 2 similar episodes of abdominal pain within the past 5 months, both of which began at the start of her menses and self-resolved several days later.

Review of systems is negative for fever, upper respiratory infection, unusual ingestions, or trauma. It is also negative for dysuria, hematuria, and hematochezia but is significant for an unintentional 30-lb weight loss over the past 5 months, which the patient attributes to decreased appetite and abdominal pain. She has no history of gastrointestinal reflux, gall bladder disease, constipation, or abdominal surgery.

She had an uncomplicated elective abortion 4 years before this episode. She reports being sexually active with 1 male partner currently but with inconsistent condom use. She has had 3 lifetime sexual partners and denies a history of sexually transmitted infection. Menarche was at age 13, and her periods have been regular monthly. She denies a history of heavy menstrual flow, prolonged menses, or spotting. She admits to occasional alcohol and marijuana use. The patient has no ongoing medical problems and is on no other medications. She has never been hospitalized.

Physical exam

The physical examination is significant for a thin, anxious, adolescent girl in mild distress but oriented to person, place, and time. Her vital signs are notable for a blood pressure of 146/92 mm Hg and a heart rate of 122 beats per minute. The oropharynx and skin are clear. The heart rhythm is regular, with no murmurs. Radial and femoral pulses are 2+. Lungs are clear to auscultation bilaterally.

The abdominal exam reveals epigastric tenderness to palpation with mild guarding but no rebound tenderness or masses and normal bowel sounds. There is no right lower quadrant tenderness. There is no stool palpated in the rectal vault. The spleen and liver are not palpable. No costovertebral angle tenderness is appreciated. The genitourinary exam is normal, with no discharge or cervical motion tenderness. The remainder of the physical exam is normal.

Laboratory testing

Laboratory testing in the ED is significant for serum sodium of 128 mEq/L (normal, 135-145 mEq/L), with blood urea nitrogen of 42 mg/dL (normal, 7-23 mg/dL) and creatinine of 1.5 mg/dL (normal, 0.5-1.3 mg/dL). The remaining electrolytes are normal, and the complete blood count is normal, with a normal mean corpuscular volume.

Urinalysis shows moderate bilirubin, negative ketones, negative blood, and 10 mg/dL protein (normal, 0 mg/dL). It also reveals 32 white blood cells/high power field (hpf; normal, 0-5/hpf), with negative leukocyte esterase, negative nitrite, and no bacteria present. The urine specimen was sent for culture.

Pregnancy testing is negative. Amylase and lipase are elevated at 263 units/L (normal, 25-125 units/L) and 329 units/L (normal, 7-60 units/L), respectively. Total serum bilirubin is normal at 0.4 mg/dL (normal, 0.2-1.2 mg/dL). Aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase and gamma-glutamyl transferase, as well as serum calcium, are all within normal limits.

Because of the findings of hypertension and tachycardia, thyroid studies are sent in the ED, but these are unremarkable. Abdominal flat-plate x-ray is performed, which shows a normal bowel gas pattern with no evidence of obstruction. A moderate amount of stool is visualized in the colon. Ultrasound of the complete abdomen and pelvis is then ordered and reveals no specific pathology and a normal-appearing pancreas. The appendix is not visualized.

How do you connect all this?

You wonder how to approach this seemingly unrelated cluster of symptoms: abdominal pain, tachycardia, hypertension, and personality change with electrolyte abnormalities and evidence of pancreatitis. One method is to pursue individual signs and symptoms, with the hope that the investigation will eventually explain other clinical findings. Another approach is to consider a cluster of the most important signs and symptoms-in this case you determine abdominal pain, emotional changes, and electrolyte abnormalities to be most significant-and think of a single diagnosis that connects them all (Table 1).

Following this strategy, you consider what renal problems could also include these 3 findings. You know that renovascular hypertension can affect many different organ systems, including the central nervous system (CNS). Within the endocrine system, you remember that the hypercalcemia induced by hyperparathyroidism causes a variety of nonspecific symptoms such as fatigue, headache, anorexia, and abdominal pain and can also lead to psychiatric symptoms.

Further, pheochromocytoma is a well-known cause of hypertension and tachycardia and may cause abdominal pain as well as weight loss and anxiety. You attempt to recall any primary psychiatric disorders that could explain these findings. You know that depression and anxiety present in a variety of ways, although they would not explain the laboratory abnormalities without a comorbid ingestion or polydipsia.

Finally, you think about which ingestions could lead to this clinical picture. Lead poisoning may cause neuropsychiatric symptoms and abdominal pain as well as constipation. Further, the abdominal pain of chronic lead poisoning is known to manifest as intermittent, discrete episodes. Some features of the anticholinergic/sympathomimetic toxidrome fit here, specifically hypertension, tachycardia, and anxiety, but the patient lacks other clinical features of these toxidromes.

You admit the patient to the floor, and your team elects to work up each major sign and symptom separately, hoping for a clue that will help eventually tie them together.

A rocky hospital course

To control her blood pressure and heart rate, your patient receives standing labetalol and multiple doses of nifedipine as needed. To rule out pheochromocytoma, urine metanephrines are sent, which are normal. Other endocrine causes are screened for with serum cortisol and aldosterone levels and plasma renin activity, all of which are within normal limits. Renal ultrasound is interpreted as normal, and the cardiac echo shows no evidence of aortic coarctation. The left and right ventricles are normal in size and function.

Ingestions are ruled out when the serum and urine toxicology screens return negative. Lead poisoning is removed from the list of differentials because of the absence of punctuate basophilia in the peripheral blood smear and a normal serum lead level.

Your patient’s serum amylase and lipase are elevated on multiple measurements, so she is given a pancreatic fat-free diet, and the values trend downward. Abdominal magnetic resonance imaging (MRI) reveals a normal-appearing pancreas. Sweat chloride testing for cystic fibrosis, a lipid panel, and a workup for hereditary causes of pancreatitis are negative. Because of persistently poor appetite, she later receives a peripherally inserted central catheter for parenteral nutrition support.

The patient’s electrolyte levels remain abnormal, with persistent hyponatremia, hypokalemia, and hypomagnesemia. She requires aggressive repletion followed by daily supplementation to maintain these electrolytes within normal range and is eventually started on fludrocortisone.

Other causes of hyponatremia are pursued in the investigation. In the workup for a syndrome of inappropriate antidiuretic hormone secretion, random serum and urine osmolality are measured and come back at 270 mOsm/L (normal, 275-295 mOsm/L) and 517 mOsm/L, respectively. Your patient’s polyuria and elevated urine sodium in the face of persistent serum hyponatremia suggest a salt-wasting process. The nephrology team is consulted to help determine the possibility of cerebral salt wasting (CSW) or sodium-losing nephropathy. Because of the association of CSW with subarachnoid hemorrhage and other CNS lesions, nephrology recommends a brain MRI, which is interpreted by the radiologist as normal.

During her hospitalization, your patient is showing persistently high levels of anxiety and emotional lability. Multiple doses of intravenous and oral lorazepam are required to induce sleep. Also, at one point she manifests 3/5 weakness in all 4 extremities and an elevated blood creatine kinase (CK) level of 1,775 U/L (normal, 25-170 U/L). Neurology is consulted but does not suggest any specific neurologic diagnosis as a cause for these symptoms. The elevated CK eventually resolves. The psychiatry team is also consulted, and they suggest that there might be an anxiety disorder.

Your patient’s hospital course is also complicated by intermittent low-grade fever; blood, urine, and stool cultures; and a respiratory viral polymerase chain reaction screening test. Are all negative.

Finally, a diagnosis

After several days of investigating various symptoms and modifying your differential diagnosis, a fortuitous clue emerges. A nurse observes that the patient’s urine is a dark “cola” color (Table 2), prompting the team to send a spot sample for porphyrin testing. The results return several days later and show elevated urine porphyrins of 5,776 µg/mL (reference, 12-190 µg/mL) and a specific elevation of porphobilinogen (PBG), reflecting an early block in porphyrin synthesis consistent with acute intermittent porphyria (AIP).

The porphyrias

The porphyrias are a group of metabolic disorders caused by genetic or acquired deficiencies in the enzymes of the heme biosynthetic pathway. Heme is produced by the binding of iron to a porphyrin ring. It is incorporated into proteins such as hemoglobin, myoglobin, and cytochromes, including p450 and elements of the electron transport chain. The porphyrias are classified as acute (hepatic) or cutaneous (erythropoietic), based on the site of the accumulation of the porphyrins. The acute porphyrias cause neurovisceral crises, which classically present with abdominal pain and psychiatric symptoms. The cutaneous porphyrias cause blistering skin lesions because of photosensitization by porphyrins. There are 7 types of porphyrias in humans: 5 hepatic and 2 erythropoietic. The most common porphyria worldwide is porphyria cutanea tarda.

Acute intermittent porphyria

Acute intermittent porphyria, an autosomal dominant disorder of heme production, has a worldwide prevalence of ~5/100,000 and is caused by a defect in the production or function of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthetic pathway.

At least 301 different PBGD mutations have been identified in AIP.¹ Because of variable penetrance, most patients who inherit the enzyme deficiency will have no clinical symptoms throughout their entire lifetime. Most symptomatic patients have only 1 severe attack; however, regular premenstrual attacks may occur in young women.² The clinical phenotype of AIP has a female predominance and typically presents after puberty.

Precipitating factors responsible for attacks in AIP are those events that cause an upregulation of delta-aminolevulinate synthase-1 (ALAS1), the rate-limiting enzyme of heme synthesis in the liver. The triggers for upregulation include stress, such as infection and fasting; hormonal changes such as pregnancy and menstruation; and drugs that increase hepatic cytochrome p450. With the upregulation of ALAS1 and the limiting levels of PGBD, an increase in precursors aminolevulinic acid (ALA) and PBG occurs, which precipitate the attack. Autonomic and peripheral neuropathy is the result of direct cytotoxic damage of ALA and PBG accumulation in tissues and a failure of cellular respiration because of impaired synthesis of the heme proteins it depends on.³

The initial sign of an acute attack is abdominal pain, which often radiates to back, thigh, or buttock. Nausea, vomiting, and constipation are common. Central nervous system symptoms may include confusion, neuropathy, and seizures. Psychiatric symptoms include anxiety, depression, phobias, and psychosis. Moderate tachycardia and hypertension are common, attributed to sympathetic overactivity. The electrolyte abnormalities of AIP-most characteristically hyponatremia-are caused by the neuropathy as well as the syndrome of inappropriate antidiuretic hormone secretion.⁴

Acute intermittent porphyria is diagnosed by the findings of elevated urinary PBG and ALA levels. Urine darkening, an effect of PGB polymerization to porphyrins and other pigments, may provide a diagnostic clue. A key to the diagnosis is to obtain urine during an attack, because the toxic metabolites are not measurable when ALAS1 is not upregulated. Because of the urgency in treating the illness, part of the urine sample should be sent for “stat” ALA and PBG determination while the rest of the urine is sent for slow pan porphyrin analysis. Other helpful tests include erythrocyte PBGD level and plasma PBG, which can be used to predict the severity of an attack.⁵

Treatment

The primary treatment for AIP is discontinuation of inciting drugs or other factors and correction of fluid and electrolyte abnormalities. Intravenous hemin (heme arginate) provides relief from symptoms in severe attacks. Hemin provides negative feedback to the hepatic ALAS1, the rate-limiting enzyme in heme production. The common adverse effects are infusion-site phlebitis, anaphylaxis, hemochromatosis, coagulopathy, and renal tubular acidosis.

Hemin therapy seems to be more effective the closer it is given to an attack. Its availability, however, is obstructed by lack of expertise, expense, and insurance approval and the fact that it is not on most hospital formularies. The treatment for mild attacks (mild pain, no paresis or hyponatremia) is oral or intravenous carbohydrate loading. Like hemin, this therapy also works by suppressing hepatic ALAS1 activity.

Supportive measures for patients in acute attacks of AIP may include opiates to alleviate pain as well as laxatives to avert constipation. Short-acting benzodiazepines may be given for anxiety or insomnia. Liver transplantation is considered in cases with severe recurrent attacks. Research is under way to investigate gene therapy as a potential cure.

The prognosis for AIP is good if the disease is recognized early. Unfortunately, most patients suffer misdiagnosis for years-often carrying inappropriate psychiatric labels-and there is also mortality associated with not considering the diagnosis in patients with an attack with life-threatening complications. Long-term complications include physical disability, chronic hypertension, renal failure, and hepatocellular carcinoma.

Back to your patient-relief, at last

By the time the diagnosis of AIP is made, your patient is already improving from supportive care and the decrease in her upregulation of ALAS1 as her hormone flux from menstruation abates. Therefore, the decision is made not to administer the costly and difficult-to-obtain hemin. She is thus administered a high glucose load through her parenteral line, which allows renal function to finally improve and stabilization of her organic mood disorder. Her serum electrolytes begin to normalize and her supplementation is weaned. After discontinuation of her parenteral feeds, she is transitioned to oral therapy and discharged home on oral glucose tablets (50 g each meal), sodium chloride tablets (5g q 2h), and labetalol, with follow-ups at her pediatrician, a regional porphyria center, and the hospital pediatric hematology/oncology outpatient clinic.

Follow-up

Because AIP has an autosomal dominant inheritance with variable penetrance, screening of all family members is recommended. Determining the specific mutation in the index case allows rapid and accurate testing of family members.⁶ Your patient is referred to a regional porphyria center for family genetic testing as well as extensive education on AIP. She is instructed to avoid all known triggers of attacks, including medications.

A discussion is initiated about starting her on a GnRH analog to reversibly suppress ovulation and thereby prevent luteal phase attacks. The patient is counseled about the mildly elevated risk of adverse events in pregnancy experienced by patients with porphyria.⁷ She is instructed before discharge to take her glucose tablets with each meal during the week before the onset of her menses. She is to be followed monthly by the hematology/oncology department at our hospital, where a supply of hemin is kept on hand for intravenous administration in the case of an acute pain attack.

Since her diagnosis, she has received hemin twice to abort attacks not controlled by oral glucose loading. Her renal function remains normal, and she is off all antihypertensive medications.

References

• Hrdinka M, Puy H, Martasek P. May 2006 update in porphobilinogen deaminase gene polymorphisms and mutations causing acute intermittent porphyria: comparison with the situation in Slavic population. Physiol Res. 2006;55(suppl 2):S119-S136.

• Anderson KE, Spitz IM, Bardin CW, Kappas A. A gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria. Arch Intern Med. 1990;150(7):1469-1474.

• Lin CS, Lee MJ, Park SB, Kiernan MC. Purple pigments: the pathophysiology of acute porphyric neuropathy. Clin Neurophysiol. 2011;122(12):2336-2344.

• Usalan C, Erdem Y, Altun B, et al. Severe hyponatremia due to SIADH provoked by acute intermittent porphyria. Clin Nephrol. 1996;45(6):418.

• Sardh E, Harper P, Andersson DE, Floderus Y. Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks. Eur J Intern Med. 2009;20(2):201-207.

• Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142(6):439-450. Erratum in: Ann Intern Med. 2005;143(4):316.

• Tollånes MC, Aarsand AK, Sandberg S. Excess risk of adverse pregnancy outcomes in women with porphyria: a population-based cohort study. J Inherit Metab Dis. 2011;34(1):217-223.