History

Fact Explanation
Positive family history This is an autosomal-dominantly inherited condition. Obstructive pulmonary disease and liver disease are common in these people. The etiology is due to the genetic alteration of the alpha1-antitrypsin molecule which is a protein produced in the liver. Because of the defect in the protein it doesn't get released from the liver and the serum alpha1-antitrypsin level gets decreased. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Yellowish discoloration of the skin, sclera, increased bleeding tendency for than 14 days after birth in neonates [8] [13] This is a cause for prolonged neonatal neonatal jaundice as it causes neonatal hepatitis. Due to the genetic alteration of the alpha1-antitrypsin molecule which is a protein produced in the liver. Because of the defect in the protein it doesn't get released from the liver The accumulation of excess alpha1-antitrypsin in liver causes destruction of liver cells and ultimately clinical liver disease. [8] [13]
Yellowish discoloration of the skin, sclera [1] [2] [3] [4] [5] [6] [8] [9] Due to the genetic alteration of the alpha1-antitrypsin molecule which is a protein produced in the liver. Because of the defect in the protein it doesn't get released from the liver. The accumulation of excess alpha1-antitrypsin in liver causes destruction of liver cells and ultimately clinical liver disease which manifests in children as hepatic cirrhosis or liver failure, and in adults as chronic liver disease in the 5th decade of life. Yellowish discoloration of the skin and sclera is due to deposition of excess bilirubin which is usually excreted by the liver under the skin and sclera. [1] [2] [3] [4] [5] [6] [8] [9]
Ankle swelling [1] [2] [3] [4] [5] [6] [8] [9] As there's liver failure, this results in increased fluid accumulation in the body. Reduced albumin production by the liver, which causes reduced oncotic pressure, Increased hydrostatic pressure at the venule end due to portal hypertension, are some of the contributory factors for this extravasation of fluid. [1] [2] [3] [4] [5] [6] [8] [9]
Abdominal swelling [1] [2] [3] [4] [5] [6] [8] [9] As there's liver failure, this results in increased fluid accumulation in the abdominal cavity. Reduced albumin production by the liver, which causes reduced oncotic pressure, Increased hydrostatic pressure at the venule end due to portal hypertension, are some of the contributory factors for this extravasation of fluid. [1] [2] [3] [4] [5] [6] [8] [9]
Increased bleeding tendency [1] [2] [3] [4] [5] [6] [8] [9] [10] [11][12] As there's liver failure, there's reduced production of clotting factors as well as vitamin K deficiency causing increased bleeding tendency. [1] [2] [3] [4] [5] [6] [8] [9] [10] [11][12]
Hematemesis [1] [2] [3] [4] [5] [6] [8] [9] [10] [11][12] This is due to oesophageal varices which are opened up porto-systemic anastomosis due to portal hypertension. [1] [2] [3] [4] [5] [6] [8] [9] [10] [11][12]
Alteration in the level of consciousness, Day time sleepiness [1] [2] [3] [4] [5] [6] [8] [9] [10] These are symptoms of hepatic encephalopathy. This is due to altered balance of neurotransmitters in the brain particularly Ammonia. [1] [2] [3] [4] [5] [6] [8] [9] [10]
Cough with sputum production, and wheezing [1] [2] [3] [4] [5] [6] [7] This is seen commonly in patients with alpha-1-Anti trypsin deficiency. Due to the genetic alteration of the alpha1-antitrypsin molecule which is a protein produced in the liver. Because of the defect in the protein it doesn't get released from the liver leading to reduced level of alpha-1-anti Trypsin in the blood. Therefore the protein normally seen in the alveoli of lungs is also decreased. The role of this molecule in the lung is to protect against neutrophil elastase which is a protease. These high levels of proteases can cause proteolytic destruction of alveolar walls and causes emphysema. The appearance of emphysema symptoms in smokers is earlier than in non smokers. [1] [2] [3] [4] [5] [6] [7]
Dyspnea [1] [2] [3] [4] [5] [6] [7] This symptom results from air way obstruction due to emphysema. As the appearance of emphysema symptoms in smokers is earlier than in non smokers this is also seen earlier in non smokers. [1] [2] [3] [4] [5] [6] [7]
References
  1. FREGONESE LAURA, STOLK JAN. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Array [online] 2008 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-3-16
  2. CURIEL D, BRANTLY M, CURIEL E, STIER L, CRYSTAL R G. Alpha 1-antitrypsin deficiency caused by the alpha 1-antitrypsin Nullmattawa gene. An insertion mutation rendering the alpha 1-antitrypsin gene incapable of producing alpha 1-antitrypsin.. J. Clin. Invest. [online] 1989 April, 83(4):1144-1152 [viewed 31 August 2014] Available from: doi:10.1172/JCI113994
  3. STOCKLEY R A. Alpha-1-antitrypsin deficiency: what next?. [online] 2000 July, 55(7):614-618 [viewed 31 August 2014] Available from: doi:10.1136/thorax.55.7.614
  4. RINGENBACH MICHAEL R, BANTA ERIN, SNYDER MELISSA R, CRAIG TIMOTHY J, ISHMAEL FAOUD T. A challenging diagnosis of alpha-1-antitrypsin deficiency: identification of a patient with a novel F/Null phenotype. Array [online] 2011 December [viewed 31 August 2014] Available from: doi:10.1186/1710-1492-7-18
  5. TANASH HANAN A, NILSSON PETER M, NILSSON JAN-ÅKE, PIITULAINEN EEVA. Survival in severe alpha-1-antitrypsin deficiency (PiZZ). Array [online] 2010 December [viewed 31 August 2014] Available from: doi:10.1186/1465-9921-11-44
  6. MAHADEVA R., LOMAS D. A. Genetics and respiratory disease bullet 2: Alpha1-antitrypsin deficiency, cirrhosis and emphysema. Thorax [online] 1998 June, 53(6):501-505 [viewed 31 August 2014] Available from: doi:10.1136/thx.53.6.501
  7. LEE P., GILDEA T. R, STOLLER J. K. Emphysema in nonsmokers: alpha 1-antitrypsin deficiency and other causes.. Cleveland Clinic Journal of Medicine [online] 2002 December, 69(12):928-929 [viewed 31 August 2014] Available from: doi:10.3949/ccjm.69.12.928
  8. SCORZA MANUELA, ELCE AUSILIA, ZARRILLI FEDERICA, LIGUORI RENATO, AMATO FELICE, CASTALDO GIUSEPPE. Genetic Diseases That Predispose to Early Liver Cirrhosis. International Journal of Hepatology [online] 2014 December, 2014:1-11 [viewed 31 August 2014] Available from: doi:10.1155/2014/713754
  9. TOPIC ALEKSANDRA, LJUJIC MILA, RADOJKOVIC DRAGICA. Alpha 1 Antitrypsin in Pathogenesis of Hepatocellular Carcinoma. Hepat Mon [online] 2012 October [viewed 31 August 2014] Available from: doi:10.5812/hepatmon.7042
  10. FIGUEIREDO ANTONIO, ROMERO-BERMEJO FRANCISCO, PERDIGOTO RUI, MARCELINO PAULO. The End-Organ Impairment in Liver Cirrhosis: Appointments for Critical Care. Critical Care Research and Practice [online] 2012 December, 2012:1-13 [viewed 31 August 2014] Available from: doi:10.1155/2012/539412
  11. BIECKER ERWIN. Gastrointestinal Bleeding in Cirrhotic Patients with Portal Hypertension. ISRN Hepatology [online] 2013 December, 2013:1-20 [viewed 31 August 2014] Available from: doi:10.1155/2013/541836
  12. MCKAY R., WEBSTER N. R. Variceal bleeding. Continuing Education in Anaesthesia, Critical Care & Pain [online] 2007 December, 7(6):191-194 [viewed 31 August 2014] Available from: doi:10.1093/bjaceaccp/mkm038
  13. BURTON B. K.. Inborn Errors of Metabolism in Infancy: A Guide to Diagnosis. PEDIATRICS [online] 1998 December, 102(6):e69-e69 [viewed 31 August 2014] Available from: doi:10.1542/peds.102.6.e69

Examination

Fact Explanation
Tachypnea [1] [2] [3] [4] [5] [6] [7] This is due to the genetic alteration of the alpha1-antitrypsin molecule which is a protein produced in the liver. Because of the defect in the protein it doesn't get released from the liver leading to reduced level of alpha-1-anti Trypsin in the blood. Therefore the protein normally seen in the alveoli of lungs is also decreased. The role of this molecule in the lung is to protect against neutrophil elastase which is a protease. These high levels of proteases can cause proteolytic destruction of alveolar walls and causes emphysema and increases respiratory work causes increases respiratory rate. [1] [2] [3] [4] [5] [6] [7]
Accessory muscles used in respiration [1] [2] [3] [4] [5] [6] [7] This is also due to increased respiratory work due to emphysema. Accessory muscles such as scalene, sternocleidomastoid and intercostal muscle retraction is seen [1] [2] [3] [4] [5] [6] [7]
Pursed-lip breathing [1] [2] [3] [4] [5] [6] [7] Emphysema results in air flow obstruction [1] [2] [3] [4] [5] [6] [7]
Rhonchi on auscultation [1] [2] [3] [4] [5] [6] [7] This is also due to air flow obstruction due to emphysema [1] [2] [3] [4] [5] [6] [7]
Pulsus paradoxus. [1] [2] [3] [4] [5] [6] [7] This is also due to air flow obstruction due to emphysema which results in increased fall (>10 mmHg) in systolic blood pressure and pulse wave amplitude during inspiration [1] [2] [3] [4] [5] [6] [7]
Barrel chest [1] [2] [3] [4] [5] [6] [7] Patients with milder forms will not exhibit this sign but chronic emphysema causes hyperinflation of the chest and results in barrel shaped chest [1] [2] [3] [4] [5] [6] [7]
Increased resonance percussion note [1] [2] [3] [4] [5] [6] [7] Hyperinflation results in increased percussion note on percussion [1] [2] [3] [4] [5] [6] [7]
Decreased breath sound [1] [2] [3] [4] [5] [6] [7] Hyperinflation results in this [1] [2] [3] [4] [5] [6] [7]
Distant heart sounds. [1] [2] [3] [4] [5] [6] [7] As lungs are hyperinflated, this obscures the heart and heart sounds are barely audible. [1] [2] [3] [4] [5] [6] [7]
Yellowish discoluration of skin and sclera [1] [2] [3] [4] [5] [6] [8] [9] [10] [11] Due to the genetic alteration of the alpha1-antitrypsin molecule which is a protein produced in the liver. Because of the defect in the protein it doesn't get released from the liver. The accumulation of excess alpha1-antitrypsin in liver causes destruction of liver cells and ultimately clinical liver disease which manifests in children as hepatic cirrhosis or liver failure, and in adults as chronic liver disease in the 5th decade of life. Yellowish discoloration of the skin and sclera is due to deposition of excess bilirubin which is usually excreted by the liver under the skin and sclera. . [1] [2] [3] [4] [5] [6] [8] [9] [10] [11]
Hepatomegaly [1] [2] [3] [4] [5] [6] [8] [9] [10] [11] There's enlargement of the liver in the initial phase of cirrhosis even though later it gets shrunken [1] [2] [3] [4] [5] [6] [8] [9] [10] [11]
Spider naevi [1] [2] [3] [4] [5] [6] [8] [9] [10] [11] These are thought to be due to altered oestrogen metabolism in liver failure. [1] [2] [3] [4] [5] [6] [8] [9] [10] [11]
Petechiae [1] [2] [3] [4] [5] [6] [8] [9] [10] [11] As there's liver failure, there's reduced platelets results in petechiae [1] [2] [3] [4] [5] [6] [8] [9] [10] [11]
Bilateral pitting ankle odema [1] [2] [3] [4] [5] [6] [8] [9] [10] [11] As there's liver failure, this results in increased fluid accumulation in the body. Reduced albumin production by the liver, which causes reduced oncotic pressure, Increased hydrostatic pressure at the venule end due to portal hypertension, are some of the contributory factors for this extravasation of fluid. [1] [2] [3] [4] [5] [6] [8] [9] [10] [11]
Ascitis [1] [2] [3] [4] [5] [6] [8] [9] [10] [11] As there's liver failure, this results in increased fluid accumulation in the abdominal cavity. Reduced albumin production by the liver, which causes reduced oncotic pressure, Increased hydrostatic pressure at the venule end due to portal hypertension, are some of the contributory factors for this extravasation of fluid. [1] [2] [3] [4] [5] [6] [8] [9] [10] [11]
Gynaecomastia, Shrunken testicles [1] [2] [3] [4] [5] [6] [8] [9] [10] [11] These are thought to be due to altered oestrogen metabolism ans accumulation of oestrogen in the body due to liver failure. [1] [2] [3] [4] [5] [6] [8] [9] [10] [11]
Caput medusae [1] [2] [3] [4] [5] [6] [8] [9] [10] [11] These are dilated veins around the umbilicus which is due to portal hypertension resulting in opening up of porto-systemic shunts. [1] [2] [3] [4] [5] [6] [8] [9] [10] [11]
Flapping tremors, Asterixis [1] [2] [3] [4] [5] [6] [8] [9] [10] [11] These are symptoms of hepatic encephalopathy. This is due to altered balance of neurotransmitters in the brain particularly Ammonia. [1] [2] [3] [4] [5] [6] [8] [9] [10] [11]
Reduced level of consciousness [1] [2] [3] [4] [5] [6] [8] [9] [10] [11] These are symptoms of hepatic encephalopathy. This is due to altered balance of neurotransmitters in the brain particularly Ammonia. [1] [2] [3] [4] [5] [6] [8] [9] [10] [11]
References
  1. FREGONESE LAURA, STOLK JAN. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Array [online] 2008 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-3-16
  2. CURIEL D, BRANTLY M, CURIEL E, STIER L, CRYSTAL R G. Alpha 1-antitrypsin deficiency caused by the alpha 1-antitrypsin Nullmattawa gene. An insertion mutation rendering the alpha 1-antitrypsin gene incapable of producing alpha 1-antitrypsin.. J. Clin. Invest. [online] 1989 April, 83(4):1144-1152 [viewed 31 August 2014] Available from: doi:10.1172/JCI113994
  3. STOCKLEY R A. Alpha-1-antitrypsin deficiency: what next?. [online] 2000 July, 55(7):614-618 [viewed 31 August 2014] Available from: doi:10.1136/thorax.55.7.614
  4. RINGENBACH MICHAEL R, BANTA ERIN, SNYDER MELISSA R, CRAIG TIMOTHY J, ISHMAEL FAOUD T. A challenging diagnosis of alpha-1-antitrypsin deficiency: identification of a patient with a novel F/Null phenotype. Array [online] 2011 December [viewed 31 August 2014] Available from: doi:10.1186/1710-1492-7-18
  5. TANASH HANAN A, NILSSON PETER M, NILSSON JAN-ÅKE, PIITULAINEN EEVA. Survival in severe alpha-1-antitrypsin deficiency (PiZZ). Array [online] 2010 December [viewed 31 August 2014] Available from: doi:10.1186/1465-9921-11-44
  6. MAHADEVA R., LOMAS D. A. Genetics and respiratory disease bullet 2: Alpha1-antitrypsin deficiency, cirrhosis and emphysema. Thorax [online] 1998 June, 53(6):501-505 [viewed 31 August 2014] Available from: doi:10.1136/thx.53.6.501
  7. LEE P., GILDEA T. R, STOLLER J. K. Emphysema in nonsmokers: alpha 1-antitrypsin deficiency and other causes.. Cleveland Clinic Journal of Medicine [online] 2002 December, 69(12):928-929 [viewed 31 August 2014] Available from: doi:10.3949/ccjm.69.12.928
  8. SCORZA MANUELA, ELCE AUSILIA, ZARRILLI FEDERICA, LIGUORI RENATO, AMATO FELICE, CASTALDO GIUSEPPE. Genetic Diseases That Predispose to Early Liver Cirrhosis. International Journal of Hepatology [online] 2014 December, 2014:1-11 [viewed 31 August 2014] Available from: doi:10.1155/2014/713754
  9. TOPIC ALEKSANDRA, LJUJIC MILA, RADOJKOVIC DRAGICA. Alpha 1 Antitrypsin in Pathogenesis of Hepatocellular Carcinoma. Hepat Mon [online] 2012 October [viewed 31 August 2014] Available from: doi:10.5812/hepatmon.7042
  10. FIGUEIREDO ANTONIO, ROMERO-BERMEJO FRANCISCO, PERDIGOTO RUI, MARCELINO PAULO. The End-Organ Impairment in Liver Cirrhosis: Appointments for Critical Care. Critical Care Research and Practice [online] 2012 December, 2012:1-13 [viewed 31 August 2014] Available from: doi:10.1155/2012/539412
  11. BIECKER ERWIN. Gastrointestinal Bleeding in Cirrhotic Patients with Portal Hypertension. ISRN Hepatology [online] 2013 December, 2013:1-20 [viewed 31 August 2014] Available from: doi:10.1155/2013/541836

Differential Diagnoses

Fact Explanation
Chronic Obstructive Pulmonary Disease [2] [3] Chronic obstructive pulmonary disease (COPD) includes both chronic bronchitis and emphysema. Emphysema is permanent enlargement of the alveoli distal to the terminal bronchioles with destruction of bronchiolar walls. Fibrosis may either be present or absent. [2] [3]
Bronchiectasis [4] [5] Bronchiectasis is usually due to infections which causes distortion of bronchioles with dilatation and tortuosity. Cough with mucopurulent sputum with a bad odour, classically referred as fishy smelling is seen. It also causes shortness of breath, pleuritic type of chest pain, wheezing, fever and over the time they get wasted due to increased catabolism in the body. [4] [5]
Cystic Fibrosis [6] This is a systemic disease which is inherited as Autosomal recessive fashion. A protein called cystic fibrosis transmembrane conductance regulator (CFTR) protein is needed to regulate the exocrine secretions including, sweat, digestive fluids, and mucus. A genetic defect is seen in this protein. Commonly lung symptoms are seen also problems in pancreatic secretions. [6]
Kartagener Syndrome [7] This is also known as primary ciliary dyskinesia (PCD), and it's rare autosomal recessive genetic disease. It causes a defect in the ciliary action of the respiratory tract. Patients have chronic respiratory tract infections due to defective action of cilia. [7]
Viral Hepatitis [9] Commonly caused by hepatitis A virus, hepatitis B virus, and hepatitis C virus. Also Hepatitis D, E are responsible rarely. Acute viral hepatitis causes liver dysfunction with jaundice, nausea, abdominal pain, and malaise [9]
Autoimmune Hepatitis [8] Autoimmune hepatitis as the name implies is an autoimmune disease which can end up in liver cirrhosis due to ongoing hepatic inflammation. Young women are affected more but can occur at any age [8]
Other types of Chronic liver cell disease [10] Alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis, hemochromatosis, Wilson disease are some of other causes which result in chronic liver cell disease and ultimate liver failure. [10]
Inborn errors of metabolism causing prolonged jaundice [1] These usually present in the newborn period but symptoms and signs can appear at any age. Galactossemia, Tyrosinaemia (Type I) are several inborn errors metabolism causing prolonged jaundice. [1]
References
  1. BURTON B. K.. Inborn Errors of Metabolism in Infancy: A Guide to Diagnosis. PEDIATRICS [online] 1998 December, 102(6):e69-e69 [viewed 31 August 2014] Available from: doi:10.1542/peds.102.6.e69
  2. MACNEE W. Chronic obstructive pulmonary disease * 7: Management of COPD. [online] 2003 March, 58(3):261-265 [viewed 31 August 2014] Available from: doi:10.1136/thorax.58.3.261
  3. MAPEL DOUGLAS W, DUTRO MICHAEL P, MARTON JENő P, WOODRUFF KIMBERLY, MAKE BARRY. Identifying and characterizing COPD patients in US managed care. A retrospective, cross-sectional analysis of administrative claims data. Array [online] 2011 December [viewed 31 August 2014] Available from: doi:10.1186/1472-6963-11-43
  4. NEVES P. C., GUERRA M., PONCE P., MIRANDA J., VOUGA L.. Non-cystic fibrosis bronchiectasis. Interactive CardioVascular and Thoracic Surgery [online] December, 13(6):619-625 [viewed 31 August 2014] Available from: doi:10.1510/icvts.2011.284208
  5. CANTIN LUCE, BANKIER ALEXANDER A., EISENBERG RONALD L.. Bronchiectasis. American Journal of Roentgenology [online] 2009 September, 193(3):W158-W171 [viewed 31 August 2014] Available from: doi:10.2214/AJR.09.3053
  6. FLUME PATRICK A, VAN DEVANTER DONALD R. State of progress in treating cystic fibrosis respiratory disease. Array [online] 2012 December [viewed 31 August 2014] Available from: doi:10.1186/1741-7015-10-88
  7. MCMANUS I, MITCHISON HANNAH M, CHUNG EDDIE MK, STUBBINGS GEORGINA F, MARTIN NAOMI. . BMC Pulm Med [online] 2003 December [viewed 31 August 2014] Available from: doi:10.1186/1471-2466-3-4
  8. MAKOL ASHIMA, WATT KYMBERLY D., CHOWDHARY VAIDEHI R.. Autoimmune Hepatitis: A Review of Current Diagnosis and Treatment. Hepatitis Research and Treatment [online] 2011 December, 2011:1-11 [viewed 31 August 2014] Available from: doi:10.1155/2011/390916
  9. ERICSSON C. D., ZUCKERMAN J. N., CONNOR B. A., VON SONNENBURG F.. Hepatitis A and B Booster Recommendations: Implications for Travelers. Clinical Infectious Diseases [online] 2005 October, 41(7):1020-1026 [viewed 31 August 2014] Available from: doi:10.1086/433182
  10. WALSH K.. Alcoholic liver disease. [online] 2000 May, 76(895):280-286 [viewed 31 August 2014] Available from: doi:10.1136/pmj.76.895.280

Investigations - for Diagnosis

Fact Explanation
Serum alpha1-antitrypsin level [1] [2] [3] This test is done for the daignostic purpose as well as to assess the severity of the disease. [1] [2] [3]
Phenotyping [1] [3] [4] [5] [6] [7] Phenotyping is the confirmatory investigation and done by isoelectric focusing (IEF) and mainly done in patients whose serum levels are inconclusive. [1] [3] [4] [5] [6] [7]
Functional assay of alpha1-antiprotease [1] [2] [3] When serum level test results are normal, but still symptoms are seen, this test is carried out. The basis of this is to assess the ability of patient's serum to inhibit human leukocyte elastase. [1] [2] [3]
Molecular diagnosis (Genotyping) [1] [3] [4] [5] [6] [7] DNA amplification techniques are used to get the molecular diagnosis [1] [3] [4] [5] [6] [7]
Liver function tests [1] [2][3] Liver function tests are important as these patients are likely to have liver disease [1] [2][3]
Pro thrombin time and international normalized ratio [1] [2][3] PT-INR is done as they have liver disease [1] [2][3]
Chest radiography [1] [10] [11] In a chest x-ray hyperlucency is appreciated but some areas can be affected more than others. As normal vasculature is not seen these hyperlucent areas are also oligemic [1] [10] [11]
High-resolution CT scanning- Chest [1] [10] [11] Loss of lung tissue causes hypoattenuation also number and the size of pulmonary vessels are low. [1] [10] [11]
CT of abdomen [1] [10] This can show hepatomegaly or changes associated with cirrhosis and also hepatocellular carcinoma [1] [10]
Lung function tests [8] [9] Spirometry is carried out to measure forced vital capacity (FVC) and forced expired volume per 1 second (FEV1) to evaluate a patient with respiratory symptoms. Determination of lung volume, diffusing capacity is also done.[8] [9]
Lung biopsy [1] [11] [12] Permanent enlargement of the alveoli distal to the terminal bronchioles with destruction of bronchiolar walls is seen. Fibrosis may either be present or absent [1] [11] [12]
Liver biopsy [1] [11] [12] This may show cirrhotic changes. [1] [11] [12]
References
  1. FREGONESE LAURA, STOLK JAN. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Array [online] 2008 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-3-16
  2. RINGENBACH MICHAEL R, BANTA ERIN, SNYDER MELISSA R, CRAIG TIMOTHY J, ISHMAEL FAOUD T. A challenging diagnosis of alpha-1-antitrypsin deficiency: identification of a patient with a novel F/Null phenotype. Array [online] 2011 December [viewed 31 August 2014] Available from: doi:10.1186/1710-1492-7-18
  3. STOCKLEY R A. Alpha-1-antitrypsin deficiency: what next?. [online] 2000 July, 55(7):614-618 [viewed 31 August 2014] Available from: doi:10.1136/thorax.55.7.614
  4. CURIEL D, BRANTLY M, CURIEL E, STIER L, CRYSTAL R G. Alpha 1-antitrypsin deficiency caused by the alpha 1-antitrypsin Nullmattawa gene. An insertion mutation rendering the alpha 1-antitrypsin gene incapable of producing alpha 1-antitrypsin.. J. Clin. Invest. [online] 1989 April, 83(4):1144-1152 [viewed 31 August 2014] Available from: doi:10.1172/JCI113994
  5. SAUNDERS DARREN N., TINDALL ELIZABETH A., SHEARER ROBERT F., ROBERSON JACQUELYN, DECKER AMY, WILSON JEAN AMOS, HAYES VANESSA M., MORTY RORY EDWARD. A Novel SERPINA1 Mutation Causing Serum Alpha1-Antitrypsin Deficiency. PLoS ONE [online] 2012 December [viewed 31 August 2014] Available from: doi:10.1371/journal.pone.0051762
  6. MAHADEVA R., LOMAS D. A. Genetics and respiratory disease bullet 2: Alpha1-antitrypsin deficiency, cirrhosis and emphysema. Thorax [online] 1998 June, 53(6):501-505 [viewed 31 August 2014] Available from: doi:10.1136/thx.53.6.501
  7. TANASH HANAN A, NILSSON PETER M, NILSSON JAN-ÅKE, PIITULAINEN EEVA. Survival in severe alpha-1-antitrypsin deficiency (PiZZ). Array [online] 2010 December [viewed 31 August 2014] Available from: doi:10.1186/1465-9921-11-44
  8. SAFERALI AABIDA, LEE JEE, SIN DON D., ROUHANI FARSHID N., BRANTLY MARK L., SANDFORD ANDREW J., SARETZKI GABRIELE. Longer Telomere Length in COPD Patients with α1-Antitrypsin Deficiency Independent of Lung Function. PLoS ONE [online] 2014 April [viewed 31 August 2014] Available from: doi:10.1371/journal.pone.0095600
  9. Survival and FEV Decline in Individuals with Severe Deficiency of α -Antitrypsin . Am J Respir Crit Care Med [online] 1998 July, 158(1):49-59 [viewed 31 August 2014] Available from: doi:10.1164/ajrccm.158.1.9712017
  10. SHAKER S B. 1-Antitrypsin deficiency {middle dot} 7: Computed tomographic imaging in 1-antitrypsin deficiency. Thorax [online] 2004 November, 59(11):986-991 [viewed 31 August 2014] Available from: doi:10.1136/thorax.2003.006569
  11. PRIMHAK R A. Alpha-1 antitrypsin deficiency. [online] 2001 July, 85(1):2-5 [viewed 31 August 2014] Available from: doi:10.1136/adc.85.1.2
  12. OLFERT I, MALEK MOH H, EAGAN TOMAS ML, WAGNER HARRIETH, WAGNER PETER D. Inflammatory cytokine response to exercise in alpha-1-antitrypsin deficient COPD patients ‘on’ or ‘off’ augmentation therapy. Array [online] 2014 December [viewed 31 August 2014] Available from: doi:10.1186/1471-2466-14-106

Investigations - Fitness for Management

Fact Explanation
Full blood count [3] [4] To exclude any anemia, and low platelets (due to liver failure) prior to surgery. [3] [4]
Coagulation studies including Prothrombin time and international normalization ratio (PT-INR) [1] [3] [4] To exclude any coagulation defects. As there's liver failure, PT-INR is likely to be prolonged. Therefore correction should be done prior to surgery [1] [3] [4]
Renal function tests- Serum creatinine, Blood urea nitrogen [3] [4] To exclude any renal dysfunction prior to anesthesia. And also to exclude hepato-renal syndrome prior to transplantation. [3] [4]
Serum albumin [1] As there's liver failure, production of Albumin is low and low albumin is likely to cause delay in wound healing after surgery [1]
Lung function tests [5] Lung function tests should be done prior to anesthesia to evaluate respiratory system, as there patients are likely to have defective lung function tests due to disease. This is also important to exclude hepato-pulmonary syndrome before liver transplantation. [5]
Echocardiography [1] [3] As liver transplantation and lung transplantation are major surgeries cardiac evaluation is also done. [1] [3]
Hepatitis screen [5] This is done prior to liver transplantation. [5]
CT- abdomen with contrast [5] This is to determine hepatic artery and portal vein anatomy and the presence of hepatocellular carcinoma (HCC) prior transplantation. [5]
Cardio-Pulmonary exercise testing [6] [7] To assess cardiac function prior to surgery [6] [7]
References
  1. LIMDI J K. Evaluation of abnormal liver function tests. Postgraduate Medical Journal [online] 2003 June, 79(932):307-312 [viewed 31 August 2014] Available from: doi:10.1136/pmj.79.932.307
  2. KUMAR A, SRIVASTAVA U. Role of routine laboratory investigations in preoperative evaluation J Anaesthesiol Clin Pharmacol [online] 2011, 27(2):174-179 [viewed 31 August 2014] Available from: doi:10.4103/0970-9185.81824
  3. SHULMAN M. A., THOMPSON B. R.. I. Not fit for a haircut ... how should we assess fitness and stratify risk for surgery?. British Journal of Anaesthesia [online] December, 112(6):955-957 [viewed 31 August 2014] Available from: doi:10.1093/bja/aeu003
  4. SCHWAIBLMAIR MARTIN, REICHENSPURNER HERMANN, MÜLLER CHRISTIAN, BRIEGEL JOSEF, FÜRST HEINER, GROH JÜRGEN, REICHART BRUNO, VOGELMEIER CLAUS. Cardiopulmonary Exercise Testing Before and After Lung and Heart–Lung Transplantation. Am J Respir Crit Care Med [online] 1999 April, 159(4):1277-1283 [viewed 31 August 2014] Available from: doi:10.1164/ajrccm.159.4.980511
  5. AVERY ROBIN K.. Recipient Screening Prior to Solid‐Organ Transplantation. CLIN INFECT DIS [online] 2002 December, 35(12):1513-1519 [viewed 31 August 2014] Available from: doi:10.1086/344777
  6. SCHWAIBLMAIR MARTIN, REICHENSPURNER HERMANN, MÜLLER CHRISTIAN, BRIEGEL JOSEF, FÜRST HEINER, GROH JÜRGEN, REICHART BRUNO, VOGELMEIER CLAUS. Cardiopulmonary Exercise Testing Before and After Lung and Heart–Lung Transplantation. Am J RespirCrit Care Med [online] 1999 April, 159(4):1277-1283 [viewed 31 August 2014] Available from: doi:10.1164/ajrccm.159.4.980511
  7. STRUTHERS R., ERASMUS P., HOLMES K., WARMAN P., COLLINGWOOD A., SNEYD J. R.. Assessing fitness for surgery: a comparison of questionnaire, incremental shuttle walk, and cardiopulmonary exercise testing in general surgical patients. British Journal of Anaesthesia [online] December, 101(6):774-780 [viewed 31 August 2014] Available from: doi:10.1093/bja/aen310

Investigations - Followup

Fact Explanation
Liver function tests [1] [2] [3] [4] [5] [6] Regular evaluation of liver function are recommended as there's a risk of chronic lever cell disease later [1] [2] [3] [4] [5] [6]
Lung function tests [1] [7] Annual lung function tests are done to determine whether replacement therapy or transplantation is needed. [1] [7]
Ultrasound scan- Abdomen [1] [2] [3] [4] [5] [6] In a patient with chronic liver cell disease, ultrasound monitoring every 6-12 months is done to detect appearance of hepatocellular carcinoma. [1] [2] [3] [4] [5] [6]
Alpha Feto protein level [8] As these patients are likely to develop hepatocellular carcinoma this level is done periodically. [8]
References
  1. FREGONESE LAURA, STOLK JAN. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Array [online] 2008 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-3-16
  2. RINGENBACH MICHAEL R, BANTA ERIN, SNYDER MELISSA R, CRAIG TIMOTHY J, ISHMAEL FAOUD T. A challenging diagnosis of alpha-1-antitrypsin deficiency: identification of a patient with a novel F/Null phenotype. Array [online] 2011 December [viewed 31 August 2014] Available from: doi:10.1186/1710-1492-7-18
  3. STOCKLEY R A. Alpha-1-antitrypsin deficiency: what next?. [online] 2000 July, 55(7):614-618 [viewed 31 August 2014] Available from: doi:10.1136/thorax.55.7.614
  4. TANASH HANAN A, NILSSON PETER M, NILSSON JAN-ÅKE, PIITULAINEN EEVA. Survival in severe alpha-1-antitrypsin deficiency (PiZZ). Array [online] 2010 December [viewed 31 August 2014] Available from: doi:10.1186/1465-9921-11-44
  5. PRIMHAK R A. Alpha-1 antitrypsin deficiency. [online] 2001 July, 85(1):2-5 [viewed 31 August 2014] Available from: doi:10.1136/adc.85.1.2
  6. MAHADEVA R., LOMAS D. A. Genetics and respiratory disease bullet 2: Alpha1-antitrypsin deficiency, cirrhosis and emphysema. Thorax [online] 1998 June, 53(6):501-505 [viewed 31 August 2014] Available from: doi:10.1136/thx.53.6.501
  7. Survival and FEV Decline in Individuals with Severe Deficiency of α -Antitrypsin . Am J Respir Crit Care Med [online] 1998 July, 158(1):49-59 [viewed 31 August 2014] Available from: doi:10.1164/ajrccm.158.1.9712017
  8. LAI QUIRINO, MELANDRO FABIO, PINHEIRO RAFAEL S., DONFRANCESCO ANDREA, FADEL BASHIR A., LEVI SANDRI GIOVANNI B., ROSSI MASSIMO, BERLOCO PASQUALE B., FRATTAROLI FABRIZIO M.. Alpha-Fetoprotein and Novel Tumor Biomarkers as Predictors of Hepatocellular Carcinoma Recurrence after Surgery: A Brilliant Star Raises Again. International Journal of Hepatology [online] 2012 December, 2012:1-9 [viewed 31 August 2014] Available from: doi:10.1155/2012/893103

Investigations - Screening/Staging

Fact Explanation
Serum Alpha-1 Anti Trypsin level [1] [2] [3] [8] This is done as a screening test in patients with family history of alpha-1-anti trypsin deficiency. [1] [2] [3] [8]
Phenotyping [1] [2] [3] [4] [5] [6] [7] [8] When serum level test results are inconclusive, phenotyping is done. [1] [2] [3] [4] [5] [6] [7] [8]
Serum bilirubin [10] [11] [12] This is included in Child-Pugh score (sometimes the Child-Turcotte-Pugh score) which is used to assess the prognosis of chronic liver disease depending on the level and also in MELD score. [10] [11] [12]
Serum creatinine [10] [11] This is included in MELD score (Model For End-Stage Liver Disease) to to quantify end-stage liver disease for transplant planning [10] [11]
Serum Albumin [12] This is included in Child-Pugh score (sometimes the Child-Turcotte-Pugh score) which is used to assess the prognosis of chronic liver disease depending on the level. [12]
Prothromin time and international normalization ratio [12] This is included in Child-Pugh score (sometimes the Child-Turcotte-Pugh score) which is used to assess the prognosis of chronic liver disease depending on the level. [12]
References
  1. FREGONESE LAURA, STOLK JAN. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Array [online] 2008 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-3-16
  2. RINGENBACH MICHAEL R, BANTA ERIN, SNYDER MELISSA R, CRAIG TIMOTHY J, ISHMAEL FAOUD T. A challenging diagnosis of alpha-1-antitrypsin deficiency: identification of a patient with a novel F/Null phenotype. Array [online] 2011 December [viewed 31 August 2014] Available from: doi:10.1186/1710-1492-7-18
  3. STOCKLEY R A. Alpha-1-antitrypsin deficiency: what next?. [online] 2000 July, 55(7):614-618 [viewed 31 August 2014] Available from: doi:10.1136/thorax.55.7.614
  4. CURIEL D, BRANTLY M, CURIEL E, STIER L, CRYSTAL R G. Alpha 1-antitrypsin deficiency caused by the alpha 1-antitrypsin Nullmattawa gene. An insertion mutation rendering the alpha 1-antitrypsin gene incapable of producing alpha 1-antitrypsin.. J. Clin. Invest. [online] 1989 April, 83(4):1144-1152 [viewed 31 August 2014] Available from: doi:10.1172/JCI113994
  5. SAUNDERS DARREN N., TINDALL ELIZABETH A., SHEARER ROBERT F., ROBERSON JACQUELYN, DECKER AMY, WILSON JEAN AMOS, HAYES VANESSA M., MORTY RORY EDWARD. A Novel SERPINA1 Mutation Causing Serum Alpha1-Antitrypsin Deficiency. PLoS ONE [online] 2012 December [viewed 31 August 2014] Available from: doi:10.1371/journal.pone.0051762
  6. MAHADEVA R., LOMAS D. A. Genetics and respiratory disease bullet 2: Alpha1-antitrypsin deficiency, cirrhosis and emphysema. Thorax [online] 1998 June, 53(6):501-505 [viewed 31 August 2014] Available from: doi:10.1136/thx.53.6.501
  7. TANASH HANAN A, NILSSON PETER M, NILSSON JAN-ÅKE, PIITULAINEN EEVA. Survival in severe alpha-1-antitrypsin deficiency (PiZZ). Array [online] 2010 December [viewed 31 August 2014] Available from: doi:10.1186/1465-9921-11-44
  8. PRIMHAK R A. Alpha-1 antitrypsin deficiency. [online] 2001 July, 85(1):2-5 [viewed 31 August 2014] Available from: doi:10.1136/adc.85.1.2
  9. 5) ANGERMAYR B. Child-Pugh versus MELD score in predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt. [online] 2003 June, 52(6):879-885 [viewed 10 August 2014] Available from: doi:10.1136/gut.52.6.879
  10. BOTTA F. MELD scoring system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with residual liver function: a European study. [online] 2003 January, 52(1):134-139 [viewed 31 August 2014] Available from: doi:10.1136/gut.52.1.134
  11. OBERKOFLER CHRISTIAN E, DUTKOWSKI PHILIPP, STOCKER RETO, SCHUEPBACH RETO A, STOVER JOHN F, CLAVIEN PIERRE-ALAIN, BéCHIR MARKUS. Model of end stage liver disease (MELD) score greater than 23 predicts length of stay in the ICU but not mortality in liver transplant recipients. Array [online] 2010 December [viewed 31 August 2014] Available from: doi:10.1186/cc9068
  12. ANGERMAYR B. Child-Pugh versus MELD score in predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt. [online] 2003 June, 52(6):879-885 [viewed 31 August 2014] Available from: doi:10.1136/gut.52.6.879

Management - General Measures

Fact Explanation
Patient education [2] [3] [4] [5] [6] Patient education is very important as this is a life long disease and mainly management relies on slowing the progression of lung disease and patient should be educated on this. Quitting smoking plays a major role and the patient should be educated about the serious consequences of smoking and referral to group therapy, nicotine replacement patches may be helpful. In addition to that they should be educated on the available treatment options and the importance of follow up for complications. [2] [3] [4] [5] [6]
Improving lung function with bronchodilators [2] [3] [4] [5] [6] Many bronchodilator drugs such as short-acting beta-adrenergic agents and ipratropium bromide are used in the form of metered dose inhalors. Long-acting inhaled beta-adrenergic drugs and anticholinergics may also have a role but they have not been studied yet [2] [3] [4] [5] [6]
Improving lung function with steroids [2] [3] [4] [5] [6] Steroids given as inhalors can help control symptoms but oral corticosteroids are only given when respiratory symptoms get worse with cough and sputum production. [2] [3] [4] [5] [6]
Improving lung function with Theophylline [2] [3] [4] [5] [6] Theophyllines may be helpful as they help to relieve air way obstruction.. [2] [3] [4] [5] [6]
Prevention of respiratory infections [2] [7] Annual influenza, Pneumococcal vaccines help to combat against respiratory infections. Antibiotics can be given when there is increased cough with purulent sputum. [2] [7]
Pulmonary rehabilitation [2] [8] This is carried out as a multi disciplinary approach to maintain optimum quality of life of the patient. Patient education, regular physical exercise is helpful with chest physiotherapy to remove sputum. Nutritional status should be optimized and psychological support also plays a big role. [2] [8]
Oxygen therapy [9] Oxygen supplementation has known to increase survival in these patients as it increases exercise tolerance, reduces shortness of breath on exertion, and improves sleep. Oxygen via a face mask, or nasal cannula may help. [9]
Diet and activity [2] [3] [4] [5] [6] As there's increased protein catabolism in these patients improving diet and nutritional status may help as well. Even though dyspnea limits activity they are encouraged to have regular physical exercise to their limit. [2] [3] [4] [5] [6]
Liver failure regime [1] When the patient goes into liver failure as a result of chronic liver cell disease, the regime includes ACE inhibitors, Furosemide as diuretics, Lactulose, Serum albumin and low salt diet. [1]
Vaccination [11] Vaccination against common blood borne infections such as Hepatitis B,C may be necessary as these patients are likely to receive enzyme replacement therapy which is a plasma derived product [11]
New born screening/ Prenatal diagnosis [10] This is now available and this helps in genetic counseling when a prenatal diagnosis is made. Newborn screening helps to plan the management from early life and reduce complications. [10]
References
  1. MOORE KP, AITHAL GP. Guidelines on the management of ascites in cirrhosis Gut [online] 2006 Oct, 55(Suppl 6):vi1-vi12 [viewed 31 August 2014] Available from: doi:10.1136/gut.2006.099580
  2. FREGONESE LAURA, STOLK JAN. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Array [online] 2008 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-3-16
  3. BRODE S. K., LING S. C., CHAPMAN K. R.. Alpha-1 antitrypsin deficiency: a commonly overlooked cause of lung disease. Canadian Medical Association Journal [online] December, 184(12):1365-1371 [viewed 31 August 2014] Available from: doi:10.1503/cmaj.111749
  4. DEMEO D L. 1-Antitrypsin deficiency {middle dot} 2: Genetic aspects of 1-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax [online] 2004 March, 59(3):259-264 [viewed 31 August 2014] Available from: doi:10.1136/thx.2003.006502
  5. PRIMHAK R A. Alpha-1 antitrypsin deficiency. [online] 2001 July, 85(1):2-5 [viewed 31 August 2014] Available from: doi:10.1136/adc.85.1.2
  6. MAHADEVA R., LOMAS D. A. Genetics and respiratory disease bullet 2: Alpha1-antitrypsin deficiency, cirrhosis and emphysema. Thorax [online] 1998 June, 53(6):501-505 [viewed 31 August 2014] Available from: doi:10.1136/thx.53.6.501
  7. JIANG DI, PERSINGER REBECCA, WU QUN, GROSS ASHLEY, CHU HONG. α1-antitrypsin promotes SPLUNC1-mediated lung defense against Pseudomonas aeruginosa infection in mice. Array [online] 2013 December [viewed 31 August 2014] Available from: doi:10.1186/1465-9921-14-122
  8. PILLAI A., STOCKLEY R.. P188 CAT Score Threshold For Symptom/Risk Assessment in Alpha-1-Antitrypsin Deficiency (AATD) Using the 2011 GOLD Algorithm. Thorax [online] December, 67(Suppl 2):A145-A146 [viewed 31 August 2014] Available from: doi:10.1136/thoraxjnl-2012-202678.249
  9. STEIN P. D., LEU J. D., WELCH M. H., GUENTER C. A.. Pathophysiology of the Pulmonary Circulation in Emphysema Associated with Alpha1 Antitrypsin Deficiency. Circulation [online] 1971 February, 43(2):227-239 [viewed 31 August 2014] Available from: doi:10.1161/01.CIR.43.2.227
  10. TECKMAN J, PARDEE E, HOWELL RR, MANNINO D, SHARP RR, BRANTLY M, WANNER A, LAMSON J. Appropriateness of Newborn Screening for ?1-Antitrypsin Deficiency J Pediatr Gastroenterol Nutr [online] 2014 Feb, 58(2):201-205 [viewed 31 August 2014] Available from: doi:10.1097/MPG.0000000000000196
  11. ERICSSON C. D., ZUCKERMAN J. N., CONNOR B. A., VON SONNENBURG F.. Hepatitis A and B Booster Recommendations: Implications for Travelers. Clinical Infectious Diseases [online] 2005 October, 41(7):1020-1026 [viewed 31 August 2014] Available from: doi:10.1086/433182

Management - Specific Treatments

Fact Explanation
Enzyme replacement therapy [1] [2] [3] [4] Prolastin, which is a purified, human plasma protein concentrate replacement is given for these patients. Inhalation form of Prolastin is still under testing. [1] [2] [3] [4]
Gene therapy [1] [5] [6] [7] Genetic repair of the abnormal gene product is also under testing. [1] [5] [6] [7]
Volume-reduction surgery of the lung [3] [9] [10] These patients have air trapping and when lung volume is reduced, there can be improvement in the symptoms. [3] [9] [10]
Lung transplantation [11] [12] when all other treatment are failed in patients with high risk of death, but apparently healthy, lung transplantation may be beneficial. [11] [12]
Liver transplantation [13] This is the definitive treatment for advanced liver disease [13]
All trans retinoic acid therapy [4] [8] Administration of ATRA is thought to reverse the emphysematous changes in the lung [4] [8]
Hyaluronic acid therapy [4] [8] Reduced levels of hyaluronic acid in their lungs is seen in these patients. Therefore treatment with this may be beneficial. [4] [8]
Antioxidants, such as vitamins A, C and/or E [4] [8] These are also still under studying to use treatments for emphysema. [4] [8]
References
  1. BLANCO IGNACIO, LARA BEATRIZ, DE SERRES FREDERICK. Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema. Array [online] 2011 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-6-14
  2. CHU ANDREW S., PERLMUTTER DAVID H., WANG YAN. Capitalizing on the Autophagic Response for Treatment of Liver Disease Caused by Alpha-1-Antitrypsin Deficiency and Other Genetic Diseases. BioMed Research International [online] 2014 December, 2014:1-8 [viewed 31 August 2014] Available from: doi:10.1155/2014/459823
  3. MAHADEVA R., LOMAS D. A. Genetics and respiratory disease bullet 2: Alpha1-antitrypsin deficiency, cirrhosis and emphysema. Thorax [online] 1998 June, 53(6):501-505 [viewed 31 August 2014] Available from: doi:10.1136/thx.53.6.501
  4. STOCKLEY R A. Alpha-1-antitrypsin deficiency: what next?. [online] 2000 July, 55(7):614-618 [viewed 31 August 2014] Available from: doi:10.1136/thorax.55.7.614
  5. FLOTTE T. R., MUELLER C.. Gene therapy for alpha-1 antitrypsin deficiency. Human Molecular Genetics [online] December, 20(R1):R87-R92 [viewed 31 August 2014] Available from: doi:10.1093/hmg/ddr156
  6. GUO SHULING, BOOTEN SHERI L., AGHAJAN MARIAM, HUNG GENE, ZHAO CHENGUANG, BLOMENKAMP KEITH, GATTIS DANIELLE, WATT ANDREW, FREIER SUSAN M., TECKMAN JEFFERY H., MCCALEB MICHAEL L., MONIA BRETT P.. Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin–related liver disease in mice. J. Clin. Invest. [online] December, 124(1):251-261 [viewed 31 August 2014] Available from: doi:10.1172/JCI67968
  7. GHOUSE R., CHU A., WANG Y., PERLMUTTER D. H.. Mysteries of 1-antitrypsin deficiency: emerging therapeutic strategies for a challenging disease. Disease Models & Mechanisms [online] December, 7(4):411-419 [viewed 31 August 2014] Available from: doi:10.1242/dmm.014092
  8. SANDHAUS R A. 1-Antitrypsin deficiency {middle dot} 6: New and emerging treatments for 1-antitrypsin deficiency. Thorax [online] 2004 October, 59(10):904-909 [viewed 31 August 2014] Available from: doi:10.1136/thx.2003.006551
  9. Survival and FEV Decline in Individuals with Severe Deficiency of α -Antitrypsin . Am J Respir Crit Care Med [online] 1998 July, 158(1):49-59 [viewed 31 August 2014] Available from: doi:10.1164/ajrccm.158.1.9712017
  10. BRODE S. K., LING S. C., CHAPMAN K. R.. Alpha-1 antitrypsin deficiency: a commonly overlooked cause of lung disease. Canadian Medical Association Journal [online] December, 184(12):1365-1371 [viewed 31 August 2014] Available from: doi:10.1503/cmaj.111749
  11. ESTENNE MARC, CASSART MARIE, PONCELET PHILIPPE, GEVENOIS PIERRE ALAIN. Volume of Graft and Native Lung after Single-Lung Transplantation for Emphysema. Am J Respir Crit Care Med [online] 1999 February, 159(2):641-645 [viewed 31 August 2014] Available from: doi:10.1164/ajrccm.159.2.9802017
  12. HERLIHY J P, VENEGAS J G, SYSTROM D M, GREENE R E, MCKUSICK K A, WAIN J C, GINNS L C. Expiratory flow pattern following single-lung transplantation in emphysema.. Am J Respir Crit Care Med [online] 1994 December, 150(6):1684-1689 [viewed 31 August 2014] Available from: doi:10.1164/ajrccm.150.6.7952633
  13. VARMA VIBHA, MEHTA NAIMISH, KUMARAN VINAY, NUNDY SAMIRAN. Indications and Contraindications for Liver Transplantation. International Journal of Hepatology [online] 2011 December, 2011:1-9 [viewed 31 August 2014] Available from: doi:10.4061/2011/121862