Analyzing Hereditary Angioedema as a Regulatory Professional - Report Example

Name Institution Course Instructor Date of Submission Hereditary Angioedema (HAE) Introduction From regulatory professional perspective, there is need for drug development Hereditary Angioedema (HAE); despite it not being a common disease worldwide.HAE is a rare genetic condition and is a potential life threat. Its main presenting features are recurring episodes of well demarcated edema which is often not accompanied by urticaria. Itcommonly attacks the skin (on the hands, legs, face or even the whole body), or the mucous tissues of the digestive system, and upper respiratory tract. Smeltzer, et.al, reveals that Edema of the larynx causes fatal asphyxia, and the pain due to gastrointestinal attack can be debilitating. There are three types of HAE, these are HAE types I and II and type III (p.1879). Patients experience the attacks very early in life and the symptoms continue for an entire lifetime. The individuals who suffer from these attacks end up having a reduced quality of life, as the disease interferes with their routine duties as well as education and careers. If the disease is not treated well or is left untreated it can be lead to death. As am matter of facts prior to introduction of any therapy to deal with the disease, the mortality rate related to airway obstruction was as high as 30% (Agarwal & Agarwal, 546-555). Signs and Symptoms HAE have the wide-ranging variability in disease manifestation. The progress of the disease is much diversified and not predictable even within a single patient within their life time. Some common physically manifested symptoms of the disease are overt swellings which are not inflamed on the skin and the mucous membranes. In about 25% of the patients erythema may appear prior to the occurrence of edema. In a fraction of patients the edema may be severe and may be accompanied by pressure vesicles or bullae (Smeltzer, et.al, 1879). The most commonly affected sites are: the subcutaneous tissues, the abdominal organs and the upper respiratory system.In Airway angioedema, one may start by experiencing an impression of throat swelling, there may also be some changes in voice quality, difficulty in swallowing (even saliva), and difficulty in breathing. Airway angioedema progresses within hours. The subcutaneous tissues are inclusive of the forearms, hind arms, face, buttocks and genital area; the abdominal organs which include the stomach, intestines, the bladder and the kidney. In this case the patient presents with vomiting, diarrhea, spasmodic colicky pain, which can very easily be confused for surgical abdomen. Symptoms that affect the laryngeal area as well as the tongue result to upper airway obstruction. Natural History of Hereditaryangioedema The disease is termed as hereditary because it is passed on from one generation to another within an affected family linage. Statistics show that an individual born within a family where the one of the parents has the disease, he/she has 50% chances of inheriting the disease form the affected parent. Scientists also say that the absence of the diseases cannot be used as a criterion for ruling out the disease during diagnosis). 5% of HAE carriers do not present with any symptoms and are only identified when their children present with the symptoms. Scientists also report that 20% of HAE cases are patients who have undergone spontaneous mutation of C1-Inhibitor gene during conception. This potentiates them to pass the defective genes to their progenies. Owing to its rare occurrence, it is very common for a patient to remain with the disease without it being diagnosed for many years. Many patients who have been diagnosed to have it report that due to severe unrelenting abdominal pains, they were sent for psychiatric review after being diagnosed inappropriately as having psychosomatic disorder. On the other hands others report having to undergo exploratory surgery due to the gastrointestinal. HAE abdominals attacks are similar to surgical abdomen. Moreover, others have been misdiagnosed as having allergic reactions. Prior to introduction of any therapy to deal with the disease, the mortality rate related to airway obstruction was as high as 30 % (Agarwal & Agarwal, 546-547). Affected patients show different symptoms of HAE I and IIwithin the first or second decade of their lives, and HAE III during the third decade of their life and there ahead. A patient with HAE attack can have a varying number of symptoms over different timescale. At least45% of those with HAE I & II experience their first HAE attack before celebrating their 5th birthday while 75% present with symptoms by 15 years of age. The incidence of the attacks heightens during puberty, and they continue for the entire lifespan. Some people have reported decreased symptoms as age goes by. In an average individual who is not under any treatment, they get an attack within every 7-14 days (Agarwal & Agarwal, 546-550).There are many things which can provoke the attacks to start. Some of these include very vigorous exercise, taking alcohol, high levels of estrogen within the body, oral contraceptives. The Incidence and Prevalence of HAE in the U.S.A Information on the epidemiology of HAE is very scares. However some sources say that the incidence is one person in every 10,000-50,000 people in the United States. It accounts for an approximate of 2% of all clinical angioedema cases in the U.S.A .Data from different hospitals in the United States of America show that HAE lead to 15,000-30,000 visits to the emergency department per year. The mortality rate is predicted at 15–33%, which is mainly as a result of asphyxia related to laryngeal edema (Smeltzer, et.al, 1879). HAE affects people from all races indiscriminately. There are no reported biases in different races or ethnic groups. It is normally present during birth. Sex is also not a predisposing factor as the disease affects both female and male. However, the attacks are more severe in women. Initially, it used to be thought HAE Type III only affected women, however with recent studies of different families it has come out clearly that it can affect both the female and male, though it is more dominant in women. The symptoms may not be seen clearly during the childhood stage of life but as one goes towards puberty they become more clear and evident. Pathophysiology The main cause of HAE is mutation of C1-INH gene or SERPING1 gene. The gene is responsible for regulating amounts of C1 inhibitor (a blood protein). The defective gene is acquired through autosomal dominant inheritance. The defect affects chromosome 11(11q12-q13.1). In most patients there is a family history of the diseases and only 25% of cases have newly detected mutation. In general, an approximate of 150 different mutations has been identified in HAE. In addition, some reports show a mutation rate of 25%. The defect leads to either inadequate level of CI inhibitor or in the production of malfunctional CI inhibitor (Agarwal & Agarwal, 546-547). As a result of low levels of CI inhibitor in the blood, there is activation of the bradykinin releasing pathway. Increased levels of bardykinin lead to increased vascular permeability and pain in the patient; the edema is due to increased vascular permeability, which allows the capillaries to release fluids to the tissues around them. There are two variations of HAE which are associated to C1-INH function, namely type I and type II. Type I accounts for 85% of all C1-INH function related mutation while type II accounts for the remaining 25%. Type I is related to mutation occurring in the entire gene, leading to either curtailed or a protein which is not well folded. The protein is not secreted in an efficient manner and thereby leading to low levels of C1-INH protein. There may be some normal alleles in this case, but more than 50% of the total proteins are malfunctional. Researches have shown than even when the levels of normal C1-INH is a half, they are not sufficient enough to counter the attacks of angioedema (Agarwal & Agarwal, 548). Type II HAE is related to mutation of the active site of exon 8.this leads to production of dysfunctional proteins. In patients with type II there are either normal or elevated amounts of dysfunctional C1-INH proteins and low levels of functional C1-INH proteins. Due to deficiency of this protein there is auto activation of the bardykinin releasing pathway. In Type III, C1-INH proteins are in sufficient amounts, and their functionality is normal. It is related to mutation during the coding of F12 gene for factor XII. This leads to inappropriate activation of the bradykinin cascade (Agarwal & Agarwal, 546). Diagnosis As evident from the presenting symptoms it is clearly difficult to diagnose HAE basing on the presenting symptoms only. This is because they tend to vary from patient to patient and within patient from time to time. In addition the symptoms may be similar to those experienced in allergic conditions or in other medical or surgical disorders. It is also clear that misdiagnosis of HAE can have very serious consequences such as doing unnecessary exploratory surgeries, referring patient for psychiatric review as well as treating patients with the wrong medications. This is likely to increase the mortality rate of people suffering from the disease (Smeltzer, et.al, 1879). A patient should be suspected to have HAE in case they presents with recurring angioedema (in absence of urticarial), in case they have recurring incidents of abdominal pain and/or vomiting, in case they have several incidences of laryngeal edema and incase there is an already identified family history of angioedema. Other than basing the diagnosis on family history or the symptoms, it is imperative to carry out a blood test. The blood test should ideally be taken during an attack episode. To differentiate the three types of HAE, one can do a complement test (Agarwal & Agarwal, 547). The components measured in the blood include the levels of CI inhibitor (C1-INH) protein, complement factor 4(C4), CI functionality testIn case the patient is suffering from type I HAE, it will recognized that there will be low levels of C1-INH, C2 and C1 and normal levels of C1q.In case of type II HAE, the levels of C1-INH are either normal or elevated but are dysfunctional. The C1q levels are within normal levels and the C4 and C2 levels are low. In type III HAE, there are normal levels of C1-INH and C4 and the functional assay of the C1-INH protein may be normal. However, mutation is recognized in the factor XII (Agarwal & Agarwal, 547). Imaging studies may also be necessary for the diagnosis of HAE. Some of them which can be helpful in the diagnosis of HAE include abdominal radiotherapy.In case of gastrointestinal edema one the radiography may demonstrate ileus. A chestx-ray can also help in the diagnosis. A chest x-ray demonstrates pleural effusion. An abdominal ultrasonography may also be necessary. In case of HAE it will show some edematous thickening of the intestinal wall, a layer of fluid surrounding the bowel and in some circumstances some free peritoneal fluid may be evident. Treatment of HAE Medications which are approved by FDA for the treatment of the symptoms of HAE were available in the U.S.A in the year 2008.Some of the treatments which have been approved in the U.S.A. Food and Drug Administration (FDA) for the management of HAE include Icatibant (Firazyr), which is antagonist working selectively on the bradykinin receptors. It was approved by FDA in the year 2011. Cinryze is another drug which was approved in the year 2008. Berinert, which is a C1-INH concentrate, was approved in 2009 Sept. for management of facial edema and in 2012 it was also approved for the management of laryngeal edema. Ecallantide (Kalbitor) was approved in December 2009 in treating patients aged 16 years and above. It is a kallikrein inhibitor and plays an important role in regulating the edema (Agarwal & Agarwal, 546-555). HAE treatment comprises prophylactic treatment and treatment of acute attack Prophylactic therapy, can either be long-term or short term. Before beginning the prophylaxis treatment it is important to do screening. All the family members of a person suffering from HAEI/II should be screened so that an early diagnosis can be made and timely treatment initiated. Children below 12 months should not be screened. Their screening should be deferred until they attain the age of 12 months. Short term prophylaxis is usually given prior to a surgical or dental procedure. C1-INH concentrate is usually used in this case. In case it is absent, and then androgen is administered in high doses for five to seven days. Long-term prophylaxis treatment is normally used in patients who experience an attack at least once in a week. Attenuated androgens are used during the initial treatment. The most commonly utilized androgen is danazol. However it has serious adverse effects and therefore the therapy should be done keenly. In the U.S.A, kallikrein inhibitors (Ecallantide, Kalbitor®, and Dyax) are preferred to danzol due to the adverse effects of danazol. There are also some commercially available C1-INH concentrates for prophylaxis treatment (Agarwal & Agarwal, 550-554). Before an individual begins the long-term therapy using androgens, it is imperative to be assessed for cardiac risk factor as well as to be done a complete blood count. It is also imperative to be done a urine analysis, liver function test and liver ultrasonography. The same examinations should be repeated at least every 6 months. These tests are important as they monitor complications of the liver and kidney which could due to the therapy (Agarwal & Agarwal, 554). Treating Acute Attacks   Attacks by HAE involving the respiratory system can be life threatening as compared to those affecting the gastrointestinal system or the skin. In most cases attacks involving the gastrointestinal system resolve by themselves within 3-4 days. Coetaneous attacks also have a less mortality rate but it interferes with individual’s routine duties if the frequency of attack is high. In case a patient has developed hypotension due to accumulation of fluid in the extravascular space, then the patient has to be given intravenous fluid replacement in order to maintain in the body fluid balance. However, the best approach towards treating HAE depends to a large extend with the type of attack one is suffering from (Agarwal & Agarwal, 546-555). Laryngeal Attacks It is clear from the presentation of laryngeal attack, that it is the most dangerous type of attack due to the risk of asphyxiation; from the blockage of airway. The priority step in management of a patient suffering laryngeal angioedema is the assessment and management of the upper airway. The edema may lead to distortion of the anatomy of the upper airway and hence making it difficult to intubate the patient, however, the airway must be managed, be it through endotracheal intubation or through a tracheostomy. This is because even if the patient is covered with HAE treatment, they may take some time before relieving the symptoms (Agarwal & Agarwal, 550-553). After the patient has stabilized, then additional therapies are considered. The patient should be managed in an intensive care unit and be monitored frequently till they are fully stable. The firstling pharmacological therapy for such a patient can be aC1-inhibitor product, icatibant, or ecallantide. Alternatively the patient can be treated with fresh frozen plasma or even detergent treated plasma (Agarwal & Agarwal, 550-553) Gastrointestinal Attacks Though in most cases gastrointestinal attack resolves by itself, at times treatment may be necessary. The first line therapy includes C1-inhibitor product, icatibant, or ecallantide. The clinical response to this first line therapy should be within the first two hours. In case it does not respond to the treatment within the first two hours then one can suspect other abdominal pathologies (Agarwal & Agarwal, 552). In case the first line therapies are not available, then supportive management of the patient is done. Fresh frozen plasma can be administered. Dehydration and pain management; Rehydration can be done using normal saline, and pain managed through diclofenac 100mg orally or tramadol 50 mg. Parenteral narcotics e.g. meperidine, can also be administered in case of severe pain. For nausea and vomiting metoclopramide or prochlorperazine, can be administered (Agarwal & Agarwal, 553). Cutaneous Attacks Acute cutaneous attacks in most cases are self-regulatory and resolve within 5 to ten days. However in cases where he attacks are severe and disfiguring the treatment is similar to that of gastrointestinal attack. Unapproved treatments ACE inhibitors are unacceptable in the treatment of HAE. This is because they aggravate accumulation of bradykinin and hence precipitating the HAE attacks. The World allergic organization also disapproves the use of oral antifibrinolytics as an on-demand medication. During the management of gynecological or obstetric conditions in a woman with HAE, estrogen is contraindicated (Agarwal & Agarwal, 550-552). After every attack, the patient should be assessed to determine the trigger to the attack. The commonly experienced triggers for patients under therapy are missed dosage of medication, taking of medications which interfere with the HAE drug or interference by narcotics. After identifying the cause the patient should be advised on how to avoid reputation of the same mistakes (Agarwal & Agarwal 555). Works Cited Brunner, Lillian S, Doris S. Suddarth, and Suzanne C. O. C. Smeltzer. Brunner & Suddarth's Textbook of Medical-Surgical Nursing. Philadelphia: Lippincott Williams & Wilkins, 2008. Print. Hemperly, SE, NS Agarwal, YY Xu, YX Zhi, and TJ Craig. "Recent Advances in the Management of Hereditary Angioedema." The Journal of the American Osteopathic Association. 113.7 (2013): 546-55. Print. Read More