α₁-Antitrypsin Deficiency Case Study

α₁-Antitrypsin Deficiency

• This is a genetic condition caused by a deficiency in α₁-antitrypsin, leading to potential cirrhosis and/or emphysema

Case Report

• A 35-year-old white male with α₁-antitrypsin deficiency had a combined liver-kidney transplant at age 18 due to complications
• Complications included cirrhosis complicated by portal hypertension
• Complications included renal insufficiency secondary to membranoproliferative glomerulonephritis
• Complications included combined restrictive and obstructive pulmonary disease
• The patient had jaundice/pruritus at 6 weeks, resolved after 2 months
• The patient was hospitalized for pneumonia at 20 months, with an enlarged liver noted
• Liver biopsy showed postnecrotic cirrhosis and globules were PAS positive and diastase resistant
• The patient was then referred for liver transplantation at age 2.5 years
• At initial evaluation the patient had a protuberant abdomen, liver edge palpable 3 cm below the right costal margin, and spleen palpable 6 cm below the left costal margin
• Laboratory tests revealed low platelet count and elevated serum glutamic oxaloacetic transaminase
• Serum protein electrophoresis was abnormal with low serum albumin and a barely visible α₁-globulin band
• The child's protease inhibitor (PI) phenotype was PIZZ, while both parents had a PIMZ phenotype
• Subsequent course was gradual hepatic deterioration
• Ascites was noted at age 3 and progressed to severe ascites and peripheral edema at age 6, requiring spironolactone
• The patient was hospitalized multiple times for ascites with scrotal edema and had persistently low serum albumin
• The patient had two episodes of primary peritonitis and one episode of a-streptococcal sepsis
• At age 11, renal function decreased with a creatinine clearance of 71 mL/min
• Protein-losing nephropathy developed with a 24-hour urinary protein excretion of 600 mg, increasing to 14 g after albumin infusions
• The patient also experienced acute hepatic encephalopathy episodes, controlled with neomycin enemas
• Gastrointestinal bleeding exacerbated hyperammonemia
• Coagulopathy prevented intracranial pressure monitor placement
• The patient was treated for presumed cerebral edema and recovered without neurological sequelae
• Protein intake was restricted (1.0 g/kg per day)
• The patient had two milder hyperammonemia episodes
• Continued treatments included limited protein intake, neomycin, and lactulose
• Subclinical hepatic encephalopathy was monitored by electroencephalography
• Despite complications, the patient maintained a relatively active lifestyle
• At age 16, renal condition deteriorated to a creatinine clearance of 23 mL/min
• The patient was approved for a combined liver-kidney transplant after a 2-year wait
• The transplant was successfully performed at age 18
• The patient completed high school and was employed full time in good health for over a decade
• Seventeen years after transplant, cirrhosis from hepatitis C (likely from blood transfusions prior to and during transplant) was found
• The patient died waiting for a second hepatic transplant

Diagnosis of α₁-Antitrypsin Deficiency

• The patient's case illustrates a complicated clinical course of the deficiency, with liver disease presenting in infancy and progressing to hepatic cirrhosis
• Exhibited complications of cirrhosis including portal hypertension with ascites, hyperammonemia, malnutrition, and variceal hemorrhage
• These complications aren't unique to the deficiency
• The deficiency is suspected in three clinical situations
• Cholestasis in infancy
• Cirrhosis of undetermined etiology at any age
• Emphysema early in life, especially if predominantly basilar
• Liver disease is commonly associated with the deficiency and may develop at any age
• Around 10-20% of deficient infants with PIZZ phenotype show neonatal cholestatic liver disease
• Conjugated hyperbilirubinemia and hepatomegaly are noted in the first month of life
• Clinical course in the first year can be mild or severe
• Most children improve with time and resolve their liver disease by 1-2 years of age
• Jaundice after 6 months suggests significant deterioration in clinical status within 1 year
• Decrease in hepatic synthetic capacity also accompanies this deterioration, manifest by a decrease in coagulation factors synthesized by the liver
• Roughly 50% of people who are PIZZ never manifest liver disease
• In the other half, liver disease develops insidiously over years, presenting in adulthood as cirrhosis
• Clinically, cirrhosis associated with the deficiency is similar to other forms of childhood liver disease
• Malnutrition, coagulopathy, and complications of portal hypertension develop to a varying degree
• In the absence of infection/dehydration, a patient may survive for years with cirrhosis and adequate hepatic function
• Hepatocellular carcinoma is more common in individuals with PIZZ-associated α₁-antitrypsin deficiency
• Carcinoma can develop in individuals without cirrhosis
• Emphysema represents the most common manifestation of the deficiency
• Occurs at a relatively early age (3rd-4th decade)
• Equal distribution between men and women
• Most young symptomatic PIZZ individuals with emphysema have a history of cigarette smoking
• Abstention from smoking may delay disease onset by 20 years
• In nonsmokers homozygous for the deficiency living in areas free of air pollution, the onset of emphysema was later than in smokers
• Emphysema presents with shortness of breath, dyspnea, and chronic cough
• Pneumothorax may result from the bursting of an emphysematous bleb
• Emphysema associated with the deficiency is indistinguishable from nonfamilial forms
• Chronic bronchitis and cough occur less frequently than in other forms of emphysema
• There is a spectrum of disability, from asymptomatic to chronic pulmonary cripples
• Most patients develop chronic obstructive pulmonary disease
• Once emphysema becomes symptomatic in the deficient individual, it usually pursues a relentless course
• A Danish study reported that the life expectancy of PIZZ smokers is 52 years and that of those who never smoked is 69 years
• Renal disease is seen in 17% of infants with the deficiency, causing massive protein loss, hypoalbuminemia, and renal failure
• Kidney disease is immunological, occurring only in patients with liver disease, resulting in membranoproliferative glomerulonephritis with immunoreactive-α₁-antitrypsin
• This should not be confused with nonspecific spotty asymptomatic glomerulonephritis or hepatorenal syndrome
• Vascular conditions have been associated with the deficiency, including panniculitis and cerebral aneurysm
• Controversial whether heterozygote (PIMZ) individuals are at risk for liver/lung disease
• Some studies suggest they are overrepresented among patients with chronic end-stage liver disease and diagnostic liver biopsies with cirrhosis
• Unclear whether carriers of the Z allele are at increased risk of emphysema if they smoke
• The diagnosis of the deficiency may be suspected during direct observation of the cellulose acetate serum protein electrophoresis
• The alpha 1-globulin band is small/undetectable
• Alpha 1-antitrypsin represents 90% of the total alpha 1-globulin peak
• Serum levels of alpha 1-antitrypsin are low in PIZZ individuals, less than 15% of normal levels
• Serum quantitative tests do not permit accurate diagnosis and genetic counseling
• The diagnostic test of choice is PI typing, in which isoelectric focusing is used to separate the various a1-antitrypsin species in the individual's serum by charge differences
• Comparison with sera of known PI type permits identification of the phenotype of the individual
• In patients with evidence of significant hepatic involvement, liver biopsy facilitates a more accurate prognosis
• PAS-positive, diastase-resistant globules representing retained α₁-antitrypsin protein are found in periportal hepatocytes on light microscopy
• The average child with α₁-antitrypsin deficiency needs only periodic exams
• PIZZ adults with symptomatic pulmonary disease require more specific evaluation

Biochemical Perspectives

• The deficiency is an inborn error of metabolism predisposing to emphysema
• Sten Eriksson and C.-B. Laurell identified The inherited deficiency In the early 1960s
• Harvey Sharp recognized the association of hepatic cirrhosis and α₁-antitrypsin deficiency in 1969
• Sequencing of the human α₁-antitrypsin gene in 1984 initiated an explosion in study of this disease
• Transgenic mice were created to study the effects of the deficiency
• Cell culture studies of the regulation of the gene became possible
• Accumulation of abnormal α₁-antitrypsin in the ER of the liver was the result of polymerization
• α₁-Antitrypsin is a 52-kd glycoprotein produced primarily by the hepatocyte and macrophages
• Serum α₁-antitrypsin is derived almost exclusively from the liver
• The function of this serine protease is to protect tissues from proteolytic enzymes released during the normal inflammatory response
• The mechanism of inhibition is an irreversible reaction between α₁-antitrypsin and elastase at the reactive center of α₁-antitrypsin, a methionine residue at position 358
• This residue is called the reactive center
• Elastase, which cleaves proteins at methionyl residues, recognizes α₁-antitrypsin as a substrate and attempts to cleave it
• This antiprotease is encoded by a 12.2-kb gene located on chromosome 14
• The gene consists of seven exons and six introns, with the transcriptional start site varying depending on the cell type in which transcription occurs
• Hepatocytes produce predominantly a single 1.6-kb transcript, although they can produce small amounts of transcripts characteristic of the monocyte cell line when stimulated by interleukin 6
• The a₁-antitrypsin promoter contains a consensus TATA box, a B-recognition element for transcription-activating factor IIB, a hepatocyte nuclear factor 1 site, and two non-tissue-specific regions that increase transcription
• There is a 3' enhancer region with five potential binding sites for transcription factors
• a₁-Antitrypsin is an acute phase reactant, which means that synthesis of the protein increases during inflammation, including malignancy, bacterial infections, and severe burns
• Sequence similarities to other serine PIs established the existence of the SERPINs
• Functionally, there is broad diversity, from functional PIs to regulators of the clotting cascade and hormone-binding proteins
• During protein synthesis, the nascent translation product of the α₁-antitrypsin gene is co-translationally translocated to the ER, where the signal peptide is cleaved and high mannose glycosylation residues are added
• Mature glycoprotein is packaged in the Golgi and secreted into the serum
• The mechanism by which Z-α₁-antitrypsin is transported out of the ER and degraded has been of interest to investigators
• The PI locus is highly pleomorphic, with more than 75 allelic variants identified
• PIM represents the normal allele; it is actually composed of four M alleles, M1-M4
• Although many variant forms of the antiprotease exist, the most common alleles associated with its deficiency are the S and Z variants, both producing proteins that migrate cathodal to the normal protein
• PIZZ individuals have approximately 10% to 20% of the normal level of a₁-antitrypsin, while PISZ individuals have approximately 35% of the normal level
• the main B-sheet of Z-α₁-antitrypsin molecule can open spontaneously, allowing the reactive loop of a second Z-α₁-antitrypsin molecule to insert itself into the opening
• polymers are created with a stable structure that resists the normal degradative processes
• PIZZ individual accumulates large amounts of endoplasmic reticular α₁-antitrypsin protein that is not released into the circulation

Therapy

• Conventional medical management of emphysema consists of supportive care, including early antibiotic treatment of all pulmonary infections
• Patients are immunized against influenza virus and Streptococcus pneunoniae
• Patients should stop smoking
• The approved administration of purified serum-derived α₁-antitrypsin to PIZZ and PI null individuals with pulmonary disease has serum levels of a₁-antitrypsin increase to those believed to be protective
• Recombinantly produced α₁-antitrypsin would reduce the risk of transfusion-related viral disease
• Lung transplantation has been used in treatment but is not the best for overall survival
• There is no evidence of recurrence of the liver disease after successful liver transplant
• Gene therapy could be a possible curative effect