Standardized application and safety monitoring of recombinant human growth hormone in pediatric clinical

Standardized application and safety monitoring of recombinant human growth hormone in pediatric clinical

In 1956, pituitary derived human growth hormone (phGH) was isolated from human pituitary and subsequently applied to the treatment of growth hormone deficiency (GHD). Since the beginning of 1984, dozens of Creutzfeldt-Jakob lesions have been reported in patients with phGH. In early 1985, phGH was banned by the US Food and Drug Administration (FDA). In the following months, biochemically synthesized growth hormone was approved by the US FDA, but it was quickly discontinued due to its high antigenicity and easy production of antibodies. In the same year, the in vitro synthesis of recombinant human growth hormone (rhGH) was successfully marketed, making it possible for a large number of clinical applications of GH. The US FDA approved its use for the treatment of children with GHD and subsequently approved for chronic renal insufficiency. Pre-transplantation, Turner syndrome, Prader-Willi syndrome, small for gestational age (SGA), idiopathic short stature (ISS), short bowel syndrome, SHOX gene deletion, Noonan synthesis Treatment of short stature in patients with non-growth hormone deficiency |

In the past 30 years, rhGH has become more and more widely used in clinical practice, and its role in promoting growth and improving lifelong high has been recognized. At the same time, the safety of rhGH treatment is also closely watched. European Pediatric Endocrinology Society (ESPE), Lawson, USA. Lawson Wilkins Pediatric Endocrine Society, International Pediatric Endocrinology Society (ISPE), Growth Hormone Research Society (GHRS), American Society of Clinical Endocrinology (AACE), etc. developed GHD and non-growth hormone deficiency short stature children rhGH diagnosis and treatment Guides and consensus are the same. 7 J. The Endocrine Genetic Metabolism Group of the Pediatrics Branch of the Chinese Medical Association also proposed the “Recommendation for the Clinical Application of Recombinant Human Growth Hormone” in 1998. In 2008, the “Guidelines for the Diagnosis and Treatment of Short Stature Children” was formulated to standardize the clinical application of rhGH. Diagnosis and treatment of short stature children [8-9]. However, the clinical application of rhGH still has many problems such as random expansion of application range, irregular diagnosis of diseases, excessive or irregular treatment, and inadvertent monitoring during treatment, which brings uncertain clinical effects and serious safety hazards to rhGH treatment. In 2013, the Endocrine Genetic Metabolism Group of the Chinese Medical Association Pediatrics Branch and the Editorial Board of the Chinese Journal of Pediatrics reorganized and revised the “Recommendations for the Application of Genetic Recombinant Human Growth Hormone Pediatric Clinical Specifications” (“Recommendation”) 010], and in this journal. Out, in order to further guide the norm application of rhGH.

1. Strictly grasp the indications for the clinical application of rhGH

Although rhGH brings good news to patients with short stature, not all patients with short stature need or are suitable for rhGH treatment. Strict control of rhGH indications is a prerequisite for normative application, and clear disease diagnosis is a prerequisite for strict control of rhGH clinical application indications. In the diagnosis of short stature, the patient’s medical history, family history, clinical manifestations, physical examination and related laboratory and imaging results must be analyzed and evaluated. Pay special attention to the following problems in the clinical diagnosis process.

1. Correct evaluation of GH challenge test: GH challenge test is an important basis for the diagnosis of GHD, but the test still has some limitations in clinical application. ‘1’”1: (1) GH challenge test reflects insulin, levodopa The secretion of GH after stimulation with drugs such as clonidine is not the secretion of GH under physiological conditions. Some GH challenge tests suggest that the natural secretion of GH in “normal” children may be lower than that in normal children. (2) Many factors affecting GH challenge test The drugs used in the challenge test, the test methods of GH, and the sexual development status of the children can affect the results of the GH challenge test. Different drug excitations, peak time and peak size are different; different laboratories use different Detection methods and reagents have different diagnostic thresholds. A part of pre-pubertal children with slow growth have been confirmed by GH challenge test to be lower than normal, but re-testing in puberty may rule out the diagnosis of GHD. Therefore, some foreign scholars have suggested that puberty Pre-children should have sex hormone pre-excitation before the GH challenge test, but there is no consensus on this. (3) GH challenge test Off threshold is set manually, Different countries and regions use different diagnostic thresholds.
At present, the international consensus and the standards adopted in China are peak <10 ̈g/L, and some countries adopt more stringent standards such as <7 ̈∥L or 5 anal g/L. (4) The GH excitation test was not reproducible. GH challenge tests were performed with different stimulating drugs, before and after rhGH treatment, and before and after puberty. The results were all different. According to the results of the GH challenge test, GHD misdiagnosis and missed diagnosis may occur. Although the GH challenge test has certain limitations, it still plays a very important role in the diagnosis and differential diagnosis of short stature diseases. Some people think that the peak of GH stimulation test <10 shirt g / L can diagnose GHD, the peak of GH challenge test > 10 bucket g / L can diagnose ISS, both are FDA-approved rhGH indications, therefore, no need to carry out GH In the provocation test, patients with short stature can start using rhGH therapy. This view is very wrong. First, it ignores the diagnostic significance of the GH challenge test. The GH challenge test is not only an important basis for the diagnosis of GHD, but also the diagnosis of GH receptor deficiency and growth hormone neurosecretory dysfunction in combination with IGF1, IGF! production test, and GH natural secretion measurement. Second, this view confuses the definition of ISS and non-growth hormone deficiency short stature. Non-growth hormone deficiency includes not only ISS, but also short stature caused by a lack of growth hormone deficiency, such as Turner syndrome, Prader. Willi syndrome, SHOX gene deletion, Noonan syndrome, etc. In addition, under the premise of unclear diagnosis, humatrope rhGH treatment is started only because of short stature, it is difficult to determine the correct treatment plan, and the safety of treatment cannot be guaranteed.
2. Defining the diagnosis of children with ISS: The diagnosis of ISS is still controversial. ISS is essentially a group of diseases that are currently short-lived due to unclear causes. Compared with normal children, children with ISS had a peak GH of >10 ̈g/L, but the basal GH level, GH peak, and total GH secretion were lower than normal children (a 0.48 SDS, a 0.36 SDS). , a 0.76 SDS); 25% of children with IGF1 decreased or were at a normal low limit, and some patients had normal or elevated IGF1 levels, but there was IGF1 resistance. 1 cited. With the in-depth study of hypothalamic-GH-IGF1 axis function and genetics, more and more evidence indicates that the hypothalamus may exist in children with current diagnosis of ISS. GH. Abnormality of IGFl axis function. Although the results of GH challenge test showed normal, the natural secretion of growth hormone was not detected 24 hours or 12 hours, but the natural secretion of GH could not be found to decrease. The abnormal function of GH promoter affected GH naturally. Secretion does not affect the peak of GH challenge test; abnormal GH molecules lead to GH deficiency biological activity; related gene defects in GH signal transduction pathway lead to decreased responsiveness to GH, such as GHR, STATSb, ALS, IGF1, IGFlR gene abnormalities, etc. 3. 14 o. With the widespread clinical application of genetic analysis technology, more GH may be found in children with ISS. IGFl axis-related genes or signaling molecules are abnormal, thereby separating the disease with a clear cause from the ISS.
3. Correct evaluation of the role of predicting adult height: The US FDA defines normal height as 160.0 ca for men and 149.9 cm for women. At present, there is a lack of scientific, effective and suitable method for predicting height evaluation of children with short stature in China. The commonly used Bayley-Pinneau (B-P) method is based on observations of healthy children in the UK in the 1950s and is not suitable for the height prediction of Chinese short stature children. And the study found that the degree of bone age lag can affect the accuracy of predicting height. The average adult height of children with a bone age of about 2 years is close to the predicted height of the adult. The height of the adult with a bone age of more than 2 years is far lower than the predicted height of the adult. The height of the adult without the bone age is much higher than the original predicted height of the adult 1151. . Predicting the inaccuracy of height makes it impossible to be the indicator ‘3’ for starting rhGH treatment. 5 J, the clinical should not simply decide whether to start rhGH treatment based on the predicted height.
4. To clarify the clinical scope of rhGH treatment: in addition to the FDA-recommended rhGH indications, clinical data showing clinical signs of central precocious puberty, congenital adrenal hyperplasia, congenital hypothyroidism, etc. After treatment, rhGH treatment can improve the growth after the growth and backwardness is predicted, and the prediction of adult height is obviously damaged. However, more evidence-based medicine is needed, which is not used as a routine clinical application. Because of the current lack of scientific psychological assessment methods, rhGH is not used for the purpose of improving the psychological behavior of children with short stature.
In addition, height is affected by many factors such as heredity, endocrine, nutrition, disease, etc., and there are obvious ethnic and individual differences. rhGH should not be used for the treatment of normal short children for the purpose of improving their height. In the course of work or life, society should also avoid discrimination or misleading of height. Second, adhere to rhGH standardized treatment standardized treatment is to obtain better efficacy and reduce the adverse reactions. Children with short stature should adhere to standardized treatment once they are clearly diagnosed with indications for rhGH treatment. This “recommendation” describes the rhGH treatment plan for different diseases.

1. Time to start medication: In addition to GHD, the initial treatment time for other indications varies with age and growth and development indicators. The age of ISS initial treatment was 5 years old; the height of children with SGA I>4 years old was still lower than the average height of children of the same age and normal sex, and the treatment was considered; the height of Turner syndrome was 5th in the growth curve of normal female children. When the percentile is below, the treatment of rhGH should be started, and treatment can be started even at 2 years of age; the age of initiation of PWS is not yet uniform, but it is generally believed that it is beneficial to start rhGh before obesity (usually around 2 years old). .
2. Therapeutic dose: Within a certain range, there is a dose-dependent effect of rhGH treatment, but the therapeutic dose is not as large as possible. Studies have shown that ̈⋯, low-dose long-term treatment can achieve better life-long. The therapeutic dose is related to the disease type, puberty status and the like. The initial therapeutic doses for different diseases vary, with lower doses for GHD patients and slightly greater doses for Turner syndrome, SGA, and ISS. The pre-pubertal treatment dose is slightly smaller, while the puberty development dose is slightly larger. However, the maximum amount should not exceed 0.2 U / (kg · d), long-term super-physiological dose of rhGH application still requires larger sample, long-term safety monitoring data.
3. Treatment course: rhGH treatment varies depending on the condition. The height SDS continues to improve with the treatment time. In order to improve adult height, rhGH treatment should last at least 1 year. In the short-term, especially within half a year, rhGH treatment is difficult to achieve the goal of improving lifelong high, and it is not recommended in clinical practice.
4. Time to stop the drug: height after treatment is greater than normal body height by 2 standard deviation; or close to adult height, that is, growth rate <2 cm / year, boy bone age > 16 years old, girl bone age > 14 years may consider discontinuation. However, children and parents’ satisfaction, economic reasons, etc. are often common factors affecting withdrawal. In order to improve body composition, lipid metabolism, cardiac function, etc., patients with GHD and PWS can be used in adulthood, but the therapeutic dose is smaller ̈’22|.
5. Efficacy assessment: dose adjustment should be made according to the patient’s treatment effect, body weight change, puberty status and IGF1 level during the treatment process, and pay attention to the efficacy evaluation. In patients with good compliance, and if the treatment dose is appropriate, if the growth rate is not increased, serum IGFI levels are not increased, usually suggesting that the treatment is ineffective, and further evaluation of the diagnosis is necessary. After 2 years of initial treatment, if serum IGF1 levels are above the normal range, especially above 2.5 SDS, reduction or discontinuation should be considered. The overall treatment of rhGH should follow the principle of individualization, using early treatment, full dose, and long course of treatment. In the rhGH treatment evaluation process, the rational allocation of medical resources should also be fully considered, especially the input-to-benefit ratio, benefit and risk assessment. Clinicians should not simply decide the treatment and treatment by the satisfaction of society, parents and patients on height. .
Third, pay attention to the safety monitoring of rhGH treatment Some clinicians pay more attention to the effectiveness of rhGH treatment, pay attention to the monitoring of growth and development indicators, neglect safety monitoring, and safety is one of the key points of standardized treatment.

1. Familiar with the possible adverse reactions during rhGH treatment: The related adverse reactions of rhGH treatment are currently reported. 2}29 o have benign intracranial hypertension, effects of glucose metabolism, hypothyroidism, femoral head slippage, scoliosis, possibility of inducing tumors, pigmented nevus, adenoid hypertrophy, enlarged hands and feet. Local redness and rash are not common, and otitis media, pancreatitis, and male breast development are also reported. Long-term treatment with rhGH can reduce insulin sensitivity and increase insulin resistance. Some patients have impaired glucose tolerance, but most of them are temporarily reversible, and rarely develop into diabetes ‘23.26I. In the first few months of rhGH treatment and even after 1 year of treatment, some children may have hypothyroidism. 2孓26I. Skeletal changes such as femoral head slip, scoliosis, and large hands and feet are caused by excessive growth, rather than direct adverse reactions of rhGH. It has been reported that rhGH has potential carcinogenicity and can promote tumor growth, but there is no clinical evidence that rhGH treatment increases tumor neoplasia, recurrence or secondary tumor development. In rhGH-treated patients, the incidence of new, recurrent, and secondary tumors was higher in organic growth hormone deficiency (OGHD), followed by chronic renal insufficiency and Turner syndrome. There is data showing that patients with first-stage tumors are leukemia and central nervous system tumors, and rhGH patients have an increased risk of secondary tumors [23.26I. Although rhGH may increase the number and size of pigmented nevi, there is no evidence to increase the risk of melanoma [27]. The current study also does not confirm that there is a causal relationship between childhood rhGH therapy and increased mortality after adulthood, but it requires close attention.

2. Strict screening before treatment and close monitoring during treatment: Although the incidence of total adverse reactions in rhGH treatment is less than 3%, in order to avoid the above-mentioned possible adverse reactions, thyroid function should be routinely checked before rhGH treatment (if there is hypothyroidism, it is necessary to adjust thyroid function to normal, and then start rhGH treatment); fasting blood glucose, insulin, glucose tolerance, glycosylated hemoglobin detection if necessary; routine pituitary MRI detection. rhGH is contraindicated in the following cases: active tumors, active psychosis, severe obesity, uncontrolled diabetes, uncontrolled severe obstructive sleep apnea, etc. Bloom syndrome, Fanconi syndrome, Down syndrome, etc. are also associated with rhGH treatment because of the risk of tumorigenesis. Have a family history of cancer or have the following diseases: central nervous system tumors, leukemia; histiocytosis; craniopharyngioma; mixed gonadal dysplasia, familial adenomatous polyposis, neurofibromatosis, etc. with caution for rhGH treatment. 2}26 o. For severe obesity, uncontrollable weight gain, gastroesophageal reflux, poor respiratory protection, respiratory problems, especially in children with obstruction of air, should also be treated with rhGH with caution. The population should weigh the pros and cons according to the condition, and decide whether to carry out rhGH treatment under the premise of full informed consent. The vast majority of tumor recurrence occurred within the first 2 years, so patients with intracranial tumors are not recommended to undergo rhGH treatment within 2 years after radiotherapy.

In the course of rhGH treatment, in addition to the measurement of growth and development indicators, biochemical indicators should be routinely monitored: thyroid function, fasting blood glucose and insulin, IGF1 and IGFBP3 levels were monitored every 3 to 6 months. Liver and kidney function, adrenal function, glycosylated hemoglobin, and bone age are monitored annually. Pituitary magnetic resonance was reviewed in some children with organic growth hormone deficiency if necessary. At each follow-up, attention should be paid to the presence of adverse reactions.

3. Strengthening long-term follow-up of rhGH therapy and domestic database construction: In order to better monitor the safety and effectiveness of long-term rhGH treatment, the National Cooperative Growth Study (NCGS) and the Pfizer International Growth Database (the Pfizer International) have been established abroad. Growth Database, KIGS), Australia and New Zealand Growth Database (Ozgrow) and other III’26’30J, large sample and long-term data from the database provide a basis for further standardization of rhGH treatment. The Endocrine Genetics Group of the Chinese Medical Association’s Pediatrics Branch led the establishment of the Chinese rhGH treatment short patient database in 2009. The construction of the database is constantly expanding and improving, and it is expected to provide data support for the standardized treatment of Chinese short patients. Although the effectiveness and safety of rhGH therapy have been widely verified, its clinical application has strong professionalism. Prescription physicians are required to have a strong endocrine basis and clinical knowledge, and are deeply aware of the importance of strict indications, standardized treatment and monitoring for the health of children. For such highly specialized drugs, medical management institutions should strengthen the hierarchical management and gradually implement the sub-professional access system to ensure the scientific, rational, effective and safe application of drugs.

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