| Abstract|| |
α1 ,-antitrypsin (α1 AT) deficiency is a relatively common genetic cause of liver disease among Caucasians. It is an autosomal recessive disorder characterized by reduced serum levels of α1 AT, a 52-kD glycoprotein that functions as an antiprotease. The deficiency state is caused by mutations in the α1 AT gene on chromosome 14. α1 AT shows considerable genetic variability, having more than 75 genetic variants (Pi types). The PiZ allele is the most common deficiency variant. PiZZ homozygotes have 15-20% of the normal plasma levels of α1 AT. The deficiency is due to lack of secretion of Z α1 AT from the hepatocyte, where inclusions are formed in the endoplasmic reticulum. Homozygous α1 AT deficiency (PiZZ) is known to predispose to emphysema and chronic liver disease. This review outlines the clinical manifestations and treatment of α1 AT deficiency associated liver disease, focusing on recent advances in the pathogenic mechanism of liver disease in this genetic disorder.
|How to cite this article:|
Elzouki AN. Alpha 1-antitrypsin deficiency and related liver disease. Saudi J Gastroenterol 1999;5:1-8
α1 -antitrypsin (α1 AT), the archetype of the serpin superfamily, is the most abundant circulating protese inhibitor (Pi). It is an acute phase glycoprotein synthesized mainly in the liver, and inhibits a broad variety of serine proteases released by activated neutrophils, including neutrophil elastase (NE) and proteinase 3 (PR3)  . The Pi locus for α1 AT is on chromosome 14 at 14g32.1  . α1 AT is characterized by considerable genetic variation, more than 75 genetic variants (Pi types) having been recognized  . The PiZ allele is the most common deficiency variant. PiZZ homozygotes have 15-20% of the normal plasma levels of α1 AT. The deficiency is due to lack of secretion of Z α1 AT from the hepatocyte, where inclusions are formed in the endoplasmic reticulum (ER). There are several rare deficiency types, including some that show lack of secretion, and some that have no product (null or QO).
α1 AT deficiency is a relatively common genetic cause of liver disease among Caucasians. Studies of this error of metabolism have not only provided new insights into the pathogenesis of emphysema, the major clinical sequela of the deficiency state, but have also provided a model for a new type of liver disease. Abnormal α1 AT is accumulated in the ER and consequently one may speak of an ER storage disease, quite distinct from the better known lysosomal storage diseases. Furthermore, several recent studies have shown that α1 AT deficiency is overrepresented in patients with systemic vasculitis ,,, . Moreover, a subnormal response of plasma α1 AT seen in vasculitic patients enhances the risk of dissemination of the vasculitic proces and the risk of a fatal outcome , . This article outlines the clinical manifestations and treatment of a,AT deficiency associated liver disease, focusing on recent advances in the pathogenic mechanism of liver disease in this inborn error.
| Childhood onset liver disease|| |
α1 AT deficiency is the most common genetic cause of liver disease in infants and children and is the most common metabolic error for which liver transplantation is indicated  . Clinically important liver disease occurs in about 10-20% of all neonates with homozygous (PiZZ) α1AT deficiency, but the majority (70%) have abnolnlal liver function tests  . The most predominant sign of liver abnormality associated with α1AT deficiency is the neonatal hepatitis syndrome characterized by pruritus, conjugated hyperbilirubinemia, increased serum aminotransferase levels, frequently with hepatomegaly and paucity of intrahepatic bile ducts on histopathological examination , . Signs of cholestasis begin between 4 days and 2 months after birth and can persist from weeks up to 8 months. Cholestasis can be severe enough to cause acholic stool and the disease can be confused with hepatic biliary atresia. Spontaneous clinical regression is common and usually occurs before 6 months of age, although mild biochemical abnormalities can persist. In minority of the homozygous (PiZZ) neonates who develop liver disease, the disease does not subside but goes on to cirhosis and liver failure  . Before age of 20, cirrhosis and/or fibrosis occurs in approximately 3% of individuals born with α1 AT deficiency, representing about 30% of all neonates who develop cholestasis. In most of these children, there is progressive liver failure, resulting in death unless corrected by liver transplantation  . Liver disease associated with α1AT deficiency may also be first discovered in late childhood when the affected individual presents with abdominal distention due to hepatomegaly and signs of portal hypertension , .
The only available prospective data on the natural history of PiZZ α1AT deficiency-associated liver injury were elicited in the Swedish nationwide screening study by Sveger  . In this study, 200,000 newborns were screened and 127 PiZZ infants identified, of them 22 manifested clinical signs of liver disease in infancy. Of these 22, two died early in life of cirrhosis. Another two children died of other causes, though autopsy showed the presence of histological signs of cirrhosis in one of them and fibrosis in the other. Approximately 50% of the remainder of the 127 children had abnormal liver function test results. Followup studies of the original cohort of 127 PiZZ children at 12 years of age  and at 18 years of age  showed that 13% of these subjects still had marginally abnormal liver function test results, but none have manifested clinical signs of liver dysfunction [Figure - 1]. Contrary to the initial indications of a poor prognosis in children with α1AT deficiency and early liver symptoms (19) , this prospective cohort has shown more than two-thirds of the children to recover from their liver damage up to age 20.
| Adult onset liver disease|| |
Cirrhosis and fibrosis of the liver were noted early on in Swedish adults with α1AT deficiency  . Larsson found 12% of 246 Swedish adults with α1AT deficiency, identified through hospital admissions, to have liver cirrhosis  ; of PiZZ individuals over 50 years of age, 19% had cirrhosis. Of a series of 115 Canadian adults with α1AT deficiency, four had biopsy or autopsy-verified cirrhosis, and two manifested definite biochemical evidence of liver disease, i.e. a total prevalence of liver disease of 5.2%  . When these patients were subgrouped by sex and age, the risk of liver disease was higher for the male than the female subgrouped by sex and age, the risk of liver disease was higher for the male than the female subgroup and reached a peak of 15.4% at age 51-60 years. No corresponding figures for the general population were reported for these studies. In an epidemiologic study based on representative autopsy cases, α1AT deficiency (PiZZ) was found to manifest strong relationship both with cirrhosis and with hepatocellular carcinoma, though the relationships were statistically significant only for male patients  . In a more recent autopsy-based case-control study we have substantiated a high risk of cirrhosis also to be inceased in female PiZZ-deficients  . Approximately 40% and 15% of α1AT-deficient adults had cirrhosis and hepatocellular carcinoma, respectively  . Cirrhosis in adults with α1AT deficiency can occur without preceding history of childhood liver disease. The liver disease in adults appears to be characterized by rapid progression and, in most patients, death occur within two years of the diagnosis of cirrhosis, partially due to concomitant emphysema. The estimated prevalence and estimated age at death due to liver disease in PiZZ-individuals are shown in [Figure - 2].
| Pathogenic mechanism of liver disease in α1AT deficiency|| |
Individuals who synthesize the PiZ variant almost always manifest an aggregation of PAS-positive inclusion bodies in the ER of hepatocytes. Biochemical studies and immunoelectron microscopy has shown this material to consist of human α1AT that has accumulated within distended regions of the hepatocyte ER  . Individuals manifesting this intrahepatic aggregation of mutant α1AT are at increased risk of developing cirrhosis, because it is directly related to liver cell injury  . There is no evidence that the liver injury in α1AT deficiency is due to a deficiency of elastase inhibitory capacity (i.e. the protease-antiprotease imbalance). The strongest clinical argument against this hypothesis is the fact that Pi null (QO) individuals, i.e. patients with no detectable α1AT in their plasma, do not develop liver disease  . More importantly, individuals with Pi null (QO) lack the PAS-positive inclusion bodies. Furthermore, those with the PiS variant, who also lack the PAS-positive inclusion bodies, do not develop liver disease despite low plasma α1AT levels.
A conceptual model for the fate of the PiZ α1AT in the ER has recently been proposed by Qu et al  . Normally, α1AT molecules are synthesized in the hepatic cells begining with the transcription of mRNA from the α1AT gene. The rnRNA is then translocated out of the nucleus and translated on the ER to form a protein in the lumen of the ER. It may transiently associate with a polypeptide chainbinding protein (PCBP) until it has folded into a conformation that allows it to translocate to the Golgi apparatus. In α1AT-deficient individuals, the abnormal molecule is translocated into the lumen of the ER and associates with PCBP but is much less efficient at folding into the translocation-component, because of a single amino acid substitution (Glu 342→Lys) in a peptide fragment of the α1AT molecule. Only 15% of the newly synthesized molecules traverse the secretory pathway to the Golgi apparatus. Most newly synthesized α1AT molecules remain bound and ultimately undergo degradation in the ER. Therefore, any factor that inceases the net balance of abnormally folded α1AT in the ER would predispose the α1AT-deficient individual to hepatic disease. Experimental results in transgenic mice, with normal plasma α1AT levels, are consistent with this theory and exclude the possibility that liver damage is caused by a 'proteolytic attack' as a consequence of diminished serum α1AT concentrations , .
| Mechanism of Z α1AT aggregation in the ER|| |
One possible mechanism of Z α1AT aggregation in the ER has recently been suggested , . These studies have shown that the α1AT can polymerize when the reactive center loop of an α1AT molecule is inserted into a gap in the β-pleated sheet of an adjacent native α1AT molecule. Lomas and coworkers  , noted that the site of the amino acid substitution in the PiZ α1AT variant was at the base of the mobile reactive center loop, adjacent to the gap in the A sheet. These authors predicted that the mutation would act to open the A sheet, thereby favoring spontaneous loop into β-sheet polymerization [Figure - 3], a process that is both concentration and temperature dependent. Presumably, an increase in body temperature during systemic inflammation may thus accelerate the polymerization process and increase the intracellular aggregation thus exacerbating subsequent liver cell damage. Using electron microscopy, these authors showed the presence of such polymers in the ER of hepatocytes in a liver biopsy specimen from a PiZZ individual  . They also showed the presence of similar polymers in the plasma of patients with other mutants of α1AT than PiZ: α1AT iivama (Ser 53Phe) and α1AT M malton (52Phe deletion ) , . As a AT is an acute-phase protein, its level will increase during episodes of inflammation. At these times, the formation of polymers is likely to overwhelm the degradative pathway, thereby promoting an increase of hepatic inclusions and exacerbating the associated hepatocellular damage  .
| Factors that may modulate liver disease in α1AT deficiency|| |
Although the structural defect resulting in aggregation of Z α1AT is known, less is known about why the aggregation of this deficient variant (PiZ) should cause liver injury. Any pathogenesis proposed for permanent liver injury must take into consideration the fact that the majority of homozygotes (PiZZ) do not develop liver disease. Because the polymerization defect is universal in such individuals, the presence of hepatocyte inclusion bodies does not provide a full explanation. This suggests that additional environmental agents or the presence of auxiliary genetic determinants may be required to produce hepatocyte injury in such individuals. Findings in a recent investigation, using mutant protein insertion into fibroblasts from α1AT-deficient patients who develop liver disease, suggest the possibility that a second inherited defect (i.e. a lag in ER degradation) exists in the ER, which does not allow adequate degradation of the Z α1AT  . Alcohol consumption has not proved to be an important additional factor in the development of liver disease in homozygous (PiZZ) adults with α1AT deficiency , but may be important as an additional factor in the development of liver disease in heterozygous (PiZ) individuals with α1AT deficiency  . An Austrian study has suggested chronic liver disease in patient with α1AT deficiency to be associated with a high prevalence of viral hepatitis, particularly hepatitis C infection  . This infection, rather than α1AT deficiency alone, was suggested to be the cause of the liver disease in such patients. But PiZ homozygosity does not seem to be associated with an increased prevalence of virus infection , . Moreover, Eigenbrodt and coworkers have shown an association to exist between heterozygous α1AT deficiency (PiZ) and end stage liver disease of several etiologies, but not of HCV infection alone  . These authors concluded that the association with some types of chronic liver disease (i.e. hepatitis C infection and alcoholic liver disease) but no others (i.e. autoimmune hepatitis) supports the concept that exaggeration of the retention of α1AT may be the pathogenetic mechanism involved. It has been shown that at least two products of hepatitis C virus bind with calnexin and are retained in the ER  ; therefore, it has been suggested that hepatitis C infection could exaggerate the hepatotoxic effect of α1AT in the heterozygote by competing with α1AT for binding to calnexin, in effect preventing the abnormal α1AT from accessing the degradative compartment  .
Isolated case reports have suggested relationship to exist between severe α1AT deficiency and genetic hemochromatosis (GH) , and more recently correlation was reported to exist between heterozygous (PiZ) α1AT deficiency and GH in a series of 15 patients referred to a liver transplantation center in the USA  . In a recent study  , no relationship was found to exist between GH and heterozygous α1AT deficiency, but unexpectedly 4.5% of the GH patients were found to be homozygous for the PiZ gene, a proportion more than 80-fold greater than that expected in the general population. The presence of the PiZ gene in these patients contributed to an earlier onset of cirrhosis. The hemochromatosis gene, HLA-H, has recently been cloned and two mutations have been described (Cys 282→Tyr and His 63→Asp) , . Further studies are needed to evaluate that frequency of these mutations of the HLA-H, gene in patients with homozygous and heterozygous α1AT deficiency.
| Heterozygous a,AT deficiency and chronic liver disease|| |
Heterozygous carriers of a single dose of the mutan PiZ-gene are frequent in the general population, close to 5% in the Scandinavian countries. Most heterozygous deficients are PiMZ and have 50-60% of nonnal plasma a,AT level and a minority, approximately 1/750, are PiSZ and have 30-40% of the normal plasma α1AT level  . Two screening programmes have provided information about the propensity of PiZ-heterozygotes to develop liver disease early in life. In the first  close to 25.000 Italian new boors were subjected to Pi-phenotyping of α1AT by isoelectric focusing. Liver function tests were performed in 833 PiMZ children. The results were noteworthy, and clearly demonstrated a partly self-limiting, predominantly subclinical liver involvement in 19% of the children with intermediate α1AT deficiency. The results of a long-term follow-up is awaited with great interest. Sveger's prospective study  , discussed above, includes not only PiZ homozygotes but also a number of PiSZ heterozygotes. In adolescence age 16 and 18 years, 8 and 12% of the PiSZ subjects had subtle serum enzyme abnormalities respectively. PAS-positive inclusion bodies are less abundant in heterozygotes than in homozygotes, and the presence of some additional factor such as chronic virus infection may be necessary to provoke serious liver disease. We have recently studied 706 consecutive patients with clinical and/or biochemical evidence of chronic liver disease, 44 were found to have the PiZ variant of a,AT deficiency, of whom one was a homozygote (PiZZ) and the remaining 43 were heterozygotes (PiZ)  . Although there was no overrepresentation of chronic viral infection (B or C) or alcohol abuse in heterozygous α1AT deficiency as compared to the non-PiZ carriers, the possibility that viral infection or alcohol abuse is associated with greater severity of liver disease in PiZ-heterozygotes could not be excluded. These findings are noteworthy, if confirmed in a larger population of PiZ-carriers, because they bear out the long-held notion of many clinicians that heterozygosity for the α1AT gene should not be accepted as a diagnostic cause of severe liver disease. One possible explanation is that exogenous factors (i.e. the presence of viral hepatitis and/or alcohol abuse) cause liver injury, which in turn brings the patient to the attention of the hepatologist, it being this attention alone that results in the detection of the PiZ heterozygous state. Were this true, then the prevalence of the heterozygosity would be the same among patients with hepatitis C infection or among alcohol abusers as it is in the general population. To the best of knowledge such data are not available. Another possible explanation is that the presence of theα1AT PiZ gene product predisposes to viral infection. Were this true, however, then the viral infection rate should be even higher among homozygotes, which we did not find to be the case  . Clearly, further studies of large series of heterozygotes for α1AT deficiency with chronic liver disease are needed to investigate the presence of such risk factors that might predispose to chronic liver disease, and to test these factors for correlation to the severity of liver disease.
| Treatment|| |
The diagnosis ofα1AT deficiency in a patient, irrespective of the mode of presentation (lung, liver or other symptoms, i.e. vasculitis), should lead to family investigations, at least of first degree relatives. It is important to identify homozygotes (25% of siblings are homozygotes) in an early and asymptomatic stage. Emphysema is the basic defect in α1AT deficiency-related lung disease. It is, however, desirable to perform lung function studies occasionally even in asymptomatic non-smoking individuals with homozygous α1AT deficiency (PiZZ). Emphysema development may occur in such individuals, particularly after age 50  . Avoidance of smoking is an important preventative therapy.
A regular assessment of liver function is appropriate for all patients with α1AT deficiency particularly the homozygotes (PiZZ). Considering the indolent nature of the liver disease test reflecting total hepatocellular function should be the most useful in monitoring. Amino transferases and bilinibin may be normal at any given time. In elderly patients with severe α1AT deficiency the significant risk of malignant transformation in a cirrhotic liver should be recognized  . Physicians should also be alert to the possible of renal disease , and vasculitic complications in both heterozygous ,,, and homozygous deficiency  .In adults rapidly progressive decompensation of liver disease is frequent. In the absence of serious pulmonary manifestations, indication for liver transplantation are essentially those for decompensation due to chronic liver disease of any type. Careful preoperative evaluation of lung function and for the presence of hepatocellular carcinoma is mandatory. In children, a ,AT deficiency (PiZZ) constitutes the largest indication subgroup of metabolic errors for liver transplantation. But, as demonstrated in the large Swedish prospective series  only a minority of all children with α1AT deficiency will develop cirrrhosis before age 20. Many of them have a slow disease progression and favourable prognosis despite biochemical (transferase) or even clinical signs (hepatomegaly) of chronic liver disease. When liver transplantation is performed survival rates in children are excellent, close to 90% at one year and 80% at five years. Survival rate in adults is lower partly due to concomitant disease manifestations such as emphysema.
At present somatic gene therapy is not a realistic therapeutic alternative for α1AT deficiency related liver disease. To have significant effect, hepatic gene therapy must ideally result in correction of the genetic defect in a majority of cells. So far, levels of transferred gene products have been too low and been maintained only transiently. Both retro- and adenoviral vectors have been disappointing and even if the gene products had reached significant levels residual PiZ genes may possibly have hepatotoxic effects via feed-back induction of the aberrant PiZ protein. Attractive alternatives for treatment of liver disease are novel types of gene therapy permitting inhibition of PiZ protein synthesis and thereby accumulation of the aberrant protein in the ER (reviewed by Qu et al, reference 27).
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Department of Medicine, Malmo University Hospital, 205 02 Malmo
Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2], [Figure - 3]