Author: Zhang Shimin
Glutamine, also known as phytosterolemia, is a rare autosomal recessive inherited metabolic disease. Due to the metabolism of plant sterols such as glutasterol, the serum content of sitosterol and legumol is abnormally elevated, causing xanthelasma, early-onset cardiovascular disease, atherosclerosis, hemolytic anemia and other lesions and thrombocytopenia. The mortality rate is high in the middle age.
The disease is caused by homozygote or compound heterozygote phenotypes caused by a co-occurring mutation in ABCG5/ABCG8 in adenosine triphosphate binding transporter.
The most characteristic manifestation is the increase in the level of plant cholesterol in the blood plasma by 20 to 100 times. Plant sterols are a naturally occurring compound found in most vegetable oils that block the absorption of cholesterol by the small intestine, whereas most people consume very few plant sterols through a normal diet.
On May 11, 2018, the disease was included in the "First Rare Disease Catalogue" jointly formulated by the National Health Commission and other five departments.
Typical cases
1
Blood routine instrument alarm
The patient, a 36-year-old man, was admitted to the general internal medicine ward with an unexplained fever. The first blood routine test after admission using the Siemens Advia2120 blood cell analyzer showed results like this:
Thrombocytopenia, suggesting thrombocytosis and platelet aggregation (red arrows and red circles)
Instead, the Sysmex XN blood cell analyzer was used for re-examination and detection, in which platelets showed a very large gap between the two channels, and the platelet histogram and scatterplot were abnormal:
The PLT of the Sysmex XN analysis system studies parametric data and scatter plots
Which result is correct? Is there platelet aggregation?
The PLT-F channel suggests macrocytosis, perhaps naïve thrombocytosis (IPF)! The WNR scatterplot also shows significant anomalies! The WFD scatterplot shows that the white blood cell classification is basically normal, but the dark blue scatter below suggests platelet aggregation? The platelet histogram is not normal, showing low platelets, and does not show problems with large platelets and small red blood cells crossing.
2
Blood smear scan retested
The results of platelet analysis by the two testing devices are quite different, but both indicate that there is a phenomenon of large thrombocytosis, and a blood smear re-examination must be performed. We first performed a cell scan re-examination of the blood smear with Cellvision DM96. Oral erythrocytes are easily seen around white blood cells.
Screenshot of Cellavision DM96 scanning and rechecking a blood smear
There is no problem with leukocyte classification.
Cellavision DM96 leukocyte classification results
Since both types of blood cell analyzers indicate a large gap between the number of large platelets and platelets, so use the device to check the platelet situation, and find that there are indeed many large platelets and huge platelets, and oral red blood cells can also be seen around.
Cellavision DM96 screenshot of large thrombocytosis detected
Check the distribution of platelets in the red blood cell analysis module, the number of platelets is quite large, and it also shows that the platelets are enlarged, so it can be confirmed that the platelets are not aggregated, not reduced, and consistent with the large thrombocytosis alarm of the instrument.
Looking closely at the screenshot of the large thrombocytosis above and the distribution of platelets in the red blood cell module, it was found that many red blood cells around the platelets were mouth-shaped red blood cells, and the estimated number was also quite large.
Red blood cell analysis module of Cellavision DM96
Since oral erythrocytosis is suspected, a preliminary analysis of the red blood cells of the blood flakes is performed using advanced red blood cell analysis software, clicking on the Stomatocytes option to show the orthoptic red blood cells in a dark color and the other non-oral red blood cells lighter.
Cellavision DM96 Advanced Red Blood Cell Analysis Software Analysis Screenshot
At the same time, the percentage of oral erythrocytes obtained by instrument analysis is obtained. Results showed oral erythrocytosis with spherical erythrocytosis.
Cellavision DM96 red blood cell classification results
3
Blood smear microscopy
Since both the hematocyte analyzer and the Cellvision indicate macrocytosis and oral erythrocytosis, microscopic verification of the blood smear is also necessary. Examine the blood smear carefully under an oil microscope:
Microscopic examination reveals macroplatelets and orthoptic erythrocytes (scale 10 μm, same below).
Microscopic examination shows large platelets and oral erythrocytes.
Microscopic examination, macrocytosis and oral erythrocytosis.
Microscopic examination, macroplatelets, large platelets, and oral erythrocytosis.
4
Manual counting verifies the number of platelets
Use platelet dilution to dilute blood samples, manually count platelets using traditional microscopy to verify platelets, calibrate the number of platelets, and minimize factors that may be inaccurate platelet counts due to large platelets, large platelets, or platelet aggregation.
Counting platelets in the disk (low magnification)
Counting platelets in the disk (hyperploidoscopy), in which large platelets are similar in size to red blood cells (the red blood cells in the counting plate have been dissolved by the dilution, so there are no red blood cells, only two white blood cells).
After accurately counting platelets under the microscope, it was found that none of the automated equipment accurately counted large platelets and huge platelets, and the final result of manual counting was 390×109/L.
5
Blood count is finally reported
After microscopic re-examination of blood tablets and verification of platelet counts, we have issued the following report. Among them, the morphological description in the remarks is: oral red blood cells and macroscopic and large platelets are easy to see, red blood cells can see H-J bodies, and platelet counts are artificial microscopic counts.
Blood routine report and remarks issued after re-examination
6
Phytosterolemia is confirmed
After the blood routine report was issued, we contacted the competent doctor, and the laboratory results were highly suspicious of phytosterolemia, and it was recommended to send genetic tests and serum plant sterol profile analysis (need to be sent for testing).
A few days later, the genetic test results were returned and the sent plant sterol profile report was returned to the clinic, and the patient was diagnosed with phytosterolemia.
Clinical manifestations
Hypercholesterolemia and early-onset cardiovascular disease:
Serum total cholesterol levels are significantly elevated in some patients, and the risk of cardiovascular diseases such as early-onset atherosclerotic coronary heart disease is significantly increased. However, some patients have normal or slightly higher serum total cholesterol.
Cutaneous xanthelasma:
Xanthelasma can occur in adolescence, manifested as a painless bulging nodule, and tends to occur around tendon attachment points such as wrists, Achilles tendons, knees, and elbows, and rarely appears on the eyelids and face.
Blood abnormalities:
Some patients present with haematological changes such as hemolytic anemia, thrombocytopenia, and abnormal bleeding.
other:
As the disease progresses, some patients develop abnormalities such as arthritis, arthralgia, liver damage, and mild splenomegaly.
Diagnosis and differential diagnosis
Diagnostic points:
1. Typical clinical manifestations (such as xanthelasma, early-onset cardiovascular disease);
2. Serum sitosterol and legumol concentration increased;
3. ABCG or ABCG8 allele mutations.
To be distinguished from the following disorders:
Hyperlipidemia, familial hypercholesterolemia, immune thrombocytopenic purpura, fatty liver, etc.
Diagnosis was confirmed by serum plant sterol profiling and genetic analysis.
Laboratory tests
Laboratory tests for phytosterolemia are key, and routine blood tests and blood smears may be an initial screening item for the detection of the disease.
Blood routine:
In some patients, erythrocytopenia, reticulocytosis, decreased (or normal) platelet count, and hemolytic anemia such as orthopause and macroplatelets may be seen on a blood smear.
Serum plant sterol profiling:
The concentration of glutasterol and legosterol in the blood of the patient was significantly increased.
Genetic testing:
AbCG5 or ABCG8 genetic testing is an important method of diagnosing sitosteremia.
Summarize the discussion
For inspectors:
For patients with thrombocytopenia, when performing re-examination and morphological examination, attention should be paid to the observation of red blood cell morphology, and if large platelets and huge thrombocytosis are seen with oral erythrocytosis, plant sterolemia can be suspected. Communicate with clinicians in a timely manner, give consultation and advice, and preferably perform serum plant sterol profiles and genetic testing.
Thrombocytopenia is mentioned in the clinical manifestations and definitions of the disease, but in this case there is no decrease in platelets, but instead large platelets and macrocytopenia. This suggests that thrombocytopenia may be an illusion, or perhaps an illusion given by instrumental methods that large platelets and huge platelets cannot be accurately counted. The blood smear should be evaluated and, if necessary, recalibrated the platelet count using microscopic counting.
For patients:
The amount of cholesterol and sitol in foods should be strictly limited, and through dietary control, it is possible to reduce the content of plasma glutasterol by 30%.
prophylaxis:
For patients, parents and family members, blood lipid assays, genetic analysis and genetic counseling blood routines and blood smear screening should be performed, and prenatal diagnosis can be performed when the mother has another child, which is conducive to eugenics.
Source: Zhang Shimin's Academic Classroom
Edited by: Yeah Reviewer: Xiao Ran