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 50-year-old male subject of Tunisian origin, followed by our outpatient chronic obstructive pulmonary disease (COPD) clinic, a former smoker (about 10 cigarettes a day for 30 years, 15 pack/years) treated with a LAMA-based inhalation therapy, and with previous monolateral spontaneous pneumothorax, treated with thoracic drainage. He worked as a driver. The patient presented digital hippocratism and, upon chest auscultation, the vesicular murmur was greatly reduced.\nArterial blood gas analysis showed values in the normal range considering the subject's age: pH 7.35, pCO2 42.9 mmHg, pO2 89.5 mmHg, HCO3 22.6 mmol/L, and sO2 97%. The 6MWT, performed without oxygen supplementation, did not register any clinically significant desaturation but a slight reduction in the distance walked (411 m measured/512 m predicted). Electrocardiogram (ECG) parameters were within the normal limits. The chest HRCT showed a severe diffuse centrolobular and paraseptal emphysema (Fig. ).\nPulmonary function tests revealed a mild airway obstruction, with a negative bronchial reversibility test (Fig. ; Table ).\nSince the AAT serum concentration was lower than normal (87 mg/dL), the patient underwent a genetic investigation with verification of the PI*M1MMalton genotype. Blood chemistry tests (total and fractionated bilirubin, CPK, gamma GT, cholinesterase, AST, ALT and renal function indices) were in the normal range. Liver and abdominal ultrasound exams were negative for liver or aneurysmal disease.