A 80-year-old woman of Algerian origin was admitted to hospital for the treatment of an acute and painful fracture of the third lumbar vertebra. A computed tomography scan (CTS) was performed for this fracture and revealed a dysmorphic and enlarged liver with signs of portal hypertension (splenomegaly, collateral veins). Her past medical history was significant for obesity, vertebral osteoporosis, monoclonal gammapathy of undetermined significance (IgG kappa) and some bronchitis episodes in the past 2 years. She had neither history of liver disease nor alcohol, tobacco or illicit drug abuse. Her medical examination revealed the absence of ascites, peripheral edema, jaundice and asterixis. Laboratory tests showed abnormal liver function tests: alkaline phosphatase, 382 UI/L (reference interval, 45–117 UI/L); gamma-glutamyl-transpeptidase, 299 UI/L (reference interval, 5–55 UI/L) aspartate aminotransferase, 56 UI/L (reference interval, 15–37 UI/L); alanine aminotransferase, 25 UI/L (reference interval, 12–78 UI/L); total serum bilirubin, 0.94 mg/dL (reference interval, 0.176–1.0 mg/dL). Serum albumin was decreased, 29 g/L (reference interval, 35–50 g/L). Blood platelets count was low, 143 × 109/L (normal range, 150–400 × 109/L). INR was 1.2 and serum creatinin was 47 μmol/L. Liver stiffness measurement by transient elastography (Fibroscan®) was pathologic with an increased value of 21.3 kPa in favor of underlying cirrhosis (normal range <7–8 kPa). A gastroscopy revealed grade 2 esophageal varices with red spots which were treated by band ligation. The serological tests for viral hepatitis and autoimmune hepatitis were negative. Serum cholesterol, triglycerides, ceruloplasmin and ferritin levels were normal.\nProtein serum electrophoresis (Capillarys®, Sebia) revealed a marked decrease of the α1-globulin fraction strongly suggesting an A1AT deficiency. The low serum A1AT level determined by immuno-nephelometry (0.34 g/L, reference interval: 1.0–1.8 g/L) and the isoelectric pattern with faint bands slightly more cathodal than M2 bands were very suggestive of a Pi Mmalton allele at the homozygous state. To confirm this diagnosis, we performed the Sanger DNA sequencing of the entire SERPINA1 gene with the ABI Prism 3130XL (Applied) as previously described []. Sequence analysis (Fig. ) revealed the presence, at the homozygous state, of a deletion of the three nucleotides TTC in codon 52 (exon 2) corresponding to the Mmalton allele (HGVS nomenclature: SERPINA1:c.154_156del; p. Phe52del). This deletion was on a M2 background since it was associated with the homozygous c.374G > A and c.1200A > C single nucleotide polymorphisms, thus defining the Pi Mmalton allele (the Phe52deletion on a M1 background has been called Pi Palermo). A percutaneous liver biopsy revealed micronodular cirrhosis, without steatosis but with periodic acid-Schiff (PAS)-positive acidophilic, diastase-resistant bodies in the cytoplasm of the hepatocytes. Immunohistochemical staining using a monoclonal antibody to A1AT was positive (Fig. ). According to Child-Pugh classification and MELD score, the cirrhosis was Child-Pugh B7, MELD 9. With regards to the lung, a thoracic CT scan revealed few lesions of bronchiectasis but without lesions of emphysema and the pulmonary function tests were within the normal range.
A 62-year-old male subject, Italian Caucasian, in good health conditions. The diagnosis of AATD was made following genotype analysis performed on the son of the subject (the patient in Case 1, with a PI*M2MMalton genotype). The patient had an AAT serum concentration of 69 mg/dL, with a PI*M3MMalton genotype. He was a former smoker (about four cigarettes a day for 5 years, 1 pack/years), and worked as a sandblaster craftsman, reporting powder working exposure.\nThe patient did not take any drug, and did not complain of any respiratory symptoms. The 6MWT, performed without oxygen supplementation, did not register a clinically significant desaturation and the distance walked was normal (424 m measured/530 m predicted). SatO2 was 100% breathing room air and the heart rate was 66 bpm. Upon thoracic auscultation, the vesicular murmur was preserved, with no pathological sound. Lung function tests were in the normal range (Table ). Blood count, liver function tests and renal function were in the standard reference range, while the total IgE concentration was 429 IU/mL. Chest X-ray showed no abnormality. Liver and abdominal ultrasound exams were negative for liver or aneurysmal disease. Prick tests were positive for dust mites, whereas bronchial hyperactivity assessed through the methacholine (MCh) test was negative.