Liver Disease In Childhood Research Articles

Children's Liver Disease Foundation

In this fifth article in the series profiling charities and organizations pertinent to gastrointestinal nursing, Catherine Arkley introduces the Children's Liver Disease Foundation, an organization dedicated to fighting childhood liver disease.

Review: Non-alcoholic fatty liver disease in childhood

Non-alcoholic fatty liver disease (NAFLD) is an often undiagnosed entity of chronic liver disease with an uncertain prognosis. Recently NAFLD has probably become the most frequent cause of chronic liver disease in children. The term NAFLD covers a spectrum of non-alcoholic fatty liver disease from benign static disease to more aggressive forms that can progress to cirrhosis within childhood. The term non-alcoholic steatohepatitis (NASH) is nowadays reserved to describe these progressive forms of NAFLD. Insulin resistance is a significant aetiological factor and hence a majority of patients with diabetes, obesity and the metabolic syndrome have the disease. Histological confirmation of NAFLD requires 5% steatosis to support the diagnosis and distinguishes an adult (NASH type 1) and a paediatric form (NASH type 2). Current treatment options focus on lifestyle changes to improve underlying obesity and glucose intolerance. This article provides an overview of currently existing data regarding diagnosis and management of children with suspected NAFLD.

Ascites in childhood liver disease

Ascites is a common clinical problem in children with liver disease. The peripheral arterial vasodilation hypothesis is mostly accepted as the pathophysiological basis of ascites. The most important complication is spontaneous ascitic fluid infection in the form of spontaneous bacterial peritonitis (SBP) and its variants. Aerobic gram-negative bacteria, primarily Escherichia coli, are the most common isolates. Diagnostic paracentesis is done in patients with ascites when diagnosed first time and at the beginning of each admission to hospital. Ascitic fluid is evaluated for cell count with differential, albumin level, total protein and culture. Serum-ascites albumin gradient (SAAG) is the best single test for classifying ascites into portal hypertensive (SAAG> 1.1 g/dL) and non-portal hypertensive (SAAG < 1.1 g/dL) causes. In patients with tense ascites LVP should be performed. A neutrophil count of > 250 cells/mm3 is highly suggestive of bacterial peritonitis. Intravenous cefotaxime is the empiric antibiotic of choice. Long-term administration of oral norfloxacin 5-7.5 mg/Kg once a day in cirrhotic patients with ascitic fluid protein content of < 1g/dL or prior episode of SBP is recommended for prevention of SBP. Oral dual diuretic therapy of single morning dose of spironolactone along with furosemide in the ratio of 5:2 is recommended. While obtaining satisfactory diuretic response dual diuretic therapy can be changed over to monotherapy with spironolactone. Patients should be on sodium restricted diet. Management of ascites might ultimately require liver transplantation.

“Let There Be Bile”‐Understanding Hepatic Injury in Cholestasis

Cholestatic liver disorders account for a large proportion of chronic liver ailments in adults, children and infants, and are among the leading indications for liver transplantation in all age groups. Recent studies have begun to characterize the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids in cholestasis. Steatocholestasis is the combined presence of hepatic steatosis and cholestasis, common in genetic causes of metabolic liver disease in childhood. Retention of hydrophobic bile acids promotes hepatocellular injury and subsequent portal fibrosis in these conditions. Investigations at the mechanistic level have revealed that activation of hepatocyte death receptors, induction of oxidative stress, mitochondrial perturbations and activation of caspases are intracellular pathways that mediate hepatocyte injury. Several compounds in licorice root have been shown to modulate bile acid-induced apoptosis and necrosis of hepatocytes. Further investigations will be needed to identify novel molecular and cellular targets for which pharmaceuticals might be developed, to reduce liver injury and fibrosis in cholestasis and steatocholestasis.

Variable Degree of Liver Involvement in Siblings With PiZZ Alpha‐1‐Antitrypsin Deficiency‐related Liver Disease

PiZZ alpha-1-antitrypsin deficiency is the commonest genetic cause of chronic liver disease, but only 10-15% of PiZZ individuals develop liver disease in childhood. Studies have demonstrated varying patterns of disease progression within siblings with the PiZZ phenotype. We retrospectively analysed the case-notes of all patients diagnosed with PiZZ A1ATD between 1978-2002 and compared the pattern of liver disease between affected siblings. We identified 29 families with more than 1 child with the PiZZ phenotype. Twenty-one (72%) PiZZ siblings of the 29 probands had liver disease, which was concordant for severity in 6 (29%), while 8 (28%) had no liver involvement. Five of 7 children requiring liver transplantation had siblings with no persistent liver dysfunction. This study suggests that there is a variable degree of liver involvement in siblings with PiZZ A1ATD-related liver disease and environmental and/or other genetic factors must be involved in determining disease severity.

Severe liver disease in early childhood due to fibrinogen storage and de novo gamma375Arg→Trp gene mutation

We report hypofibrinogenemia and massive hepatic storage of fibrinogen in a child with cryptogenic chronic liver disease. Fibrinogen gene analysis revealed a de novo Aguadilla (c.1201C>T; p.Arg375Trp) mutation. This mutation should be considered in childhood hypofibrinogenemia associated with chronic liver disease.

Immune Phenotype and Serum Leptin in Children with Obesity-Related Liver Disease

Little is known about pathogenesis of obesity-related liver disease in childhood. Data on the relationship among leptin, immunological parameters, and liver disease in obese children are lacking. Thus, the objective of this study was to evaluate immune phenotype and leptin serum levels in obese children with and without obesity-related liver disease. The study was performed in two groups of consecutive obese children: the first formed by children with obesity-related liver disease, diagnosed in the presence of chronic hypertransaminasemia, liver steatosis at ultrasound, and absence of known etiologies; the second composed of children with isolated obesity. In all patients serum leptin, immunoglobulins, peripheral T, B, and natural killer (NK) cells were evaluated. Twenty-three children in the first group and 16 children in the second were considered eligible. Serum leptin was increased in both groups but without any significant difference. No significant correlation was found between leptin and aminotransferases, lipid serum levels, and all tested lymphocyte subpopulations. Patients with obesity-related liver disease showed significantly higher peripheral NK and B cell counts and IgA levels than children with isolated obesity. Furthermore, no correlation was found between severity of liver disease and lymphocyte subpopulations. In our study, leptin did not correlate with hepatic steatosis, aminotransferases, and serum lipids. Children with obesity-related liver disease showed significantly higher peripheral NK and B cells and IgA levels. Additional studies are required to define the pathogenetic role of these immunological findings.

Increased susceptibility of fat-laden Zucker-rat hepatocytes to bile acid-induced oncotic necrosis: An in vitro model of steatocholestasis

Metabolic liver disorders cause chronic liver disease and liver failure in childhood. Many of these disorders share the histologic features of steatosis and cholestasis, or steatocholestasis. In this study we sought to (1) develop an in vitro model of steatocholestasis, (2) determine the mechanisms of cell death in this model, and (3) determine the role of mitochondrial disturbances in this model. Hepatocytes were isolated from 8-week-old obese (fa/fa) and lean Zucker rats. Cell suspensions were treated with glycochenodeoxycholic acid (GCDC), after which reactive oxygen species (ROS) generation, oncotic necrosis, apoptosis, and ATP content were assessed. Isolated liver mitochondria were exposed to GCDC and analyzed for ROS generation, mitochondrial membrane-permeability transition (MPT), and cytochrome c release. Oncotic necrosis was significantly increased and apoptosis reduced in fa/fa hepatocytes exposed to GCDC compared with that in lean hepatocytes. Necrosis occurred by way of an ROS- and MPT-dependent pathway. Basal and dynamic ATP content did not differ between fa/fa and lean hepatocytes. GCDC stimulated ROS generation, MPT, and cytochrome c release to a similar extent in purified mitochondria from both fa/fa and lean rats. These findings suggest that fat-laden hepatocytes favor a necrotic rather than an apoptotic cell death when exposed to low concentrations of bile acids. The protective effects of antioxidants and MPT blockers suggest novel therapeutic strategies for the treatment of steatocholestatic metabolic liver diseases.

Non-alcoholic fatty liver disease (NAFLD) in children

Childhood NAFLD has become an important childhood liver disease, and it is probably highly prevalent. The full of spectrum of NAFLD has been identified in children. It is not currently known whether or not simple hepatic steatosis in children is benign or whether it evolves to NASH over time. In contrast, childhood NASH certainly can have serious consequences. Cirrhosis is apparently rare in children with NAFLD, but it definitely occurs. Childhood NAFLD may occur in very young children, and there is no female predominance in the pediatric age bracket. Children present with vague abdominal pain, if they have any symptoms at all, but frequently hepatic steatosis is found incidentally on abdominal imaging. Laboratory studies show that serum aminotransferase abnormalities are rather moderate, with serum alanine aminotransferase (ALT) more elevated than serum aspartate aminotransferase (AST). Hypertriglyceridemia is the typical blood lipid abnormality, although hypercholesterolemia may occur. NASH may be more severe in children from certain ethnic groups, including Hispanics and Asians, or in association with certain metabolic disorders characterized by abnormalities in insulin receptor structure or signaling, such as lipodystrophy syndromes. Weight loss through dietary redesign and a regimen of regular exercise remains the mainstay for treatment for childhood NAFLD. A dietary strategy to minimize postprandial hyperinsulinemia and overall fat intake, such as a low glycemic index diet, may be the best dietary strategy. The real efficacy of drug treatments in children requires further investigation. The overriding message is that childhood obesity poses important health problems, including but not limited to potentially severe chronic liver disease. Early diagnosis of children who are only overweight is a worthy goal so that strategies to limit obesity can be instituted as early as possible. Identification of genetic risks is important, but management will invariably require changes in environmental factors. In addition to individual treatment, a multifaceted, societal initiative is required for solving the childhood obesity epidemic.

P0202 PROGRESSIVE FAMILIAL INTRA HEPATIC CHOLESTASIS (PFIC) WITH LOW GAMMA GLUTAMYL- TRANS PEPTIDASE (GGT) LEVELS IN TUNISIAN INFANTS ABOUT 32 CASES

Introduction: Progressive familial intra hepatic cholestasis has been distinguished from other forms of cholestatic liver disease in childhood by clinical findings, clinical-laboratory observations and morphologic studies in biopsy. The aim of the study is to investigate the clinical aspects of PFIC with low GGT in Tunisian patients. Methods: 32 cholestatic infants from 16 unrelated families were retrospectively reviewed. The diagnosis was performed by combination of clinical (pruritus) biological (cholestasis with normal or low level of GGT and normal level of chlesterol), histological features, familial history and high level of serum primary bile acids (done for 40%). Results: The age at presentation ranged from the neonatal period to 12 months. Consanguinity was found in 80%. The constant features were pruritus and hepatomegalia. Short stature found in 58% of infants. Twelve infants have lichenification and enlargement of hands and feet. The cytolysis was important in 45% (> 10N). The histological study was performed for all the patients and showed cirrhosis with inflammatory features and cholestasis. For infants have vesicular lithiasis (12.5%). Response to AUCD treatment was in 55%. Eleven infants (34%) developed portal features respectively at age 5 months and 7 years old. Nine infants (28%) were dead at age from 5 months to 15 years old. Six of them had important cytolysis (>10N) at the presentation. The age of survival infants was ranged from 3.5 to 21.8 years. Conclusion: The prognosis of infants with PFIC can be ameliorated by the development of hepatic transplantation not yet available in our country. Only molecular study if performed will be able to distinguish different form of PFIC 1 and 2.

P0219 IMMUNE PHENOTYPE AND SERUM LEPTIN IN CHILDREN WITH OBESITY-RELATED LIVER DISEASE.

Introduction: Aim: to define the role of leptin and immunological parameters, such as serum immunoglobulins, T and B lymphocyte subpopulations (CD3+, CD4+, CD8+, CD19+) and NK cells in pathogenesis of obesity-related liver disease in childhood. Methods: Two groups of consecutive obese children were studied: the 1st with obesity-related liver disease, the 2nd with isolated obesity. Obesity was defined in presence of a BMI >95° percentile for age, according to CDC criteria. Obesity-related liver disease was diagnosed in presence of hypertransaminasemia, liver steatosis at ultrasound and absence of known causes of liver disease. All patients were tested for liver function tests. All patients underwent an ultrasound assessment of the liver, aimed at identifying presence and severity of liver steatosis. The two groups were compared for leptin serum levels, erythrocyte sedimentation rate, immunoglobulin serum levels, CD3+, CD4+, CD8+, CD19+ and NK in the peripheral blood. Leptin, T and B lymphocyte subpopulations and NK concentrations were tested as previously described (1). Statistical analysis was performed by Student’s t test, Chi-square test and Fisher’s exact test, when appropriate. Results: The 1st group was composed by 23 obese children (18 males; median age 9 years, range 5–14.5) with hypertransaminasemia (mean ALT value 98,8 ± 92,1 IU/L) and steatosis at ultrasound. The 2nd group was composed by 16 obese children (7 males; median age 10.1 years, range 5–15)without signs of liver disease. In both groups leptin serum levels were increased (mean value 28.3 ± 14.7 ng/ml; normal range 10–15 ng/ml) but without significant difference between the two groups. All children with obesity-related liver disease showed significantly higher NK cells in peripheral blood (475 ± 259 cell/mm3; normal range 212–318) than obese children without liver disease (285 ± 138 cell/mm3) (p<0.01). No significant difference between the two groups was found for CD3+, CD4+, CD8+ cells. The value of CD19+ was significantly higher (508 ± 233 cell/mm3; normal range 200–400) in the first than in the second group (344 ± 154 cell/mm3; normal range 200–400) (p<0.01). Conclusion: Although leptin serum levels in adults correlate with liver steatosis (2), in the present study no correlation between circulating leptin concentrations and liver involvement was found. Since children with obesity-related liver disease showed significantly higher levels of CD19+ and NK in peripheral blood, it may be hypothesized that these cells play a role in pathogenesis of obesity-related liver disease.

Liver

The liver’s unique metabolism and relationship to the gastrointestinal tract make it an important target of the toxicity of drugs and xenobiotics. The developmental changes that occur in the liver’s metabolic activity from birth to adolescence contribute to the varied sensitivity to toxins seen in the pediatric population. Hepatic drug metabolism, often with an imbalance between the generation of toxic metabolites and detoxification processes, can influence the degree of hepatotoxicity. The decreased capacity of the neonatal liver to metabolize, detoxify, and excrete xenobiotics explains the prolonged action of drugs such as phenobarbital, theophyline, and phenytoin. The reduced capacity of glucuronide conjugation in the neonate not only predisposes them to physiologic jaundice but also is probably responsible for the chloramphenicol-induced gray infant syndrome. Age-related sensitivity to drugs is attributable in part to differences in metabolic activity. For example, young children are more resistant to acetaminophen hepatotoxicity when compared with adults, whereas children are more susceptible to valproic acid–induced toxicity. The resistance to acetaminophen toxicity is attributable to biochemical differences in young children. In children, sulfation predominates over glucuronidation, leading to decreased formation of toxic intermediates. In addition, infants have a greater capacity to synthesize glutathione, thereby inactivating toxic metabolites of acetaminophen more effectively. Hepatic toxicity as a result of drugs and environmental toxins presents a wide spectrum of clinical disease. Hepatitis is the most common presentation, but every major type of liver pathology can occur. Most drug reactions are attributable to idiosyncratic hepatotoxins; therefore, liver injury occurs rarely. The diagnosis of toxin-induced liver disease requires a high index of suspicion and often entails the exclusion of other causes of liver disease in children. Drug or environmental xenobiotic-induced hepatotoxicity should be considered in the setting of identified exposure or when other causes of childhood liver disease are excluded. Children who take medications that are known to be hepatotoxic, such as anticonvulsants and antineoplastic drugs, need frequent monitoring for evidence of hepatic toxicity. The treatment is often nonspecific; the most important intervention is the prompt discontinuation of the drug or removal of the environmental toxin. A specific antidote is available only for acetaminophen intoxication. In cases of severe toxicity, the patient may develop liver failure. Liver transplantation may be necessary for patients whose liver failure does not resolve.

Adverse Childhood Experiences, Obesity, and Liver Disease—Reply

Adverse Childhood Experiences, Obesity, and Liver Disease—Reply

Hypertrophic osteoarthropathy in a child with biliary atresia

Hypertrophic osteoarthropathy is a syndrome characterized by clubbing of the digits of the hand/foot, periosteal reaction and arthralgia or arthritis which is usually secondary to cyanotic congenital heart disease and chronic pulmonary infections. This syndrome rarely occurs in association with chronic liver disease in childhood. Here, we report on a child with biliary atresia who developed arthralgia and arthritis during follow‐up and which was diagnosed as hepatic hypertrophic osteoarthropathy. It is emphasized that hypertrophic osteoarthropathy should be considered in the differential diagnosis of arthralgia and arthritis in children with long‐standing chronic liver diseases, especially if finger clubbing is also present.

Abnormalities in villin gene expression and canalicular microvillus structure in progressive cholestatic liver disease of childhood

The molecular basis of clinical cholestasis is a subject of intense investigation. Villin is an actin binding, bundling, and severing protein needed for maintenance of structural integrity of canalicular microvilli, in which membrane transporters required for bile secretion are located. We aimed to investigate the role of canalicular cytoskeletal proteins in three genetically unrelated children with a biliary atresia-like clinical disorder, each of whom developed liver failure requiring liver transplantation. Explanted livers from the three patients were examined by standard pathological methods followed by transmission and cryoimmunoelectron microscopy. With archival tissue samples, a panel of cytoskeletal proteins was investigated by immunohistochemistry and western blotting, with purified canalicular membrane preparations. Villin mRNA analyses were undertaken on liver homogenates, with primers from coding regions of the human villin gene. Classic biliary atresia, other types of cholestasis, and normal livers served as controls. In patients, pronounced ultrastructural deformities of canaliculi and especially of their microvilli were noted, which correlated with absence of villin protein by immunostaining of liver tissue sections and by western blot analysis. Additionally, villin mRNA was strikingly reduced or absent. These results differed greatly from those in controls. These results suggest that the disorder described mimics biliary atresia, but structural and molecular pathological findings differ. We propose that a functional abnormality in villin gene expression is key to the mechanism of cholestasis in patients with progressive cholestasis and hepatic failure.

Liver and Biliary Disease in Childhood

Liver and Biliary Disease in Childhood

Steatohepatitis in children

Steatohepatitis in children occurs in the childhood version of non-alcoholic fatty liver disease (NAFLD), as a result of hepatotoxicity and with certain genetic/metabolic diseases. Until recently, NAFLD was considered to be rare in children. It is now recognized as an important childhood liver disease, especially because childhood obesity is much more common. Children with NAFLD may present as young as 4 years old; males tend to predominate; fibrosis is often found on liver biopsy and cirrhosis has been reported. Treatment for childhood NAFLD currently consists of weight reduction plus regular aerobic exercise; vitamin E may be an effective adjunctive therapy. Drug hepatotoxicity and genetic/metabolic diseases that can cause fatty liver, such as Wilson's disease and cystic fibrosis, must be excluded since treatment is radically different. Other causes of chronic hepatitis, such as chronic viral hepatitis, must also be excluded. Multisystemic inherited diseases with hyperinsulinaemia plus insulin resistance may have NAFLD as hepatic involvement and should be identified.

Introducing the New NASPGHAN Web Site

Effective on August 31, 2001, a newly redesigned Internet site for the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) went online for the first time. The introduction of the new site was accomplished concurrently with the official adoption of the new name of the organization, adding “Hepatology” to the previous name. The Internet is arguably the most important medium for dissemination of public information and shaping public perception of an organization. The leaders of NASPGHAN recognized this and charged the Internet Committee with the task of redesigning and improving the old site with all possible speed. Readers of this Journal are encouraged to visit the new site, http://www.naspghan.org, to see what we have been able to accomplish. For the next year, those entering the old address, http://www.naspgn.org, will also be directed to the new site. Those familiar with the old site will be very pleased with the dramatically improved appearance, which will also have much more visual appeal to the general public. The goals of the redesign process were to modernize the look of the site, streamline navigation of the site, and improve the online content. The purpose of the new site is to be the premier Internet address sought by the public for information on childhood digestive and liver diseases. We have also been able to improve the members-only section, easing the access of NASPGHAN members to the services provided by the organization. The new site incorporates the following features: Colorful, modern design. This design, and the many internal improvements listed below, has been accomplished by a highly qualified Web site design firm, Active Web Corporation (Guelph, Ontario, Canada; http://www.activeweb.net). NASPGHAN reviewed bids from several candidates before choosing Active Web. This new graphic design is the most visible of the many exciting changes to the site. Much improved navigation features, with cascading drop-down menus that enable access to all parts of the site from any page. Improved navigation also includes attention to the logical arrangement of pages within the site, making site exploration intuitive and easy. NASPGHAN policy statements are formatted as they appear in the Journal of Pediatric Gastroenterology and Nutrition and are viewable as PDF files. Hidden in the site design is a powerful database. New database-driven features enable improved access to members-only page, allow smart membership directories, rapid self-update of changes in members' information (address, e-mail address, phone number, among others), and advanced features, such as meeting registration. Search feature. The public can search for pediatric gastroenterologists in North America by name and location Enhanced availability of disease information for the public (this will be an ongoing effort, coordinated with the Public Education Committee. Improved search engine for keyword searching of site A fellow's section within the membership-only area Threaded discussion forums for NASPGHAN committee use Searchable job listings within membership-only area Still in development by various NASPGHAN committees are new patient and professional education materials. Our goal of achieving “premier site” status for education of the public will not be reached until such content is expanded. NASPGHAN has a major commitment to this task, and the site can be expected to grow steadily. This will be a continuous process, with regular additions of new materials and continuous review and update of existing information. All new educational materials for the site will be carefully reviewed by the appropriate NASPGHAN committee (Public Education or Professional Education) and approved by the executive council before addition to the site. This editorial process will ensure the quality and consistency of educational materials posted on the Web site. NASPGHAN members can be proud of what their organization is accomplishing to advance the science and art of pediatric gastroenterology and hepatology and to educate the public. The Internet Committee of NASPGHAN has been pleased to be able to take an active role in this process. We as a committee are interested in the input of all members of the organization. Those of you with ideas, including possible additions to the site, are encouraged to contact a member of the Internet Committee, listed below.

Autoimmune hepatitis.

Autoimmune hepatitis is one of the causes of chronic progressive liver disease in childhood. Here we report 14 cases with clinical findings, therapeutic management and prognosis, in order to define the course of the disease. Diagnosis of autoimmune hepatitis was done with the presence of at least one of these autoantibodies; antinuclear antibody, smooth muscle antibody, liver-kidney microsomal type 1 antibody, and perinuclear antineutrophilic cytoplasmic antibody. Patients were seen every 3 to 6 months. After doing a complete physical examination, biochemical parameters and autoantibodies determined at each visit. Mean age at diagnosis was 10.9 +/- 2.6 years (range, 7-15.5 years) and female to male ratio was 1:3. Thirteen patients had jaundice and all had high levels of ALT, AST and gammaglobulin. Hepatomegaly was found in 71.4% and splenomegaly in 64.3% of the patients. All patients were classified as type 1 autoimmune hepatitis. Liver biopsies revealed severe active hepatitis with mononuclear cell infiltration in portal areas, piecemeal necrosis. Drug therapy consisted of prednisone (2 mg/kg/day) per oral at the beginning, and addition of azathioprine (1.5 mg/kg/day) per oral at the 3rd-6th month with slow tapering of prednisone in 12 children. Both drugs were started together to two patients. Follow-up period was 30.7 +/- 15.6 months (range, 12-72 months). Sustained normalization of ALT could not be obtained with tapering doses of prednisone alone. Decrease in ALT levels did not correlate with disappearance of serum autoantibodies. None of the patients showed decompensation of liver disease. Azathioprine administration is necessary to decrease prednisone dose and to maintain a sustained normal transaminase values.

Heterozygous M3Mmalton α1-Antitrypsin Deficiency Associated with End-Stage Liver Disease: Case Report and Review

Alpha1-antitrypsin (alpha1AT) deficiency is an autosomal recessive disorder that can cause pulmonary emphysema and liver disease. We report here the case of a 59-year-old woman who was admitted to hospital for evaluation of jaundice. She had no history of hepatitis or childhood liver disease. She had never received a blood transfusion, nor had she abused drugs or alcohol. Transjugular liver biopsy was then performed and revealed a micronodular cirrhosis. Ten months later, because of persistent liver cell failure and ascites, she underwent an orthotopic liver transplantation. Investigation of alpha1AT system in the proband revealed a substantial decrease in serum alpha1AT associated with a low elastase inhibitory capacity. The Pi phenotype revealed a PiM-like profile. Sequencing of exons 1-5 demonstrated the presence of the M3 allele. Moreover, a triple nucleotide deletion was detected in exon 2 of one allele. This caused an "in-phase" frameshift, coding for a protein deficient in a single Phe residue, which corresponded to the Mmalton variant. After liver biopsy, periodic acid-Schiff-positive acidophilic bodies resistant to diastase digestion were observed in the cytoplasm of hepatocytes. These results demonstrated that our patient had a heterozygous M3Mmalton alpha1AT genotype related to a deficiency phenotype. This observation is the first of a patient with heterozygous Mmalton genotype associated with an alpha1AT deficiency that induced severe liver disease requiring orthotopic liver transplantation.