A RARE CASE OF GIANT EMPHYSEMATOUS BULLAE IN LEFT LUNG DUE TO ALPHA 1- ANTI-TRYPSIN DEFICIENCY

1. Surgical Oncology Resident, Aiims Bhopal, Madhya Pradesh, India. 2. General Surgery, Senior Resident, Aiims Raipur, Chhattisgarh, India. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 25 June 2020 Final Accepted: 30 July 2020 Published: August 2020


Introduction:-
Alpha-1-antitrypsin deficiency [AATD] was first reported in 1963 by Carl-BertilLaurell and Sten Eriksson who noted a link between low plasma serum levels of alpha-1-antitrypsin and symptoms of pulmonary emphysema [1]. Since these first cases were described, an understanding of the biochemical mechanisms and genetic abnormalities involved has developed [2], and alpha-1-antitrypsin deficiency is now thought to be one of the most common hereditary disorders worldwide, comparable in frequency to cystic fibrosis [3,4]. The protein alpha-1-antitrypsin is a 52 kDa molecule produced primarily in hepatocytes and released into the blood circulation by the liver [5]. The protein is present in all body tissues but appears to have its primary physiologic significance in the lungs, where it protects the healthy but fragile alveolar tissue from proteolytic damage by enzymes like neutrophil elastase [6]. Alpha-1-antitrypsin is an acute phase protein which means that production by the liver is subject to various stimuli, including inflammatory mediators induced by fever [2]. Therefore, protein levels in the circulation may vary depending on the medical condition of an individual. The normal serum concentration may range between 1.5 to 3.5 g/L (or 20 to 48 μM) [2]. Among clinicians and patients some confusion may arise about the clinical significance of deficiency in alpha-1-antitrypsin. The first cases described by Laurell and Eriksson were related to a very low serum concentration of the protein and subsequently it was discovered that these patients had a particular gene defect (defined as Z deficiency) in both alleles of the chromosome making them prone to the development of lung and liver disease. Later in time it was discovered that various other gene defects exist and most of them cause their own range of serum concentrations below the normal range [5]. A serum concentration below 0.5 g/L (11 μM) is considered a reason for further analysis. In addition, individuals who carry a genetic defect in only one allele of the chromosome (heterozygotes) may also have a reduced serum concentration. Often, when patients with emphysema are told that they are deficient of alpha1-antitrypsin, they fear that their deficiency will cause the clinical events described by Laurell and Eriksson. However, as described below, it will be explained why in contrast to heterozygous MZ type, in most cases only the homozygous Z type of deficiency, as well as some very rare Null phenotypes with absent alpha-1-antitrypsin serum levels result in clinical significant disease.

Case Presentation:
A 22 years old male presented with complaint of Breathlessness since 6 month, Pain over left chest since 4 months. Patient was chronic smoker from past 7 years and used to smoke 12 cigarettes daily.Past history suggested of Pulmonary Tuberculosis 6 years back for which he took Anti-tubercular treatment category I for 6 Months.Physical examination revealed an expiratory wheeze and fine crackles during forced expiration. Radiographically, giant thinwalled bullae were detected in left lungs, characteristic of vanishing lung syndrome [5][6][7]. Chest X-ray was suggestive of Emphysematous Bulla in left lower lung with underlaying compressed lung with mediastinal shift to right side [ FIGURE 1A]. CT chest was suggestive of middle sections of the left lungs contains gigantic bullae over ½ of hemithorax volume. Pulmonary parenchyma in lower sections is preserved, but emphysematous and Fibrotic Patch and Similar Emphysematous Bullae on right side[FIGURE 1B].Serum Alpha-1-antitrypsin level was 0.2g/L. Routine blood investigation was done and it was normal in limit. Pre operative preparation was done.Antero-lateral skin incision was taken a large Emphysematous Bullae was found and excision of that part of lung lobe was done (lobectomy) [FIGURE 2]. After operation patient was not able to maintain the SpO2 over one lung, which was also compromised hence patient kept in ICU and tracheostomy was done. Patient kept on mechanical ventilation for 12 days.Weaning off from ventilator was done gradually and under higher antibiotic coverage to avoid lung infection.Once patient got use to one lung ventilation, he was shifted to ward from ICU. ICD drain was removed on 14 TH post operative day once drain fluid become serous and 48hrs drain output was less than 100ml. After one month follow-up X-ray of left lung suggested of expansion of left lung [FIGURE 3]. After two year expanded lung with no recurrence of bullae.

Discussion:-
The lung manifestations of AAT deficiency include emphysema and chronic obstructive pulmonary disease (COPD) [8]. Emphysema usually develops by the third to fourth decade in affected individuals who smoke cigarettes and may appear in the fifth or sixth decade in individuals who have never smoked. It is currently hypothesized that two mechanisms contribute to the development of lung disease, in particular to emphysema. First, the serum level of alpha-1-antitrypsin appears to be important. It is observed that cigarette smokers who produce no alpha-1antitrypsin at all in their liver or in monocytes, defined as individuals with the very rare homozygous Null variant, develop emphysema at younger age than subjects with the homozygous Z allele related deficiency [9]. Under appropriate circumstances, cigarette smoke recruits inflammatory cells in the lung which may release proteolytic enzymes in alveolar areas. For the development of emphysema, plasma levels of alpha-1-antitrypsin are important in the protection against proteolytic damage of alveoli in the lung, in particular by neutrophil elastase activity [10,11]. Diagnosis for alpha-1-antitrypsin deficiency? First of all, all newborns with a bleeding disorder or prolonged neonatal jaundice should be tested [8]. Secondly, all individuals with a history of asthma or chronic obstructive lung disease, particularly below the age of 40 [8]. Thirdly, all siblings of index cases [8]. Finally, all individuals with unexpected liver cirrhosis should be tested [2]. With respect to lung disease, individuals should not start cigarette smoking or should stop urgently when smoking already started. This is the only available effective treatment to reduce the progression of decline in lung function. There is consensus in the scientific community on how to test, expressed in an ATS/ERS Statement on the diagnosis and treatment of alpha-1-antitrypsin deficiency [8]. This important document states that a physician should start with the detection of a serum level of alpha-1-antitrypsin. If reduced below the reference value of the laboratory, physicians should obtain a genotype or phenotype of alpha1antitrypsin. There are now commercial kits that test for presence of Z and S alleles in the gene [12]. If the serum level of alpha-1-antitrypsin is low, but the genotype test does not reveal a Z or S deficiency, isoelectric focusing of serum may reveal rare Null variants of alpha-1-antitrypsin which can be further characterized by genotyping. Once new cases of alpha-1-antitrypsin have been detected, it is recommended by the Alpha1 International Registry (AIR) [13] to contact the national representative for alpha-1-antitrypsin deficiency matters to submit the clinical phenotype of the patient to the database of AIR and to obtain a plasma sample and DNA sample for future scientific studies and potential participation of the newly detected patient in future clinical trials for new drugs. Differential diagnosis Often physicians diagnose patients with emphysema at age 30 to 40 but who have no alpha-1-antitrypsin deficiency.
There are no known other genetic deficiencies that are as strongly related with emphysema as Pi ZZ alpha-1antitrypsin deficiency. These include viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. The formation of rapidly progressing giant emphysematous bullae is often associated with COPD progression [14, [15][16][17], and if combined with a FEV1 decrease to less than 25%, may be an indication for lung transplantation [18]. Significant progressive reduction of spirometry indications and reduced exercise tolerance accompanied with dyspnea are characteristic to patients with vanishing lung syndrome (VLS). Surgical treatment is possible and effectively reduces dyspneic symptoms and significantly lowers the risk of spontaneous pneumothorax in patients with VLS [18]. Despite the associated risks of bulla recurrence, VATS bullectomy significantly improves patient respiratory function and reduces risks of serious complications associated with giant emphysematous bullae. Our case reports shows, that within a two year follow-up period it is possible that no recurrence of giant bullae manifests, which underlines the efficacy of surgical treatment of patients with VLS. VLS in patients with COPD is complicated by significant reduction in healthy lung tissue, and is often accompanied by severe respiratory function morbidity. VATS giant bulla resection should be accompanied by proper pharmacological therapy and strict respiratory exercise regimen. Surgical excision of giant bullae significantly reduce the ratio of pleural cavity to lung volume, so we recommend gradual expansion with controlled pneumoperitoneum to reduce risk of postoperative complications and spontaneous pneumothorax.

Conclusion:-
In conclusion, surgical resection of giant emphysematous bullae and appropriately prescribed therapy (drug treatment and hygiene regime) allowed us to achieve a positive effect and maintain the patient's life quality for a long time. It is important to plan a surgical intervention with compensation of lung volume reduction (controlled pneumoperitoneum, pleural cavity draining), appropriate pharmacological therapy and respiratory exercises to maintain the positive effect of VLS treatment.