PURPOSE: It has been stated that arteriohepatic dysplasia is a form of biliary paucity with a good prognosis. We wished to determine the long-term morbidity and mortality associated with arteriohepatic dysplasia.PATIENTS AND METHODS: The charts of all patients with arteriohepatic dysplasia followed by the pediatric gastroenterologists of the University of Minnesota into adulthood were reviewed.RESULTS: Over the last 33 years, the pediatric gastroenterologists have followed 16 children with syndromic paucity, six of whom are now beyond age 18 years. Although five of six patients responded to medical therapy with improvement in their cholestasis and appeared stable clinically through childhood, five of six patients had complications of arteriohepatic dysplasia after age 16 years that resulted in severe morbidity (three) or death (two). These complications included hepatic failure (two), renal failure (one), cerebellar herniation (one), and hepatocellular carcinoma (one). In only one patient were symptoms of the complications present prior to the age of 18 years.CONCLUSION: As more patients with arteriohepatic dysplasia reach adulthood, it appears that this syndrome may be accompanied by long-term manifestations extending beyond childhood. It is important that physicians assuming management of these patients from pediatricians be aware that new abnormalities may appear without warning and that the hepatic disease may deteriorate despite apparent stability through childhood.

Women with severe liver disease often have amenorrhea that resolves as liver disease abates. We describe three patients with mild to moderate chronic liver disease and amenorrhea. In each case amenorrhea resolved when spironolactone therapy was discontinued. We suggest that spironolactone, an androgen inhibitor, may also cause reversible amenorrhea.

To further define the clinicopathologic spectrum and pathogenetic mechanism of the nephropathy associated with alpha 1-antitrypsin (A1AT) deficiency, we evaluated renal specimens from 34 patients with chronic hepatic disease, including 20 with A1AT deficiency (study patients), and correlated these findings with urinalysis evaluation. Glomerular lesions were noted in 79% (15 of 19) of A1AT patients with the PiZZ phenotype, including seven with mesangio-capillary glomerulonephritis (MPGN and focal segmental MPGN), six with mesangial proliferative glomerulonephritis (Mes GN), one with diffuse endocapillary proliferative glomerulonephritis (DPGN), and one with focal segmental mesangial proliferative glomerulonephritis with segmental necrosis (FS Nec GN). One A1AT patient with the PiMZ phenotype did not demonstrate glomerular abnormalities. Focal segmental Mes GN was found in 43% (six of 14) of patients in an age-matched group with chronic hepatic failure unrelated to A1AT deficiency. In nine study patients, glomerular pathology was noted in the presence of a normal urinalysis. Immunofluorescence studies revealed the presence of immunoproteins and the A1AT protein isoelectric forms, PiM and PiZ, in the subendothelial region of glomerular basement membranes in A1AT patients with MPGN, Mes GN, and DPGN. Our results emphasize the heterogeneity of glomerular lesions associated with A1AT deficiency and hepatic disease and the relatively high incidence of MPGN in these children. The presence of abnormal PiZ protein in the subendothelial region of the glomerular basement membrane in A1AT patients with glomerulonephritis suggests a possible role for this protein in the pathogenesis of this lesion.

In an effort to better understand chronic liver transplant rejection, we studied 110 children and adults who survived for at least 2 mo after the transplant procedure. Chronic rejection was defined using a combination of clinical and histopathological criteria and was diagnosed in 10 of the 110 patients for an incidence of 9.1%. All 10 patients were children with the mean age 3.4 yr vs. 21.7 yr for patients without chronic rejection (p less than .001). Males and females were equally represented, and nine received a liver from a gender-matched donor. Four patients were non-Caucasian, resulting in an incidence of 21.7% in non-Caucasian recipients vs. 6.6% in Caucasian recipients (p less than .05). All chronic rejection patients received a liver from an ABO-compatible donor. T-cell crossmatch was negative in all patients in whom it was assessed, and no significant disparity in either the class I or class II human leukocyte antigen loci was noted. Patients who had chronic rejection experienced acute rejection earlier, 11 days vs. 16 days (p less than .05), than patients who did not. In 8 of 10 patients, chronic rejection appeared to evolve directly from early episodes of acute rejection that were unresponsive to immunosuppressive therapy. Two distinct histological presentations were noted. One was progressive loss of bile ducts without hepatocellular injury (four patients), and the other was characterized by worsening ischemic hepatocellular damage and fibrosis (six patients) in addition to severe ductular injury. The first was associated with a more benign clinical course, the second with rapidly deteriorating hepatic function. Three patients recovered spontaneously 9 to 14 mo after transplant, one died awaiting a donor for retransplant, and five had retransplants. We conclude that chronic rejection after the operation is a relatively uncommon complication of liver transplantation with a variable clinical course and unpredictable outcome.

We reviewed the clinical presentation, subsequent course, and outcome of 98 patients with alpha 1-antitrypsin deficiency seen at our institution during the past 20 years to obtain answers to the following questions: (1) What prognostic factors aid in determining the course of liver disease in affected patients? (2) When is the appropriate time for referral to a liver transplant center? (3) Does breast-feeding prevent chronic liver disease? (4) What is the incidence of severe liver disease in family members? Our analysis revealed that the initial values of alanine aminotransferase, prothrombin time, and trypsin inhibitory capacity may have prognostic value. During clinical follow-up the recurrence or persistence of hyperbilirubinemia along with deteriorating results of coagulation studies indicated the need for liver transplantation because of imminent poor outcome. Girls had a worse prognosis than boys. Initial breast-feeding versus feeding of commercial formulas did not influence overall overcome. The incidence of significant liver disease among "at risk" siblings was 21% (3/14); if one assumes mendelian inheritance from heterozygous parents, the overall risk for siblings in our families was 5%.

Journal of Pediatric Gastroenterology and NutritionVolume 10, Issue 1 p. 5-12 REVIEW: PDF Only Pathogenesis of α1–Antitrypsin Deficiency-Associated Liver Disease, 1990 Sarah Jane Schwarzenberg, Sarah Jane Schwarzenberg Department of Pediatrics and The Liver Center, University of Minnesota, Minneapolis, Minnesota, U.S.A.Search for more papers by this authorHarvey L. Sharp, Harvey L. Sharp Department of Pediatrics and The Liver Center, University of Minnesota, Minneapolis, Minnesota, U.S.A.Search for more papers by this author Sarah Jane Schwarzenberg, Sarah Jane Schwarzenberg Department of Pediatrics and The Liver Center, University of Minnesota, Minneapolis, Minnesota, U.S.A.Search for more papers by this authorHarvey L. Sharp, Harvey L. Sharp Department of Pediatrics and The Liver Center, University of Minnesota, Minneapolis, Minnesota, U.S.A.Search for more papers by this author First published: 01 January 1990 https://doi.org/10.1002/j.1536-4801.1990.tb09927.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Volume10, Issue1January 1990Pages 5-12 RelatedInformation

The genes encoding three distinct serine protease inhibitors (Spi) have been cloned from rat liver. These inhibitors are highly homologous with each other and are similar to alpha 1-antitrypsin at the nucleic and amino acid sequence level. Although previous investigators have examined the regulation of the Spi 2 locus by inflammation, the use of various techniques and the complexity of this genetic locus have led to incomplete and somewhat confusing results. Oligonucleotide probes specific for Spi 2.1, Spi 2.2, Spi 2.3, and a 3' mouse cDNA probe for alpha 1-antitrypsin mRNA were used to measure these mRNA after induction of inflammation with subcutaneous turpentine in Fischer rats. alpha 1-Antitrypsin mRNA increased 1.8-fold, and Spi 2.2 increased 7-fold. In contrast, Spi 2.1 and 2.3 mRNA sequences decreased fourfold. The maximal changes occurred between 24 and 48 h after inflammation, with a gradual return toward normal over the next 4 days. Since Spi 2.1, Spi 2.3, and alpha 1-antitrypsin mRNA sequences are responsive to growth hormone, two other growth hormone-responsive mRNA sequences, alpha 2u-globulin and insulin-like growth factor I, were measured, and they also decreased after induction of inflammation. The results of this study show that, despite a marked similarity of nucleotide sequence, Spi 2.1 and 2.3 genes respond very differently from Spi 2.2 and alpha 1-antitrypsin to both growth hormone and inflammation. We speculate that the functions of Spi 2.1 and 2.3 products are different from those of Spi 2.2 and alpha 1-antitrypsin and may involve the regulation of growth.

ABSTRACT: Low IGF-I levels are found in patients with chronic liver disease, but it is not known whether these reductions in IGF-I are secondary to hepatic dysfunction or to malnutrition. To determine whether malnutrition associated with hepatic dysfunction causes the decrease in these levels, serum and liver IGF-I concentrations and liver IGF-I mRNA content were compared in three groups of Sprague-Dawley rats: 15 rats underwent bile duct obstruction; 10 rats were sham-operated and pair-fed with operated rats to control for nutritional status; and 12 rats were sham-operated controls fed ad libitum. In addition, IGF-I peptide and mRNA were compared with food intake, crude nitrogen balance, total wt gain, tail length increase and leg muscle wt. All the parameters were lower in cholestatic and nutritionally deprived animals than in control animals (p < 0.001). There was no difference in serum and hepatic IGF-I and liver IGF-I mRNA values between the 10 cholestatic and pair-fed animals, despite lower crude nitrogen balance, tail length gains, and leg muscle wt in the bile duct-obstructed animals. These studies suggest that in chronic bile duct obstruction, the low serum and hepatic IGF-I levels are primarily due to decreased food intake and appear unrelated to cholestatic liver disease itself. However, factors in addition to suboptimal nutrition and decreased IGF-I levels must also contribute to cholestasisinduced growth failure.

This report describes a new disorder resembling hereditary tyrosinemia (HT) but differing from it in several respects. Similarities include failure to thrive with hypoproteinemia, micronodular cirrhosis, alpha-fetoprotein positive hepatocellular carcinoma, renal Fanconi syndrome with renal tubular ectasia, hypermethioninemia, and hypoglycemia associated with islet cell hyperplasia. However, the tyrosine metabolic pathway was intact. Unique findings include optic atrophy, cerebellar degeneration, and exocrine pancreatic hypoplasia. Polyunsaturated fatty acid (PUFA) status was evaluated in the serum and liver. Initial PUFA profile to serum phospholipids revealed grossly elevated linoleic acid and subnormal linolenic acid. All PUFAs derived from these precursors were absent suggesting gross abnormalities in the utilization of these two essential fatty acids for synthesis of longer chain highly unsaturated structural PUFA. Analysis of liver phospholipids indicated that linoleic acid was lower and w3 and monenoic acids were higher than in the liver specimens from two cases of HT. The gross abnormalities in PUFA pattern, although perhaps secondary to another cause, represent serious structural and functional abnormalities of essential membrane lipids and potentially of eicosanoids derived from them.

Liver transplantation has revolutionized the field of pediatric hepatology. The present status of this therapy is reviewed in this article from a nonsurgical perspective.