AHP is an autosomal dominant genetic disorder caused by the defect of the enzymes during heme biosynthesis pathway(15). Due to the partial deficiency of these enzymes, excess amounts of 5-aminolevulinic acid (ALA) and PBG accumulate and cause dysfunction of the autonomic system and neuropathy(16). Common presentations of AHP include abdominal pain (85–95%), constipation (48–84%), extremity pain (50–52%), nausea and vomiting (43–88%), tachycardia (28–80%), and hypertension (36–54%)(1). Bullous skin lesions may be present during an attack of VP or HCP(17). In severe cases, seizures, hallucination and respiratory distress might also present and patients could require intensive care(18). In our study, 100% of patients complained of abdominal pain, which was much higher than that reported in previous studies. This might be due to a potential missed diagnosis of AHP patients with other symptoms caused by the poor awareness of physicians in our hospital.
The key issue in AHP management is to suspect the diagnosis(19), and the elevation of urinary PBG is the main diagnostic criteria for AHP including AIP, HCP and VP (17). However, the urine PBG detection, which is not a routine examnation, is only ordered and performed when AHP is suspected by physicians. In our study, we found that 50% of the patients were diagnosed by endocrinologist, which was rare in the published articles whose authors usually were from the neurology, general surgery or emergency departments. This finding highlights the importance of experienced physicians for AHP diagnosis. However, as a rare disease, awareness of AHP in China is limited(7). According to a previous investigation carried out in a tertiary hospital in China, the misdiagnosis rate of AHP was 70% in their hospital(12). Further, case reports are barely reported from secondary or communal hospitals. Thus, finding an indicator during routine examinations is needed to help physicians notice the possibility of AHP.
In the present study, we found that all the AHP patients showed a false-positive result of urinary urobilinogen which could be used as a sentive marker for AHP screening in patients with abdominal pain. However, true-positive results of urinary urobilinogen caused by the elevated serum total bilirubin were found in several of the patients with cholecystitis and gallstones. Furthermore, we found that most of the AHP patients showed normal serum bilirubin levels, consistent with the literature(12, 18, 20–22). This indicated that urinary urobilinogen combined with serum total bilirubin could be used to distinguish the false-positive result from the true-positive result. So we analyzed the urinary urobilinogen/serum total bilirubin ratio in a cohort of patients with abdominal pain including AHP and other causes. Here, for the first time, we reported the important role of the urinary urobilinogen/serum total bilirubin ratio in the screening of AIP, HCP and VP. Compared to the abdominal pain patients of other causes, the AHP patients showed a significantly higher urinary urobilinogen level and urinary urobilinogen/serum total bilirubin ratio. Via ROC curve analysis, we found that the cutoff point for AHP diagnosis was 3.22. So in patients with typical clinical symptoms such as abdominal pain, the AHP diagnosis should be considered and further investigation of urinary PBG and ALA should be carried out when the urinary urobilinogen was positive. Especially when the urinary urobilinogen/serum total bilirubin ratio was above 3.22, a very high specifity was found for AHP screening.
In certain diseases, such as hemolytic anemia and hepatic jaundice, the serum bilirubin level is greatly elevated and leads to the excessive production of urobilinogen. Thus, a true-positive result shows in the urinalysis(10, 11). And according to previous reports, sulfonamides, p-aminosalicylic acid, and drugs containing Azo dyes (nitrofurantoin, riboflavin, methyldopa) could also react with Ehrlich's reagent(23), leading to a false-positive result. However, abdominal pain is not common in these disease and a detailed history taking and physical examination are really necessary.
The potential clinical use of the urinary urobilinogen/serum total bilirubin ratio suggests the importance of urinalysis in the diagnosis of AIP, HCP and VP. Unlike the serum total bilirubi, which is a routine examination used for differential diagnosis of abdominal pain, urianlysis is often overlooked both by patients and physicians. In fact, dark urine is very common in AHP patients and sometimes becomes the first clue for AHP patients with seizures in the intensive care unit(3, 24). However, all the urine specimens showed amber color during urinalysis, but only two patients mentioned a change of urine color in their complaints in the present study. In addition, a menstrual period is a common predisposing factor of an acute attack, but urinalysis is often avoided both by the physicians and female patients during their periods. Therefore, we strongly suggest that all patients with abdominal pain undergo urinalysis, and the urinary urobilinogen/serum total bilirubin ratio should be calculated to indicate a diagnosis of potential AIP, HCP and VP.
Our study has several limitations. Since the urinary ALA examination were not available in our hospital, it is difficult to identify the accurate class of AHP. Meanwhile, neither the urinary urobilinogen and PBG is quantitative detection, so we could not analyze the relation between these two results. Moreover, since AHP is a rare disease, we only enrolled 12 patients from one single center in this study. Due to the limited sample size and semiquantitative result of urinary urobilinogen, there might be variations in the cut-off point. Future multi-center studies with larger sample sizes are needed. And this ratio is not suitable for the hospital where the urianlysis was detected using a diazonium salt in an acid buffer.