Inherited metabolic liver disease

Current Opinion in Gastroenterology

Volumn 21, Issue 3, 2005, Pages 275-282

  Schilsky, Michael L ^a   Oikonomou, Ioannis ^a  

^a WEILL CORNELL MEDICAL CENTER   (United States)

Author keywords

Alpha one anti trypsin; Copper; Hemochromatosis; Iron; Wilson disease

Indexed keywords

4 PHENYLBUTYRIC ACID; ADENOSINE TRIPHOSPHATASE; ALPHA 1 ANTITRYPSIN; ATOX 1 PROTEIN; COPPER; CYTOPLASM PROTEIN; FERRITIN; FERROPORTIN 1; FK 506 BINDING PROTEIN; HEMOJUVELIN; HEMOPROTEIN; HEPCIDIN; IRON; TRANSFERRIN; UNCLASSIFIED DRUG;

ALPHA 1 ANTITRYPSIN DEFICIENCY; CHROMOSOME 2; COPPER METABOLISM; GENE; GENE MUTATION; GENETIC DISORDER; HEMOCHROMATOSIS; HUMAN; IRON METABOLISM; IRON OVERLOAD; LIVER DISEASE; METABOLIC DISORDER; MURR1 GENE; REVIEW; WILSON DISEASE;

ALPHA 1-ANTITRYPSIN DEFICIENCY; HEMOCHROMATOSIS; HEPATOLENTICULAR DEGENERATION; HUMANS;

EID: 17844367116     PISSN: 02671379     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.mog.0000159821.78532.21     Document Type: Review

References (24)

1. Kulaksiz H, Gehrke SG, Janetzko A, et al. Pro-hepcidin: expression and cell specific localization in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia. Gut 2004; 53:735-743. This study demonstrates the presence of the hepcidin precursor molecule (pro-hepcidin) in liver tissue and in the circulation treated as well as untreated patients with genetic hemochromatosis, providing further evidence for hepcidin dysregulation in HFE-associated genetic hemochromatosis.
2. Jacolot S, Le Gac G, Scotet V, et al. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood 2004; 103:2835-2840. (Epub 2003 Dec 11) Phenotypic expression of disease was examined in a cohort of 392 patients with GH and C282Y homozygosity HAMP (hepcidin) mutations. The presence of heterozygous mutations for two different genes involved in iron metabolism therefore could result in an adult-onset form of iron overload, whereas heterozygosity for these mutations by itself is unable to cause iron overload.
3. Pietrangelo A. Hereditary hemochromatosis - a new look at an old disease. N Engl J Med 2004; 350:2383-2397. An excellent review of the current understanding of the many genes involved in iron overload disorders
4. Frazer DM, Wilkins SJ, Millard KN, et al. Increased hepcidin expression and hypoferraemia associated with an acute phase response are not affected by inactivation of HFE. Br J Haematol 2004; 126:434-436. These investigators used a model the HFE knockout mouse subjected to acute phase activation to increase hepcidin expression. Findings suggest that mutations of HFE do not entirely remove the connection between hepcidin and iron absorption, but modify their regulation in an unexplained manner.
5. Barton JC, West C, Lee PL, Beutler E. A previously undescribed frameshift deletion mutation of HFE (c.del277; G93fs) associated with hemochromatosis and iron overload in a C282Y heterozygote. Clin Genet 2004; 66:214-216. An individual with iron overload was found to be heterozygous for the C282Y mutation but absent H63D or S65C HFE mutations. Study of the other allele revealed a novel frameshift mutation of HFE that resulted in a premature stop-codon for this gene in exon 2. This led to expression of only a single copy of the mutant protein expressed in this individual and associated iron overload. The frequency of this novel mutation in the population is unknown.
6. Davies PS, Enns CA. Expression of the hereditary hemochromatosis protein HFE increases ferritin levels by inhibiting iron export in HT29 cells. J Biol Chem 2004; 279:25085-25092. (Epub 2004 Mar 25) Using the enterocyte derived cell line HT29 that can polarize in specific culture conditions, no change in transferrin mediated iron uptake was seen upon HFE expression, however iron efflux decreased. These results contrast with prior studies by these investigators showing in other cell lines derived from tissues not involved in iron export and metabolism like macrophage or reticuloendothelial cells, HFE functions to decrease transferrin mediated iron uptake. HFE protein may therefore be multifunctional, interacting with different pathways involved in iron metabolism to maintain homeostasis in different cell types.
7. Huang FW, Rubio-Aliaga I, Kushner JP, et al. Identification of a novel mutation (C321X) in HJV. Blood 2004; 104:2176-2177. (Epub 2004 May 11) Novel mutations of the HJV gene were detected in a patient with juvenile hemochromatosis and unaffected parents. The mother was heterozygous for two novel mutations, including a mutation resulting in premature termination and another conservative mutation in the HJV peptide; the father was heterozygous for a previously identified missense mutation of HJV. The patient was a compound heterozygote with all three mutations. The occurrence of iron overload in such young patients in non-HFE iron overload in a patient with HJV mutations suggests that we need a different threshold for the age at which screening for iron overload should begin.
8. Wallace DF, Clark RM, Harley HA, Subramaniam VN, Autosomal dominant iron overload due to a novel mutation of ferroportin 1 associacted with parenchymal iron loading and cirrhosis. J Hepatol 2004; 40:710-713. Cirrhosis was found in a family member at age 32 with ferroportin mutation and associated sarcoidosis. Levels of ferritin and transferrin saturation were elevated. Tissue iron deposition was mainly parenchymal with only a small amount present in Kuppfer (reticuloendothelial) cells. The occurrence of cirrhosis at such a young age may be due to the concurrent sarcoidosis, and suggests that other diseases may affect clinical expression of iron overload and hepatic fibrogenesis in patients with underlying genetic disorders that may lead to iron overload phenotype.
9. Power TE, Adams PC. Hemochromatosis patients as voluntary blood donors. Can J Gastroenterol 2004; 18:393-396.
10. Delatycki MB, Powell LW, Allen KJ. Hereditary hemochromatosis genetic testing of at-risk children: what is the appropriate age? Genet Test 2004; 8:98-103. These authors screened the literature for information on the onset of disease expression and currently published recommendations for hemochromatosis. They found that for patients with C282Y homozygosity, only rare individuals manifested iron overload in the first two decades of life, and associated morbidity was reported in only one. The authors therefore recommended delaying genetic testing for hemochromatosis until late teenage years.
11. Crawford DH, Fletcher LM, Hubscher SG, et al. Patient and graft survival after liver transplantation for hereditary hemochromatosis: Implications for pathogenesis. Hepatology 2004; 39:1655-1662. Examined the outcomes of liver transplantation for 22 male patients with GH, and graft function and iron mobilization in 12 recipients of iron-loaded grafts (compared to cohort of 3600 adult primary orthotopic liver transplants).
12. Stuart KA, Anderson GJ, Frazer DM, et al. Increased duodenal expression of divalent metal transporter 1 and iron-regulated gene 1 in cirrhosis. Hepatology 2004; 39:492-499. The expression of proteins involved in iron transport and transfer in enterocytes was examined in duodenal tissue samples from 46 patients with cirrhosis and 20 controls. Demonstrated that DMT1 and Ireg1 expression was increased 1.5-3-fold in cirrhotic patients compared to iron replete controls. DMT1 expression was influenced by serum ferritin and cirrhosis, but only serum ferritin was associated with changes in Ireg1 expression. The mechanism by which DMT1 was altered in cirrhosis is unknown, but speculatively could be due to reduced hephaestin production in a severely impaired liver.
13. Dhungana S, Taboy CH, Zak O, et al. Redox properties of human transferrin bound to its receptor. Biochemistry 2004; 43:205-209. This study showed that the human transferrin receptor plays more than a passive role in the process of iron uptake by raising the reduction potential of ferric iron by more than 200 mV when tranferrin is bound to the transferrin receptor. Therefore, the interaction of transferrin and its receptor are essential for the physiological reductive release of iron from transferrin, an Important step in iron uptake by cells.
14. Iorio R, D'Ambrosi M, Marcellini M, et al. Persistence of elevated aminotransferases in Wilson's disease despite adequate therapy. Hepatology 2004; 39:1173-1174. A retrospective review of data from 107 consecutively treated children with Wilson disease who were treated for at least 12 months. In 35% of children with liver disease due to Wilson disease, aminotransferases remained elevated, although the median elevation was markedly diminished by two-threefold in most compared to pretreatment values.
15. Pinter R, Hogge WA, McPherson E. Infant with severe penicillamine embryopathy born to a woman with Wilson disease. Am J Med Genet 2004; 128A:294-298. Case report of an infant born to a mother treated with d-penicillamine with multiple defects that included dermatologic and neurological problems, only some of which resolved with time. Fetal copper deficiency induced by treatment may be a possible cause of the abnormalities, though other toxic effects of the medication cannot be excluded.
16. Muller T, Langner C, Fuchsbichler A, et al. Immunohistochemical analysis of Mallory bodies in Wilsonian and non-Wilsonian hepatic copper toxicosis. Hepatology 2004; 39:963-969. These investigators explored the pathogenesis of Mallory bodies by immunohistochemical analysis.
17. Stuehler B, Reichert J, Stremmel W, Schaefer M. Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients. J Mol Med 2004; 82:629-634. MURR1 gene sequences were analyzed in 3 exons of the MURR1 gene in 63 Wilson disease patients. This study suggests that changes in other genes involved in copper homeostasis may influence the phenotypic expression of Wilson disease.
18. Sanokawa-Akakura R, Dai H, Akakura S, et al. A novel role for the immunophilin FKBP52 in copper transport. A novel role for the mmunophilin FKBP52 in copper transport. J Biol Chem 2004; 279:27845-27848. Using two-hybrid system technology to examine protein-protein interactions, these investigators identified interactions of the metallochaperone Atox-1 with FK506-binding protein 52 (FKBP52), an immunophilin that has been implicated in the regulation of neuronal survival and nerve regeneration. Results suggest that FKBP52 may be involved in copper efflux and could be neuroprotective in the face of copper toxicosis.
19. Meng Y, Miyoshi I, Hirabayashi M, et al. Restoration of copper metabolism and rescue of hepatic metabolism in LEC rats, an animal model of Wilson disease, by expression of human ATP7B gene. Biochim Biophys Acta 2004; 1690:208-219. Study clearly shows that introduction of ATP7B gene alone can correct the phenotype of Wilson disease.
20. Lawless MW, Greene CM, Mulgrew A, et al. Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency. J Immunol 2004; 172:5722-5726. An in vitro model system of PiZZ A1AT ER accumulation was used to investigate the ER stress signals induced by PiZ A1AT. Study findings could influence the design of future treatment of this disorder.
21. Teckman JH, An JK, Blomenkamp K, et al. Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol 2004; 286:G851-G862. ([Epub 2003 Dec 18]) New evidence is presented in this study demonstrates that the autophagic response induced by ER retention of A1ATZ involves the mitochondria.
22. Rudnick DA, Liao Y, An JK, et al. Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency. Hepatology 2004; 39: 1048-1055. In this transgenic mouse model of A1AT deficiency, an increased proliferation of hepatocytes and caspase 9 activation in male mice compared to females was paralleled with similar increased A1AT Z accumulation in males. Testosterone treatment of females increased A1ATZ expression and hepatocellular proliferation to levels seen in mate animals. In the diseased liver, cells without accumulated mutant protein selectively increased, however following partial hepatectomy, similar increases were seen:for cells with A1ATZ accumulation as was observed for those without accumulated retention.
23. Teckman JH. Lack of effect of oral 4-phenylbutyrate on serum alpha-1-antitrypsin in patients with alpha-1-antitrypsin deficiency: a preliminary study. J Pediatr Gastroenterol Nutr 2004; 39:34-37. Clinical trial of an experimental chemical chaperone that did not demonstrate efficacy for this compound in increasing A1AT in the circulation of treated patients.
24. Duan YY, Wu J, Zhu JL, et al. Gene therapy for human alpha1-antitrypsin deficiency in an animal model using SV40-derived vectors. Gastroenterology 2004; 127:1222-1232. In these studies, a transgene containing a ribozyme (an RNA fragment designed to specifically targets a unique mRNA) was introduced into the livers of an animal model for A1AT with mutant human A1AT protein using recombinant simian virus 40 (rSV40) vectors. Expression of the ribozyme for the mutant human protein resulted in a decrease in the expression of A1AT with reduced circulating levels of the A1AT protein at 3-16 weeks after the introduction of the transgene. In other studies, a human construct for A1AT that was resistant to the ribozyme was introduced. Multiple injections of the rSV40 vector with the transgene led to over 90% of liver cells with transgene expression, and levels of A1AT in the circulation at levels > 1 mcg/ml for a year.