Background: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are two kinds of diseases caused by inborn errors of metabolism. So far, the epidemiological data on them are limited in China. The aim of our study is to investigate the proportion and characteristics of hospitalized pediatric patients with MMA and PA in China. Methods: The data in this study were obtained from the Hospital Quality Monitoring System, a national inpatient database in China, with information on the patients hospitalized during the period from 2013 to 2017. We identified the data related to the patients who were under 18 years old and were diagnosed with MMA/PA, and extracted the information on demographic characteristics, hospital location, total cost and other related clinical presentations from the data. Results: Among all hospitalized pediatric patients with liver diseases, there were increasing trends in the proportion of individuals diagnosed with MMA or PA during the period from 2013 (0.76% for MMA; 0.13% for PA) to 2017 (1.61% for MMA; 0.32% for PA). For both MMA and PA, children under 2-year-old accounted for the highest proportion. The median of total cost per hospitalization was relatively high (RMB 7388.53 for MMA; RMB 4999.66 for PA). Moreover, most patients hospitalized in tertiary class A hospitals (MMA: 80.96%, PA: 76.21%); and a majority of pediatric patients admitted in the hospitals in Shanghai and Beijing are from outside districts. Manifestations of nervous system-related symptoms, and metabolic acidosis or anemia in laboratory findings were more common during hospitalization. Conclusions: The study is the first nationwide one in providing epidemiological and clinical information on hospitalized pediatric patients with MMA/PA. An increasing hospitalization with various presentations and a heavy financial burden were observed. In addition, geographically, the medical resources in China have been unevenly distributed.
Keywords: Hospitalized; MMA; PA; Pediatric
Yi-Zhou Jiang and Yu Shi contributed equally to this work.
Methylmalonic acidemia (MMA) (OMIM #251000, MMA mut type; OMIM #251100, MMA cblA type; OMIM #251110, MMA cblB type; OMIM #277410, MMA cblD-variant 2) and propionic acidemia (PA) (OMIM #606054), two diseases caused by inborn errors of metabolism, are the most common organic acidurias [[
MMA and PA are both rare disorders of propionate catabolism among children. Compared with PA, MMA has been commonly reported with higher prevalence rate, but the incidence varies greatly worldwide [[
Since China is a country with a huge population and MMA/PA are increasingly recognized diseases, the two diseases may pose a potential challenge to China's national health system. Hence, to obtain information about the epidemiology and clinical presentations of MMA/PA is critical to the comprehensive perception of both of them and will be conducive to early diagnosis and even prognosis. Considering the low incidence and the cost of epidemiological survey, analyzing existing big data is a more rational way. Therefore, the purpose of this study was to 1) provide epidemiological information and financial burden status; 2) evaluate frequency of different clinical manifestations and laboratory results of MMA and PA hospitalizations among pediatric patients in China based on a large national database.
The database we used is the Hospital Quality Monitoring System (HQMS) [[
Physicians were in charge of completing the data on the front page of records, and the diagnosis was coded based on the International Classification of Diseases, revision 10 (ICD-10) coding system by certified professional medical coders at each participating hospital. Data quality was controlled automatically at the time of data submission.
The study included all hospitalizations of patients who were under 18 years of age with a primary or secondary diagnosis of underlying liver disease (including viral hepatitis, non-viral infectious liver disease, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), liver neoplasms, autoimmune liver disease, drugs/toxin-induced liver injury, trauma, biliary atresia, metabolic liver disease, other congenital diseases, hepatic vascular/anatomical abnormalities and idiopathic portal hypertension) using ICD-10 from 1 January 2013 to 31 December 2017. Among these diseases, MMA and PA were defined with the following ICD-10 codes: MMA (E71.102), PA (E71.101), all of whose hospital discharge data were extracted and analysed retrospectively. Other diagnosis related to MMA and PA (possible symptoms/comorbidities mostly based on the proposed guidelines for the diagnosis of MMA and PA [[
Demographic characteristics including age, sex and residence were extracted from the front page of the hospitalization medical record. Hospital location, length of stay and expenditure were also collected.
Continuous data were expressed as mean ± standard deviation, or as median (inter-quartile range) for highly skewed variables. Categorical variables were presented as frequency and percentage (%). Cochran-Armitage test for trend was performed to assess the trend of the proportion of MMA or PA pediatric patients.
All P values were 2-tailed. A P value less than 0.05 was considered to be significant. All analysis was performed using SAS software, version 9.4 (SAS Institute Inc., Cary, NC, United States). The maps were drawn by JMP software, version 14 (SAS Institute Inc., Cary, NC, United States).
During the period from 2013 to 2017, total frequency of hospitalizations of the pediatric patients identified, with MMA and PA were 2610 and 538 in the database respectively. Among all hospitalized pediatric patients with liver diseases, the proportion of hospitalized pediatric patients with MMA showed an increasing trend from 2013 (n = 282 (0.76%)) to 2017 (n = 716 (1.61%)) with statistical significance (P
Graph: Fig. 1 The proportion of MMA and PA in hospitalized pediatric liver disease during the period from 2013 to 2017
The demographic characteristics of patients with MMA and PA were shown in Table 1. The median age (y) of patients with MMA (1.00 (0.25–3.00)) was almost equal to that of patients with PA (1.00 (0.83–3.00)). The age distribution was further analysed. The group of infants under 1-year-old had the highest proportion in the hospitalized pediatric patients with MMA, and the children under 2-year-old accounted for 61.5 percentage of all hospitalizations with MMA. Yet infants under 2-year-old accounted for 49.6% of those with PA (Fig. 2). There were more male patients than female for both MMA (Male: 57.85%, Female: 42.15%) and PA (Male: 67.66%, Female: 32.34%).
Demographic characteristics of patients with MMA and PA from 2013 to 2017
MMA PA Age (year) 1.00 (0.25–3.00) 1.00 (0.83–3.00) Sex Male 1510 (57.85%) 364 (67.66%) Female 1100 (42.15%) 174 (32.34%) Length-of-stay (days) 8.0 (4.0–13.0) 7.0 (4.0–10.0) Hospital level Tertiary class A hospital 2113 (80.96%) 410 (76.21%) Tertiary class B hospital 497 (19.04%) 126 (23.42%) Secondary hospital 0 2 (0.37%) Type of admission Emergency or Referral 858 (32.87%) 161 (29.93%) Routine 1564 (59.92%) 316 (58.74%) Other 188 (7.20%) 61 (11.34%) Total costs (RMB) per hospitalization 7388.53 (3298.72, 15,464.66) 4999.66 (2545.03, 10,032.57) In-hospital death Yes 44 (1.69%) 12 (2.23%) No 2566 (98.31%) 526 (97.77%)
Graph: Fig. 2 The age distribution of MMA and PA
As shown in Table 1, the median of length of stay (LOS) for MMA (8.0 (4.0–13.0)) was slightly higher than that of PA (7.0 (4.0–10.0)). Most of MMA pediatric patients (80.96%) were hospitalized in tertiary class A hospitals. There was relatively lower percentage of PA patients hospitalized in tertiary class A hospitals (76.21%). Moreover, the total cost of every hospitalization of MMA (RMB 7388.53 (IQR: 3298.72-15,464.66)) was higher than that of PA (RMB 4999.66 (IQR: 2545.03-10,032.57)). Over 50% of MMA and PA patients were admitted to hospital through routine, followed by nearly 30% through emergency or referral. The in-hospital mortality of PA was 2.23%, which was slightly higher than that of MMA (1.69%).
In the relatively developed districts, there are a high proportion of patients from other districts. As shown in the Fig. 3a, 86.8% of MMA pediatric patients seen in the hospitals in Shanghai are from outside districts, followed by Beijing (80.5%), and Chongqing (70.4%). 90.0% of PA pediatric patients seen in the hospitals in Beijing are from outside districts, followed by Chongqing (86.7%), Jiangsu (83.3%) and Shanghai (60.9%).
Graph: Fig. 3 Cross-district attendance of MMA. a. The percentage of the hospitals in different districts which admitted MMA pediatric patients from outside districts. b. The percentage of MMA pediatric patients from different districts who went to the hospitals in other districts
A certain proportion of patients from some areas went to hospitals outside. Up to 82.6% of MMA pediatric patients in Gansu went to the hospitals in other districts, followed by Anhui (80.2%), Tianjin (80.0%) and Heilongjiang (72.4%) (shown in Fig. 3b). And 55.6% of PA pediatric patients in Jiangsu chose to see doctors outside, followed by Anhui (50.9%), Sichuan (42.4%) and Jiangxi (36.4%).
The frequency of different signs and symptoms of these two diseases among all hospitalizations are listed in Table 2. Nervous system has been more susceptible for MMA/PA patients and in-patients tend to have related clinical features: seizures/epilepsy (MMA: 14.64%, PA: 14.50%), developmental delay (MMA: 7.82%, PA: 9.48%), movement disorder/dystonia (MMA: 2.84%, PA: 2.97%), and encephalopathy (MMA: 6.32%, PA: 7.43%). Patients also manifested with renal, cardiac damage; or gastrointestinal symptoms, hematologic findings, immunodeficiency; or other symptoms including hearing loss, visual deterioration and skin lesions. Compared with those with PA, patients with MMA may be more likely to have a chronic renal damage and cardiac insufficiency. It is noteworthy that prolonged QTc interval is potentially specific in PA.
Frequency of different clinical presentations of MMA&PA
MMA ( PA ( Nervous system Seizures/ Epilepsy 382 (14.64%) 78 (14.50%) Developmental delay 204 (7.82%) 51 (9.48%) Encephalopathy 165 (6.32%) 40 (7.43%) Movement disorder/Dystonia 74 (2.84%) 16 (2.97%) Altered level of consciousness 4 (0.15%) 0 Optic atrophy 1 (0.04%) 1 (0.19%) Kidney Acute renal failure 14 (0.54%) 3 (0.56%) Chronic renal failure 20 (0.77%) 1 (0.19%) Chronic renal insufficiency 32 (1.23%) 0 Heart Cardiomyopathy 100 (3.83%) 21 (3.90%) Cardiac insufficiency 93 (3.56%) 5 (0.93%) Arrhythmia 21 (0.80%) 8 (1.49%) Prolonged QTc interval 0 3 (0.56%) Gastrointestinal system Failure to thrive 123 (4.71%) 37 (6.88%) Abnormal feeding behavior 66 (2.53%) 11 (2.04%) Vomiting/Ketoacidosis 5 (0.19%) 1 (0.19%) Pancreatitis 1 (0.04%) 0 Hepatomegaly 2 (0.08%) 0 Hematologic findings Neutropenia 84 (3.22%) 30 (5.58%) Pancytopenia 8 (0.31%) 10 (1.86%) Involvement of bone marrow 9 (0.34%) 5 (0.93%) Immune system Immunodeficiency 9 (0.34%) 3 (0.56%) Others Skin lesions 42 (1.61%) 8 (1.49%) Hearing loss 27 (1.03%) 5 (0.93%) Visual deterioration 6 (0.23%) 0
Laboratory findings are shown in Table 3. In-patients with MMA/PA, the appearance of metabolic acidosis (MMA: 13.14%, PA: 19.14%) and anemia (MMA: 19.23%, PA: 15.61%) were relatively common, followed by elevated ALT/AST/LDH, low PLT, elevated NH3, hypoglycemia, low WBC, decreased eGFR and elevated uric acid. In addition, elevated lactic acid, myocardial enzyme and EEG abnormalities were specific features in MMA.
Frequency of different laboratory findings of MMA&PA
MMA ( PA ( Metabolic acidosis 343 (13.14%) 103 (19.14%) Anemia 502 (19.23%) 84 (15.61%) ↓ PLT 66 (2.53%) 27 (5.02%) ↓ WBC 20 (0.77%) 6 (1.12%) ↑ ALT/AST/LDH 139 (5.33%) 21 (3.90%) ↑ NH3 44 (1.69%) 42 (7.81%) Hypoglycemia 38 (1.46%) 16 (2.97%) ↓ eGFR 24 (0.92%) 5 (0.93%) ↑ Uric acid 13 (0.50%) 1 (0.19%) ↑ Lactic acid 8 (0.31%) 0 ↑ Myocardial enzyme 5 (0.19%) 0 EEG abnormalities 4 (0.15%) 0
PLT platelets, WBC white blood cell, ALT alanine transaminase, AST aspartate transaminase, LDH lactate dehydrogenase, eGFR estimated glomerular filtration rate, EEG electroencephalography
Our study is the first nation-wide study aimed to provide epidemiological information, including the proportion, demographic feature and characteristics of hospitalized pediatric patients with MMA or PA. Although MMA and PA are rare diseases, the national database provided data on a certain amount of MMA and PA pediatric patients. Therefore, this study helps bring reliable data for our understanding of these two rare diseases.
Several of our findings are noteworthy. First, in this national dataset of hospitalized patients, the proportion of hospitalized pediatric patients with MMA or PA showed an overall increasing trend from 2013 to 2017. This phenomenon presented that there had been a growing pressure on the national health system in China. One plausible explanation is that the increase is mainly due to the accumulation of experience in recognition and diagnosis of MMA and PA over time, as MMA and PA have become the most common organic acidurias. The clinical manifestations of patients with these diseases are complex and vary in severity. They can be manifested as a single or multiple organ damages, which makes them difficult to be identified except relying on biochemical and genetic analysis to make a definite diagnosis [[
Though all the pediatric patients were just from the nationwide hospitalized data, the MMA-to-PA number ratio of hospitalized admission might represent overall incidence ratio of MMA and PA in the population of China to some extent. In the worldwide context, the actual incidence of MMA and PA is still unknown in some areas [[
This study also found that the median ages of hospitalized patients with MMA or PA were both one-year-old. The reason for infant predominance is probably that organic acidurias can be diagnosed early owing to the development of neonatal mass screening nowadays. After MMA and PA are diagnosed correctly and treatment regimen are made, maintenance of protein restriction and drug treatment including L-carnitine, antimicrobial therapy and biotin supplementation are always implemented in outpatient or at home [[
In recent years, MMA and PA have been reported to be associated with increasing burden deserving intense attention [[
Regarding to the distribution of hospital level, the study found that most of MMA and PA pediatric patients (80.96 and 76.21% respectively) were hospitalized in the highest level of hospitals, namely, tertiary class A hospital. Moreover, the hospitals located in Beijing, Chongqing, Shanghai and Jiangsu, admitted a majority of MMA or PA pediatric patients from other districts. This may be related to the unbalanced distribution of medical resources including experienced, specialized pediatricians and advanced equipment. For instance, measurement of serum/urine organic acid and genetic analysis has been generally available only in tertiary hospitals and rarely available in primary health care settings in China. These two diseases also require multidisciplinary team for nutritional, biochemical, neurodevelopmental and psychological assessment. Regular monitoring of metabolic parameters, developmental delay, long-term complications, compliance with therapy, along with overall nutritional status are strongly advised [[
It has been already known that symptoms of MMA/PA may vary considerably and are nonspecific especially in childhood since multiple organ systems are affected [[
There are several limitations to our study. Firstly, the HQMS database is not able to distinguish each patient with repeated admissions, since ID numbers for children on the front page of medical records are usually unavailable. Secondly, we relied merely on ICD-10 codes for case identification, since we had no access to all medical records of studied population. This could have led to a less precise estimation of burden of hospitalized pediatric patients with MMA and PA to some extent. Thirdly, there were lack of follow-up outcomes for these pediatric patients in this study, as the study was based on sequential cross-sectional data.
Despite these limitations, our study provides epidemiological and clinical information of MMA and PA hospitalizations based on a nation-wide database, which would help us better understand the general profile of these two rare diseases in China.
In conclusion, this study is the first one to provide epidemiological, health economic and clinical presentation information on hospitalized pediatric patients with MMA and PA in China based on a national database. An increasing hospitalization with various presentations and a heavy financial burden per hospitalization were observed, while the medial resources were still relatively centralized in only several districts, such as Beijing, Chongqing, Shanghai and etc.
This work (collection, analysis, and interpretation of data) was supported by The Capital Research Project of Specialty Clinical Application (Z181100001718220); Beijing Municipal Administration of Hospitals Ascent Plan [Code: DFL20150101] and Research Foundation of Beijing Friendship Hospital, Capital Medical University [No. yyqdkt2017–27].
None.
Z-JZ, L-YS, Y-ZJ and Yu-Shi: study concept and design. Y-ZJ, Yu-Shi: acquisition of data; analysis and interpretation of data; drafting of the manuscript. Yu-Shi, Ying Shi and L-XG: statistical analysis and analysis of data; Z-JZ, H-BW, L-YS and Y-YK: study supervision; critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
Data collection and analysis were performed according to the ethical standards of the Helsinki Declaration. The study was approved by the Ethical Committee of Beijing Friendship Hospital, Capital Medical University (Approval ID: 2019-P2–154-01).
Not applicable.
All authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
By Yi-Zhou Jiang; Yu Shi; Ying Shi; Lan-Xia Gan; Yuan-Yuan Kong; Zhi-Jun Zhu; Hai-Bo Wang and Li-Ying Sun
Reported by Author; Author; Author; Author; Author; Author; Author; Author