Clinical Chemistry 63:12 1806–1811 (2017)
Clinical Case Study
Unusual Cause of Abdominal Pain and Anemia Cilie C. van ‘t Klooster,1* Jan J. Uil,1 Joep van der Leeuw,1 Elaine F. Eppens,1 and Susanne C. Marczinski1
CASE DESCRIPTION A 46-year-old man, originally from Iran, with no relevant medical history, was admitted with intermittent acute colic pain in the lower abdomen with nausea and vomiting over the past few weeks. On physical examination, the patient had lower abdominal pain without guarding. Laboratory findings showed a microcytic anemia, a heterozygote -thalassemia, mild leukocytosis, and slight liver enzyme activity increases (Table 1, case 1). Hepatitis, cytomegalovirus, and Epstein–Barr virus were negative. Ultrasonography and computed tomography scan of the abdomen did not suggest liver, kidney, or pancreas disease, and gastroscopy and colonoscopy revealed no pathology. The patient denied substance abuse. The symptoms improved spontaneously and the patient awaited further diagnostics in the outpatient clinic. Within 1 week, the patient returned with similar symptoms. Acute intermittent porphyria (AIP)2 was suspected and urine porphyrins were measured. Urine ␦-aminolevulinic acid (ALA) concentration was increased at 96.9 mmol/mol of creatinine (reference interval ⬍3.9 mmol/mol creatinine), porphobilinogen (PBG) concentration was normal at 8 mol/L (reference interval 0 –9 mol/L), and coproporphyrinogen III concentration was increased at 91.8 nmol/mmol of creatinine (reference interval 2.9 –19.3 nmol/mmol of creatinine). These findings excluded the diagnosis AIP, as the PBG concentrations remained normal and both ALA concentration and coproporphyrinogen III concentrations increased. Another 42-year-old man, originally from Iran and with no relevant medical history, presented with similar complaints of acute diffuse colic abdominal pain with nausea and vomiting. He complained of diffuse abdominal pain without guarding. Laboratory findings showed microcytic anemia, without signs of iron deficiency or thalassemia; basophilic stippling of red blood cells; mild leukocytosis; and increased liver enzyme activities (Table 1, case 2). Viral serology was negative. The patient denied
1
Ziekenhuis Gelderse Vallei, Ede, the Netherlands. * Address correspondence to this author at: UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. Fax 887-555-639; e-mail
[email protected]. Received October 17, 2016; accepted January 24, 2017. DOI: 10.1373/clinchem.2016.267823 © 2017 American Association for Clinical Chemistry 2 Nonstandard abbreviations: AIP, acute intermittent porphyria; ALA, aminolevulinic acid (ALA); PBG, porphobilinogen; ALAD, ALA dehydratase.
1806
QUESTIONS TO CONSIDER 1. What are the main causes of microcytic anemia? 2. What are the diagnostic tests for acute intermittent porphyria? 3. Which secondary porphyria can mimic acute porphyria?
substance abuse. Considering a gastric ulcer, a gastroscopy was performed that showed no abnormalities. Doppler ultrasonography of the abdomen was negative for liver, kidney, or pancreas disease, or mesenteric ischemia. On the basis of the symptoms, porphyrin analysis was performed, with the following results: ALA concentration was increased at 79.6 mmol/mol of creatinine and the free erythrocyte protoporphyrin concentration was also increased at 126.3 g/dL (reference interval 0 – 65 g/dL). The patient’s gums revealed Burton’s lines. Unknown to the medical team at the time, the 2 patients were friends. Soon after, a third patient, sibling of the aforementioned second case, presented with similar complaints, and the laboratory tests revealed similar results (Table 1, case 3). DISCUSSION Microcytic anemia is most commonly caused by thalassemia, anemia of chronic disease, iron deficiency, lead poisoning, or congenital sideroblastic anemia (acronym, TAILS). Microcytic anemia can also be caused by vitamin B6 (pyridoxine) deficiency. AIP, a rare metabolic disorder characterized by a deficiency in the enzyme PBG deaminase, is not normally associated with microcytic anemia but it was considered in these patients because of the complaint of acute abdominal pain. AIP is associated with increased urine PBG and ALA concentrations. Lead poisoning and hereditary tyrosinemia type I can mimic AIP. CASE FOLLOW-UP The second patient, during hospital stay, demanded prescription of opioids for pain management; finally, he admitted to having an opium addiction. Soon it was revealed that the patients were friends (they accompanied
Clinical Case Study
Table 1. Biochemical and hematological findings in the described cases. Reference interval
Hemoglobin (g/dl)
Men 14.0–17.5
Case 1
Case 2
10.3
8.4
Case 3
9.5
Women 12.3–15.3 Mean corpuscular volume (fL)
80–100
White blood cell count (/nL)
4.0–11.0
Red blood cell Gamma glutamyl transpeptidase (IU/L)
60 —
78
78
11.3
12.5
5.0
Basophilic stippling
Basophilic stippling
Basophilic stippling
0–55
57
354
Alkaline phosphatase (IU/L)
0–120
121
197
91
Alanine aminotransferase (IU/L)
0–45
71
91
27
each other to the outpatient clinic) and had been ingesting opium orally from the same Iranian supplier. A previous case series has reported oral opium as a cause of lead poisoning and described patients who presented with similar clinical and biochemical symptoms (1 ). Hence, the possibility of lead poisoning was investigated in our patients, revealing the following lead concentrations: case 1: 124.2 g/dL (reference interval ⬍10 g/dL); case 2: 223.6 g/dL; and case 3: 190.5 g/dL. A sample of the opium they were ingesting was requested for analysis. Lead was detected in the sample (225 g/g), thus confirming the diagnosis of lead poisoning. Lead poisoning is preventable, and it is caused primarily by either inhalation or ingestion. The incidence of occupational lead poisoning has declined worldwide because of improved industrial safety measures and the limited use of lead in various applications, such as paint, water pipes, and canned goods (2 ). However, the number of nonoccupational lead intoxications is increasing among illicit abusers of drugs (1 ) such as opium, marijuana, and methamphetamine (3, 4 ). Lead is either introduced in opium during the processing technique or is deliberately added to increase the weight in order to fetch a higher price (5 ). The 3 patients self-reported daily opium intake of 10 g for several years exceeded the WHO-recommended daily lead intake limit of 3.6 g/kg body weight by almost 10 times. In 2010, WHO withdrew this set limitation because the lead dose is not directly related to the key adverse effects and did not establish new recommendation (6 ). In 2015, because blood lead concentrations ⬍10 g/dL can adversely affect health, the cutoff level for normal blood lead concentration was reduced from 10 to 5 g/dL (Adult Blood Lead Epidemiology and Surveillance Program). After gastrointestinal absorption, about 5% lead is distributed to blood and soft tissues and ⬎90% to the skeleton. Lead elimination is considerably quicker via the kidneys, with a mean half-life of 30 days compared with that of decades in the bones (7 ). Lead is a
49
toxic metal that influences several body processes. Symptoms are usually nonspecific, including colic abdominal pain and joint and muscular pain; peripheral neuropathy, concentration problems, convulsions, and even coma; and microcytic anemia and abnormal kidney and liver function tests (1, 2, 8, 9 ). Burton’s lines and basophilic stippling on a blood smear are some of the more specific symptoms (2 ). Anemia is caused both by the interference of lead with heme biosynthesis and the shortening of red blood cell survival. Because of these physiological interferences, basophilic stippling appears on blood smear (2 ). Lead causes a disruption in heme synthesis by the inhibition of ALA dehydratase (ALAD), coproporphyrin oxidase, and ferrochelatase. Ferrochelatase catalyzes the incorporation of iron into protoporphyrin to form heme. Therefore, in lead poisoning, protoporphyrin accumulates in red blood cells, as reflected by an increased free erythrocyte protoporphyrin concentration (10 ). However, effects of lead on ALAD are most profound. Because of ALAD inhibition, lead poisoning bears biochemical and clinical resemblance to ALAD porphyria, a rare form of porphyria, as well as tyrosinemia type I, another secondary cause of porphyria (Table 2) (10 ). In lead poisoning, ALA and coproporphyrin III are increased, and PBG concentrations are normal. Similarly, in ALAD porphyria and hereditary tyrosinemia type I, urine ALA concentrations are increased and PBG concentrations are normal. In contrast, in AIP, variegate porphyria, and hereditary coproporphyria, urine PBG concentrations are increased as are urine ALA concentrations (Table 2). Clinically, patients with lead poisoning present with colicky abdominal pain, partly because of the ALA accumulation as seen in acute porphyria. However, the exact pathophysiological mechanism of “lead colic” is unclear. Burton’s lines on patients’ gums are caused by deposition of lead sulfide because of a reaction between lead and sulfur ions produced by the oral bacteria (11 ). Neurological symptoms arise because of lead-induced alteration in the permeability of Clinical Chemistry 63:12 (2017) 1807
1808
Clinical Chemistry 63:12 (2017)
Secondary porphyrias [hematologic or metabolic disorders, hepatobiliary diseases, toxins (e.g., alcohol, benzene, lead)]
Cutaneous porphyrias
Acute porphyrias
ALA
Not increased
Erythropoietic protoporphyria
Hereditary tyrosinemia type I
Not increased
X-linked dominant protoporphyria
ALA
Not increased
Hepatoerythropoietic porphyria
Lead
Not increased
PBG>ALA
Variegate porphyria
Congenital erytropoietc porphyria
PBG>ALA
Hereditary coproporphyria
Not increased
PBG>ALA
Acute intermittent porphyria
Porphyria cutanea tarda
ALA
ALA dehydratase porphyria
ALA, PBG
porphyrins
Copro III
Copro III
Not increased
Not increased
Uroporphyrinogen III, heptacarboxylate
Uroporphyrinogen I>coproporphyrinogen I
Uroporphyrinogen>heptacarboxylate
Coproporphyrinogen III
Coproporphyrinogen III
Uroporphyrinogen I
Coproporphyrinogen III
Urine
—
—
Protoporphyrin
Protoporphyrin
Isocoproporphyrinoge, heptacarboxylate
Coproporphyrinogen I
Isocoproporphyrinoge, heptacarboxylate
Red blood cells
Protoporphyrin
Protoporphyrin
Protoporphyrin
Protoporphyrin
Protoporphyrin
Copro coproporphyrinogen I, uro coproporphyrinogen I
Not increased
Not increased
Not increased
Not increased
Protoporphyrin
porphyrins
Protoporphyrin, coproporphyrinogen III
Coproporphyrinogen III
Not increased
Not increased
Stool
Table 2. Biochemical and hematologic abnormalities in acute, cutaneous, and secondary porphyrias (14,15). Major increases in urine, stool, plasma, and red blood cells are shown.
Clinical Case Study
Clinical Case Study POINTS TO REMEMBER • The 5 main causes of microcytic anemia are thalassemia, anemia of chronic disease, iron deficiency, lead poisoning, and congenital sideroblastic anemia (TAILS). • AIP is associated with increased urine PBG and ALA concentrations. • Lead poisoning and hereditary tyrosinemia type I can mimic acute intermittent porphyria. • Lead poisoning should be considered in cases of increased urinary ALA and normal PBG concentrations, microcytic anemia, and liver enzyme abnormalities. • Colicky abdominal pain and anemia are symptoms of lead intoxication. • The origin of lead intoxication can be chronic ingestion of lead-contaminated drugs, such as opium, marijuana, or methamphetamine.
ities were in the normal range, and the lead concentrations decreased slowly with time. Lead poisoning should be considered in the differential diagnosis of patients with opium addiction presenting with abdominal complaints and anemia. This is particularly relevant with regard to the high influx of refugees originating from countries with a higher prevalence of opium abuse. Furthermore, other drugs are potentially at risk of lead contamination as well, emphasizing the importance of considering lead intoxication in patients with symptoms of abdominal pain and anemia and any drug addiction.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
the blood– brain barrier and subsequent accumulation of lead in the astroglia (2, 8 ). Therapy includes discontinuation of lead exposure and chelation therapy. Chelation therapy is recommended when blood lead concentrations exceed 100 g/dL (12 ). Calcium disodium EDTA is a potential chelation agent. Lead is bound by EDTA, which forms a water-soluble complex that is subsequently excreted by the kidneys. Treatment is given for not ⬎5 days because of the risk of nephrotoxicity and requires intravenous administration, as gastrointestinal uptake is insufficient (2 ). Additional therapy with ascorbic acid can be initiated to increase renal excretion of lead (13 ). Because of the high blood lead concentrations, chelation therapy was indicated in these 3 patients (12 ). They were admitted for treatment that included 5 days of intravenous administration of calcium disodium EDTA (2000 mg/24 h) based on their body surface area. In cases 1, 2, and 3, the kidney function remained unaffected and lead concentrations decreased to 49.3 g/dL (from 124.2 g/dL), 52.6 g/dL (from 223.6 g/dL), and 76.0 g/dL (190.5 g/dL), respectively. Liver enzyme and hemoglobin concentrations normalized and symptoms improved remarkably in all 3 patients. Considering the opium abuse, addiction counseling was provided and patients were temporarily provided with low-dose methadone. At 6 months’ follow-up, they had no complaints. Hemoglobin and liver enzyme activ-
References 1. Masoodi M, Zali MR, Ehsani-Ardakani MJ, Mohammad-Alizadeh AH, Aiassofi K, Aghazadeh R, et al. Abdominal pain due to lead-contaminated opium: a new source of inorganic lead poisoning in Iran. Arch Iran Med 2006;9:72–5. 2. Gracia RC, Snodgrass WR. Lead toxicity and chelation therapy. Am J Health Syst Pharm 2007;64:45–53. 3. Busse F, Omidi L, Timper K, Leichtle A, Windgassen M, Kluge E, Stumvoll M. Lead poisoning due to adulterated marijuana. N Engl J Med 2008;358:1641–2. 4. Allcott JV, 3rd, Barnhart RA, Mooney LA. Acute lead poisoning in two users of illicit methamphetamine. JAMA 1987;258:510 –11. 5. Aghaee-Afshar M, Khazaeli P, Behnam B, Rezazadehkermani M, Ashraf-Ganjooei N. Presence of lead in opium. Arch Iran Med 2008;11:553– 4. 6. Joint FAO/WHO Expert Committee on Food Additive. WHO (in preparation). Safety evaluation of certain food additives and contaminants in food. http://www.who.int/ entity/foodsafety/publications/chem/summary73.pdf (Accessed October 21, 2016). 7. Rabinowitz MB. Toxicokinetics of bone lead. Environ Health Perspect 1991;91:33–7. 8. Struzynska L, Walski M, Gadamski R, Dabrowska-Bouta B, Rafalowska U. Lead-induced abnormalities in blood-brain barrier permeability in experimental chronic toxicity. Mol Chem Neuropathol 1997;31:207–24. 9. Thomson RM, Parry GJ. Neuropathies associated with excessive exposure to lead. Muscle Nerve 2006;33:732– 41. 10. Lubran MM. Lead toxicity and heme biosynthesis. Ann Clin Lab Sci 1980;10:402–13. 11. Pearce JM. Burton’s line in lead poisoning. Eur Neurol 2007;57:118 –19. 12. Kosnett MJ, Wedeen RP, Rothenberg SJ, Hipkins KL, Materna BL, Schwartz BS, et al. Recommendations for medical management of adult lead exposure. Environ Health Perspect 2007;115:463–71. 13. Simon JA, Hudes ES. Relationship of ascorbic acid to blood lead levels. JAMA 1999; 281:2289 –93. 14. Thadani H, Deacon A, Peters T. Diagnosis and management of porphyria. BMJ 2000; 320:1647–51. 15. Puy H, Gouya L, Deybach J-L. Porphyrias. Lancet 2010;375:924 –37.
Clinical Chemistry 63:12 (2017) 1809
