Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantion

Background/Aim: Alpha-1-antitrypsin deficiency (α₁ATD) is the commonest metabolic disease leading to liver transplantation (LT) in children. Approximately 10–15% of the PiZZ population develops liver disease. Five percent of them will require LT within the first 4 years of life. This study aimed to investigate the prognosis of the liver disease associated with PiZZ α₁ATD in the era of liver transplantation and to determine predictors of outcome.Methods: We reviewed retrospectively the clinical notes of 97 consecutive patients referred from January 1989, when LT became routinely available in our Unit, to July 1998.Results: Of 26 (27%) patients who developed endstage liver disease, 24 have been transplanted and two are waiting for LT. Twenty-one (81%) of these patients presented with neonatal hepatitis at a median age of 2.1 months. Of 71 (73%) children who have not required LT, 61 (86%) presented with neonatal hepatitis at a median age of 1.6 months. Among infants with neonatal hepatitis who required LT, 18 out of 21 (86%) had jaundice for more than 6 weeks compared with 34 of 61 (56%) who survived without LT (p<0.01). Children requiring LT had higher aspartate aminotransferase (AST) at presentation (p<0.0001) and both higher AST and gamma-glutamyl transferase (GGT) at 6 months (p<0.001), 1-year (p<0.0003) and 5-year (p0.01) follow up when compared to those who are well without LT. Furthermore, children who developed end-stage liver disease more frequently had severe bile duct reduplication (p<0.01), severe fibrosis (p<0.03) with bridging septa (p<0.02) and established cirrhosis (p<0.04) in the initial liver biopsy. Ninety-five of the 97 children (98%) are currently alive; two died after LT.Conclusions: The advent of liver transplantation has significantly improved the prognosis of liver disease associated with PiZZ α₁ATD. Duration of jaundice, severity of histological features and biochemical abnormalities predict outcome at an early stage of the disease.     

Heterozygous MZ alpha-1-antitrypsin deficiency in adults with chronic liver disease

Pi phenotype was determined in 335 patients with liver diseases and compared with the results in 2830 healthy blood donors. Eleven of 335 patients had phenotype MZ (3.3%, compared with 2.9% in healthy blood donors (NS]. None of 53 patients with autoimmune chronic active hepatitis had the MZ phenotype, but it was found in 2 of 18 patients (11.1%) with cryptogenic cirrhosis, 3 of 78 (3.8%) with alcoholic liver cirrhosis, 2 of 36 (5.6%) with primary sclerosing cholangitis, and 1 of 26 (3.9%) with primary biliary cirrhosis. Altogether, 3 of 335 patients were homozygous for Pi ZZ and had cirrhosis. One of them (a male) developed a hepatoma and died. We conclude that the reported association between Pi MZ phenotype and chronic non-B active hepatitis does not seem to include patients with autoimmune chronic active hepatitis, whereas the possibility of an association between cryptogenic cirrhosis and the MZ phenotype cannot be excluded.     

alpha-1-antitrypsin deficiency in liver disease: the extent of the problem.

A prospective screening program was undertaken at the Royal Free Hospital, London, to ascertain the incidence of alpha-1-antitrypsin (AAT) deficiency in patients with liver disease. Quantitative determinations of serum alpha-1-antitrypsin were performed on 469 patients with hepatobiliary disease and 98 subjects with no known liver disease. Sera with low values of AAT were phenotyped. The homozygous state was rare and comprised only 1% of the patients with liver disease. All of the 5 homozygous deficient (ZZ phenotype) patients had a history of neonatal liver disease. Other phenotypes (partial deficiency) were found in 4.7% of patients with liver disease and 6.1% of subjects with normal liver function. Types of liver disease in the patients with other phenotypes were widely varied. Routine determination of serum AAT level and phenotype and special staining for AAT in liver biopsies in all adults with liver disease appears unnecessary. Investigation of possible AAT deficiency should be carried out, however, in children and young adults, in those with a history of neonatal liver disease, and possibly in all patients with liver disease of unknown aetiology.     

Late manifestation of chronic liver disease in adults with alpha-1-antitrypsin deficiency

A review of 19 adult patients with alpha-1-antitrypsin deficiency (A₁AT deficiency) and chronic liver disease revealed a late onset of symptomatic hepatic abnormalities in this condition. Thirteen patients (68%) were 60 years or older when the liver disease was discovered. The mean age of the patients with the ZZ, SZ, and MZ phenotypes was 58, 66, and 72.5 years, respectively; this suggested a later onset of the liver disease in the heterozygotes. At the time of diagnosis, the hepatic condition usually was advanced; in eight patients (42%) the survival was less than two years. The most important associated condition was chronic obstructuve lung disease which was found in 10 patients (53%). We conclude that advanced age and the high incidence of obstructive lung disease make it unlikely that liver transplantation will become a common therapeutic option for adult patients with A₁AT deficiency and associated liver disease. Periodic screening of liver function may be indicated in patients with A₁AT deficiency so that chronic liver disease can be diagnosed early, particularly if current attempts to develop effective medical therapy for this condition are successful.     

Hyperinflation in children with liver disease due to alpha-1-antitrypsin deficiency.

Fifty-nine patients (median age 6.0 years) with liver disease and ten healthy children without liver disease (median age 7.5 years) had serial measurements of functional residual capacity (FRC) over a period of at least 6 months. Twenty-eight children with alpha-1-antitrypsin deficiency (A1ATD) tended to have higher lung volumes than 26 with extrahepatic biliary atresia (EHBA). Fifteen children had persistent hyperinflation (FRC greater than 120% predicted for height; 2 SD above the mean of controls); in five children (four with A1ATD) this was unresponsive to bronchodilator therapy. Two of the children with A1ATD who had persistent unresponsive hyperinflation on three serial measurements were only 3 and 4 years of age. No healthy child without liver disease was hyperinflated. These results suggest that A1ATD may be associated with lung function abnormalities even in very young children.     

Molecular pathogenesis of alpha-1-antitrypsin deficiency-associated liver disease: a meeting review

In recent years, we have witnessed several important paradigm shifts in understanding the molecular basis of liver disease in alpha-1-antitrypsin (AT) deficiency. These shifts have become possible as a result of a number of advances in research on the cell biology of aggregation-prone mutant proteins and in research on the pathobiological mechanisms of liver disease in general. Late-breaking research in these areas was the subject of an AASLD/Alpha-1 Foundation Single Topic Conference in Atlanta, Georgia, on January 26 to 28, 2006. The conference was titled "Alpha-1-Antitrypsin Deficiency and Other Liver Diseases Caused by Aggregated Proteins." Investigators from all over the world, representing a broad array of scientific disciplines and perspectives, discussed the pathobiology of AT deficiency, mechanisms of cell injury in diseases associated with aggregation-prone proteins, pathways by which cells respond to protein aggregation and mislocalization, and mechanisms of liver injury in general and in diseases related to AT deficiency. A session of the meeting was devoted to novel therapeutic strategies being developed for AT deficiency as well as to strategies either in development or already being applied to the class of diseases associated with mutant proteins.     

Minimal liver disease in young persons with homozygous and heterozygous alpha-1-antitrypsin deficiency

Of 120 patients who were investigated for moderately elevated liver function tests as the only sign of liver disease, 6 young persons had alpha-1-antitrypsin (AAT) deficiency. Three had a homozygous (Pi ZZ) and three had a heterozygous (Pi MZ) AAT deficiency as measured with isoelectric focusing. An extensive investigation ruled out all other causes of liver disease. The three homozygous patients showed typical periodic acid-Schiff (PAS)-positive globules in their liver biopsies and slight fibrosis, whereas none of the heterozygous patients showed these features. Electron microscopical investigation also showed typical findings in the homozygous but not in the heterozygous patients. Further development of liver disease in these young and apparently healthy AAT-deficient patients with early signs of liver damage is not known. It is possible that these patients will develop severe liver disease later in life. It was possible to detect only the three homozygous patients by histochemical examination of liver tissue, since the heterozygous patients did not show PAS-positive globules in their liver.     

Polymerase chain reaction for detection of the alpha-1-antitrypsin Z allele in chronic liver disease

The genetic locus for alpha-1-antitrypsin (alpha-AT) is highly polymorphic, but all protein variants are encoded by a single locus on chromosome 14. Periportal hepatocyte granules are described in association with chronic liver disease and the Z variant. A Z-specific point mutation in exon V of the alpha-AT gene, converting amino acid 342 from Glu to Lys, is thought to be responsible for the hepatocyte accumulation. We describe the use of the polymerase chain reaction (PCR) to amplify exon V of the alpha-AT gene and subsequent detection of the wild-type M- and Z-specific sequences by hybridisation to 32P-labelled-allele-specific oligonucleotides. We applied this technique to leucocyte DNA from 37 patients with suspected chronic liver disease, 25 of whom had hepatocyte alpha-AT inclusion granules on liver biopsy. All 25 were homozygous or heterozygous for the Z allele. One patient, phenotyped as PiS, was found to be PiSZ and another phenotyped as PiZ (presumed homozygous), was found to be a Z heterozygote. No Z allele was detected in any of the twelve patients without alpha-AT inclusion granules. This sensitive PCR technique could be used to assess the relative risk of chronic liver disease in PiZ heterozygotes and to determine whether individuals without the Z amino acid 342 substitution can developed periportal alpha-AT granules.     

Diagnosis of alpha-1-antitrypsin deficiency by DNA analysis of children with liver disease

BACKGROUND: Alpha-1-antitrypsin deficiency is a genetic disorder which is transmitted in a co-dominant, autosomal form. Alpha-1-antitrypsin deficiency affects mainly the lungs and the liver leading, in the latter case, to neonatal cholestasis, chronic hepatitis or cirrhosis. A precise diagnosis of Alpha-1-antitrypsin deficiency may be obtained by biochemical or molecular analysis. OBJECTIVE: The purpose of this study was to use DNA analysis to examine the presence of an alpha-1-antitrypsin deficiency in 12 children suspected of having this deficiency and who showed laboratory and clinical characteristics of the disease. PATIENTS AND METHODS: Twelve patients, aged 3 months to 19 years, who had serum alpha-1-antitrypsin levels lower than normal and/or had hepatic disease of undefined etiology were studied. The mutant alleles S and Z of the alpha-1-antitrypsin gene were investigated in the 12 children. Alpha-1-antitrypsin gene organization was analyzed by amplification of genome through the polymerase chain reaction and digestion with the restriction enzymes Xmnl (S allele) and Taq-1 (Z allele). RESULTS: Seven of the 12 patients had chronic liver disease of undefined etiology and the other five patients had low serum levels of alpha-1-antitrypsin as well as a diagnosis of neonatal cholestasis and/or chronic liver disease of undefined etiology. Five of the 12 patients were homozygous for the Z allele (ZZ) and two had the S allele with another allele (*S) different from Z. CONCLUSION: These results show that alpha-1-antitrypsin deficiency is relatively frequent in children with chronic hepatic disease of undefined etiology and/or low alpha-1-antitrypsin levels (41.6%). A correct diagnosis is important for effective clinical follow-up and for genetic counseling.     

Indomethacin increases liver damage in a murine model of liver injury from alpha-1-antitrypsin deficiency

Homozygous (PIZZ) alpha-1-antitrypsin (alpha(1)-AT) deficiency is associated with the development of liver damage in children as well as chronic liver injury and hepatocellular carcinoma in adults. The alpha(1)-AT mutant Z gene encodes a mutant protein that accumulates in the endoplasmic reticulum of hepatocytes rather than being secreted appropriately into serum. Liver injury is caused by the accumulation of alpha(1)-AT mutant Z protein in hepatocytes, which triggers downstream intracellular injury pathways. However, development of clinical liver disease among PIZZ homozygotes is highly variable, suggesting other genetic or environmental factors contribute to liver injury. In this study, we tested whether nonsteroidal anti-inflammatory drugs (NSAIDs) could be a comorbid factor in the development of liver injury in alpha(1)-AT deficiency using the PiZ mouse. This mouse model is transgenic for the mutant Z allele of the human alpha(1)-AT gene, in which alpha(1)-ATZ expression is regulated by the human promoter regulatory sequences. Our results showed that administration of indomethacin to PiZ mice resulted in increased hepatic injury, indicated by increased hepatocellular proliferation and increased activation of caspase 9. This indomethacin-induced injury was associated with activation of IL-6-STAT3 signaling, increased expression of alpha(1)-AT mRNA, and greater accumulation of mutant polymerized alpha(1)-ATZ protein in livers of indomethacin-treated PiZ mice compared to vehicle-treated PiZ animals. In conclusion, environmental factors, such as exogenous medication administration, can significantly potentiate the liver injury associated with alpha(1)-ATZ hepatic accumulation; NSAIDs may be especially injurious to patients with alpha(1)-AT deficiency, possibly by increasing the expression and accumulation of the hepatotoxic mutant protein.     

Hereditary alpha-1-antitrypsin deficiency in duodenal ulcer

An alpha-1-antitrypsin study was carried out on 184 patients with endoscopically proven duodenal ulcer, 66 first degree relatives of the patients and in 150 healthy controls, to establish the role of genetic factors in the etiology of duodenal ulcer. Alpha-1-antitrypsin served as a genetic marker in this study; it was estimated in terms of serum trypsin inhibitor capacity by the method of Jaccobson. Deficiency of alpha-1-antitrypsin level was recorded in patients as well as their family members when compared with controls.