Inherited metabolic disease of the liver

Current Opinion in Gastroenterology

Volumn 24, Issue 3, 2008, Pages 278-286

  Taddei, Tamar ^a   Mistry, Pramod ^a   Schilsky, Michael L ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

1 antitrypsin; ATP7B; Glycogen storage disease; Hemochromatosis; Hepcidin; Wilson disease

Indexed keywords

ADENOVIRUS VECTOR; BONE MORPHOGENETIC PROTEIN 2; COPPER; DEFERIPRONE; DEFEROXAMINE; GLYCOGEN; HEPCIDIN; IRON; PENICILLAMINE; TRIENTINE; ZINC;

ALPHA ANTITRYPSIN DEFICIENCY; COPPER METABOLISM; CYSTIC FIBROSIS; DISEASE ASSOCIATION; EARLY INTERVENTION; ENZYME REPLACEMENT; GAUCHER DISEASE; GENE MUTATION; GENETICS; GLYCOGEN METABOLISM; GLYCOGEN STORAGE DISEASE; HEMOCHROMATOSIS; HUMAN; IRON METABOLISM; IRON OVERLOAD; IRON TRANSPORT; LIVER ADENOMA; LIVER CELL CARCINOMA; LIVER METABOLISM; LIVER TRANSPLANTATION; MALIGNANT TRANSFORMATION; METABOLIC DISORDER; MODULATION; NONHUMAN; PHENOTYPE; PLASMAPHERESIS; PROTEIN FOLDING; PROTEIN FUNCTION; REVIEW; VIRAL GENE THERAPY; WILSON DISEASE;

ALPHA 1-ANTITRYPSIN DEFICIENCY; HUMANS; LIVER DISEASES; METABOLISM, INBORN ERRORS;

EID: 42149174905     PISSN: 02671379     EISSN: None     Source Type: Journal    
DOI: 10.1097/MOG.0b013e3282fcbc0f     Document Type: Review

References (40)

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2. Wang RH, Li C, Xu X, et al. A role for SMAD4 in iron metabolism through positive regulation of hepcidin expression. Cell Metab 2005; 2:399-409.
3. Piperno A, Girelli D, Nemeth E, et al. Camaschella blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Blood 2007; 110: 4096-4100. Hepcidin levels from urine samples of 88 hemochromatosis patients (61 C282Y/C282Y, 27 C282Y/H63D) and 23 healthy controls were analyzed before and 24 h after a 65-mg oral iron dose. The hepcidin/ferritin ratio was decreased in both homozygotes (P < 0.001) and heterozygotes (P = 0.017), confirming dysregulated hepcidin production in hemochromatosis patients. After oral iron was given, mean urinary hepcidin excretion increased in controls (P = 0.001), but not in hemochromatosis patients, irrespective of genotype and iron status. This lends further credence to the role of HFE in iron sensing and its link to hepcidin as the effector mechanism for iron loading in afflicted patients.
4. Milet J, Dehais V, Bourgain C, et al. Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance. Am J Hum Genet 2007; 81:799-807. A significant association was detected between serum ferritin level and rs235756, a common SNP in the BMP2 genic region. Mean ferritin level differed, adjusted for age and sex, amongst genotypes. A second interactive effect on serum ferritin level was detected for rs235756 in BMP2 and a SNP in HJV, and a small additive effect of a SNP in BMP4. These data suggest that modulation in the BMP-regulatory pathway plays a role in phenotypic expression of iron loading in hemochromatosis.
5. Harrison-Findik DD, Klein E, Crist C, et al. Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology 2007; 30:46. Alcohol suppressed the upregulation of hepcidin mRNA expression in a mouse and rat model of iron loading. The iron-induced increase in DNA-binding activity of C/EBP α was also suppressed by alcohol. These studies suggest that alcohol negates the protective effect of hepcidin by perturbing the normal response to iron loading.
6. Swinkels DW, Venselaar H, Wiegerinck ET, et al. A novel (Leu183Pro-) mutation in the HFE-gene co-inherited with the Cys282Tyr mutation in two unrelated Dutch hemochromatosis patients. Blood Cells Mol Dis 2007; 23 Nov [Epub ahead of print]. Novel mutations in exon 3 of HFE (c548T → C resulting in a change in leucine to proline at position 183, Leu183Pro) that were coinherited with Cys282Tyr resulted in phenotypic iron overload in two unrelated Dutch males. The Leu183Pro mutation was found in 1 : 100 healthy controls of Dutch descent, suggesting unique populations may benefit from specific mutation testing. Phenotypic testing is, however, required to demonstrate actual iron overload.
7. Adams PC, Reboussin DM, Press RD, et al. Biological variability of transferrin saturation and unsaturated iron-binding capacity. Am J Med 2007; 20:999. Screening of 101 168 individuals for iron-overload disorder was performed as part of the Hemochromatosis and Iron Overload Screening Study. Transferrin saturation and UIBC were performed initially and months later on the same patient. Using transferrin saturation cutoff of 45% females, 50% males or UIBC 150 μmol/l females, 125 μmol/l males, 33% (n = 68, 19 men, 49 women) of C282Y homozygotes would have been missed while 58 homozygotes were missed by the UIBC cutoffs. Fasting samples proved no advantage to nonfasting samples. These data suggest that within-person biological variability of transferrin saturation and unsaturated iron-binding capacity limits their usefulness for initial screening for C282Y homozygotes with iron overload.
8. Waalen J, Felitti VJ, Gelbart T, et al. Screening for hemochromatosis by measuring ferritin levels: a more effective approach. Blood 2007; 19 Nov [Epub ahead of print]. Of 29 699 white subjects enrolled in the Scripps-Kaiser hemochromatosis study, 59 had serum ferritin levels above 1000 ng/ml. Homozygous mutant or compound heterozygous mutant HFE genotypes were found in 24 of 59 patients. Twenty of the remaining 25 had excessive alcohol intake, cancer or liver disease while in five the cause was unknown. These data suggest that using ferritin concentrations to screen for hemochromatosis detects most patients with phenotypic disease and may detect other clinically significant disease in nonaffected patients. The authors also noted that the ferritin level of the vast majority of adult homozygotes for HFE mutations did not rise over long periods of time, therefore they suggest that excluding subjects with serum ferritin levels less than 1000 ng/ml should not result in missed opportunities for early treatment of those who could benefit.
9. Ko C, Siddaiah N, Berger J, et al. Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry. Liver Int 2007; 27:1394-1401. The association between hepatic iron overload and HCC was examined in 5224 patients undergoing liver transplantation by review of explant pathology in consecutive specimens obtained from many centers in the US. In the overall cohort, iron overload was significantly associated with HCC even after adjustment for the etiology of the liver disease. When looked at by disease etiology, biliary cirrhosis, HCV and genetic hemochromatosis had the strongest associations. These data suggest a possible carcinogenic or cocarcinogenic role for iron in chronic liver disease, suggesting that removal of iron in patients with end-stage liver disease might be beneficial.
10. Yu L, Ioannou GN. Survival of liver transplant recipients with hemochromatosis in the United States. Gastroenterology 2007; 133:489-495. A review of UNOS transplant data for patients designated with hemochromatosis from 1990 to 2006. From 1990 to 1996, 177 patients were identified with hemochromatosis. These patients had a reduced posttransplant survival of 79.1% at 1 year, 71.8% at 3 years and 64% at 5 years relative to all patients transplanted during this period. By contrast, the 217 patients from 1997 to 2006 had equivalent survival as the overall population of transplanted patients.
11. Silvestri L, Pagani A, Fazi C, et al. Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis. Blood 2007; 109:4503-4510. Specific HJV mutants and the role of their intracellular processing in HJV function were examined in the human cell lines, HeLa and HepG2. They demonstrated two forms of HJV - a membrane form with a GPI anchor and a soluble form. The membrane form of HJV with a GPI anchor was composed of a cleaved protein whose level increases in response to iron. Those mutant HJV where the GPI anchor was lacking were retained in the endoplasmic reticulum and the level did not respond to iron. A soluble form of the protein is, however, released for all mutant types studied, the cleavage being essential for export, suggesting different roles for the membrane and soluble forms of HJV.
12. Fabio G, Minonzio F, Delbini P, et al. Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Blood 2007; 109:362-364. Case report of combination chelation therapy with deferiprone and deferoxamine for a patient with HJV associated iron overload. Reversal of cardiac failure followed iron removal in this patient.
13. Babitt JL, Huang FW, Xia Y, et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 2007; 117:1933-1939. When a recombinant and soluble form of HJV was administered in rodent models, hepcidin expression was reduced and serum iron increased due to mobilization of splenic iron stores. Administration of BMP2 resulted in increased hepcidin levels and reduced serum iron. These data demonstrate the important modulatory role of the BMP pathway in iron homeostasis and suggest novel therapeutic avenues for the treatment of disorders of iron metabolism.
14. Johnson EE, Wessling-Resnick M. Flatiron mice and ferroportin disease. Nutr Rev 2007; 65:341-345. A murine model of ferroportin disease demonstrating an autosomal dominant inheritance of iron overload.
15. Xuan A, Bookman I, Cox DW, Heathcote J. Three atypical cases of Wilson disease: assessment of the Leipzig scoring system in making a diagnosis. J Hepatol 2007; 47:428-433. Three atypically presenting cases of Wilson disease, two with cirrhosis and one with neuropsychiatric manifestations who presented after the age of 40 years posing a diagnostic challenge. When the proposed 2003 Leipzig scoring system was applied [16], each was found to meet diagnostic criteria for Wilson disease. Each was subsequently confirmed to have Wilson disease by molecular diagnosis for mutations of the Wilson disease gene, ATP7B.
16. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Consensus conference from the International Conference on Wilson Disease, Leipzig, Germany. Liver Int 2003; 23:139-142.
17. Müller T, Koppikar S, Taylor RM, et al. Re-evaluation of the penicillamine challenge test in the diagnosis of Wilson's disease in children. J Hepatol 2007; 47:270-276. The effectiveness of a urinary copper above 25 μmol/24 h following penicillamine in diagnosing Wilson disease was re-evaluated. The study group contained 98 subjects, 38 with Wilson disease (19 females; median age 10.3 years; range 5-16 years) and 60 with other liver disorders (24 females; median age 10.1, range 2.3-15 years). Urinary copper was estimated for 24 h before (basal copper) and while giving penicillamine 500mg orally 12 hourly x 2 (postpenicillamine copper). A postpenicillamine copper above 25 μmol/24 h was observed in 29 of 38 patients with Wilson disease (25 were symptomatic) and in four of 60 controls. The test had an overall sensitivity of 76% (95% confidence interval 59.8-88.6%) and a specificity of 93% (95% confidence interval 83.8-98.2%). Sensitivity was better in symptomatic patients [92% (95% confidence interval 74-99%)] than asymptomatic [46% (95% confidence interval 19.2-74.9%)], leading the authors to conclude that this test was most valuable in the diagnosis of Wilson disease with active liver disease, but is unreliable to exclude the diagnosis in asymptomatic siblings.
18. Arnon R, Calderon JF, Schilsky M, et al. Wilson disease in children: serum aminotransferases and urinary copper on triethylene tetramine dihydrochloride (trientine) treatment. J Pediatr Gastroenterol Nutr 2007; 44:596-602. Retrospective analysis of treatment in a pediatric cohort of patients with Wilson disease using trientine. Successful treatment was marked by trends toward normalization or normalization of transaminases and a reduction in urine copper excretion after the initial marked elevation following initiation of trientine; however, nonadherence was noted in four of 10 patients detected first by elevations in transaminases.
19. Sinha S, Taly AB. Withdrawal of penicillamine from zinc sulphate-penicillamine maintenance therapy in Wilson's disease: promising, safe and cheap. J Neurol Sci 2008; 264:129-132. Treatment of 45 patients with Wilson disease (28 male, age at diagnosis 13.5 ± 63 years), with penicillamine and zinc sulfate for a mean of 107.4 ± 67.3 months followed by zinc sulfate alone for 27.2+8.5 months was successful with respect to neuropsychiatric manifestations in 44 patients. One patient reported dysarthria while on zinc. This retrospective study suggests that zinc sulfate may be used for maintenance therapy, but that there are rare individuals in which the therapy may not work.
20. Jhang JS, Schilsky ML, Lefkowitch JH, Schwartz J. Therapeutic plasmapheresis as a bridge to liver transplantation in fulminant Wilson disease. J Clin Apher 2007; 22:10-14. Plasmapheresis was used for a patient with fulminant Wilson disease to reduce hemolysis and renal injury while the patient awaited liver transplantation. Five daily therapeutic plasmapheresis procedures using fresh frozen plasma as a replacement fluid were performed over 6 days. Serum copper, urinary copper excretion and hemolysis were significantly reduced and renal function improved.
21. Asfaha S, Almansori M, Qarni U, Gutfreund KS. Plasmapheresis for hemolytic crisis and impending acute liver failure in Wilson disease. J Clin Apher 2007; 22:295-298. A report of a patient presenting with severe hemolysis and impending acute liver failure that recovered with plasmapheresis and chelation therapy.
22. Marin C, Robles R, Parrilla G, et al. Liver transplantation in Wilson's disease: are its indications established? Transplant Proc 2007; 39:2300-2301. Four patients of 15 with progressive neurological deterioration that were transplanted for Wilson disease had compensated cirrhosis, Child's A classification. One of these four patients died due to infectious complications after treatment for steroid unresponsive rejection and the other three fared well with neurological improvement. Their overall cohort survival was 87.5%.
23. Medici V, Mirante VG, Fassati LR, et al., Monotematica AISF 2000 OLT Study Group. Liver transplantation for Wilson's disease: the burden of neurological and psychiatric disorders. Liver Transpl 2005; 11:1056-1063.
24. Senzolo M, Loreno M, Fagiuoli S, et al. Different neurological outcome of liver transplantation for Wilson's disease in two homozygotic twins. Clin Neurol Neurosurg 2007; 109:71-75. Case report on two homozygotic twins, both with liver cirrhosis due to Wilson's disease, one of them with severe neuropsychiatric involvement, who underwent liver transplantation. The neurological impairment remained significant following transplantation. The authors recommended caution in patients with neurological manifestations in Wilson's disease because irreversible brain damage may exist.
25. Brewer GJ, Askari F, Lorincz MT, et al. Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch Neurol 2006; 63:521-527. A randomized, double-blind, controlled, two-arm study of 48 patients with the neurologic presentation of Wilson disease where patients were treated either with trientine or tetrathiomolybdate; both groups also received zinc two times per day. Six of 23 treated with trientine and only one of 25 patients in the tetrathiomolybdate arm had neurologic deterioration (P < 0.05). Adverse effects of anemia and/or leucopenia occurred in three on tetrathiomolybdate and four had further transaminase elevations. One patient receiving trientine had anemia. Four patients receiving trientine died during follow-up, three having shown initial neurologic deterioration. Neurologic and speech recovery continued over a 3-year follow-up period.
26. Ala A, Walker AP, Ashkan K, et al. Wilson's disease. Lancet 2007; 369:397-408. Review of diagnosis and treatment of Wilson disease from authors in the UK and US, with a discussion of the indications for liver transplantation for Wilson disease.
27. Czlonkowska A, Tamacka B, Moller JC, et al. Unified Wilson's disease rating scale - a proposal for the neurological scoring of Wilson's disease patients. Neurol Neurochiur Polska 2007; 41:1-12. The authors create a unified Wilson disease rating scale that combines the features of several validated clinical rating scales used for other neurological disorders for use for studies for patients entered into EuroWilson clinical trials. The initial publication focuses on a limited patient population of only six and further validation of the rating scale will follow with study of more patients.
28. Yatsunyk LA, Rosenzweig AC. Cu(I) binding and transfer by the N terminus of the Wilson disease protein. J Biol Chem 2007; 282:8622-8631. The six N-terminal copper-binding regions of ATP7B have similar capacities to interact with copper and a stronger affinity for copper than the metallochaperone ATOX1. Potential differences in the activity of each of these metal-binging regions would therefore result from intramolecular or intermolecular interactions given their equivalent metal-binding properties.
29. Cater MA, La Fontaine S, Mercer JF. Copper binding to the N-terminal metal-binding sites or the CPC motif is not essential for copper-induced trafficking of the human Wilson protein (ATP7B). Biochem J 2007; 401:143-153. The N-terminal metal-binding domains of ATP7B were found not to be critical for copper-dependent relocalization of ATP7B from the trans-Golgi network to a cytosolic site. Mutation of the critical aspartic acid residue in the phosphorylation domain blocked copper-induced movement from the trans-Golgi, while mutation of the phosphatase domain caused retention in cytosolic vesicular compartments. These data indicate that ATP7B intracellular trafficking is a regulated process involving different posttranslational protein modifications.
30. Cox DW, Kenney SM, Deeb TM, Macintyre G. Functional analysis of ATP7B variants as an aid to diagnosis of Wilson disease. Hepatology 2007; 46:888A.
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32. Franco LM, Krishnamurthy V, Bali D, et al. Hepatocellular carcinoma in glycogen storage disease type 1a: a case series. J Inherit Metab Dis 2005; 28:153-162.
33. Reddy SK, Kishnani PS, Sullivan J, et al. Resection of hepatocellular adenoma in patients with glycogen storage disease type 1a. J Hepatol 2007; 47:658-663. Although a retrospective study, this is the first examination of resection of HCA in GSD-1a compared to a general population. Seven of 38 patients who underwent resection for HCA from 1998 to 2006 had GSD-1a. There was substantial early morbidity associated with resection (86 vs. 20%) and shorter time to adenoma progression in GSD-1a patients. Six of seven GSD-1a patients had no evidence of HCC and recovered without long-term morbidity.
34. Iyer SG, Chen C-L, Wang C-C, et al. Long-term results of living donor liver transplantation for glycogen storage disorders in children. Liver Transpl 2007; 13:848-852. Of 244 patients who underwent LDLT from 1994 to 2005, 12 had GSD (nine with type 1, three with type 3). Median age at transplantation was 7.27 years. Eleven patients received left lobe grafts, one received a right lobe graft. Three patients had hepatic adenomas in the explant. There was a single mortality at 2 months post-LDLT due to pancreatitis and sepsis. Metabolic abnormalities were corrected, renal function remained normal, growth retardation was reversed, and a mean follow-up of 47.45 months confirmed excellent graft and patient survival.
35. Belingheri M, Ghio L, Sala A, et al. Combined liver-kidney transplantation in glycogen storage disease 1a: a case beyond the guidelines. Liver Transpl 2007; 13:762-764.
36. Chou JY, Mansfield BC. Gene therapy for type 1 glycogen storage diseases. Curr Gene Ther 2007; 7:79-88. An excellent review of the state of the science of gene therapy for type 1 GSDs. Protein replacement is not an option for therapy as glucose-6-phosphatase is a hydrophobic protein tightly associated with the endoplasmic reticulum and is not active in a soluble form. In available animal models that mimic the human disorder, adenoviral therapy produces only short-term corrections and only impacts liver expression of the gene. AAV-mediated therapy delivers transgene to both the liver and kidney, achieving longer-term correction of the disorder. Efficacy is dependent upon the AAV serotype used.
37. Yu Z, Sawker AR, Kelly JW. Pharmacologic chaperoning as a strategy to treat Gaucher disease. FEBS J 2007; 274:2944-2950.
38. Chappell S, Hadzik N, Stocklet R, et al. A polymorphism of AAT gene represents a risk factor for liver disease. Hepatology 2008; 47:127-132. In a case-control study of 42 patients with established liver disease and 335 homozygous Pi-ZZ patients who mostly presented with chronic obstructive pulmonary disease with no evidence of liver disease, it was found that one of nine SNPs in the A1AT gene (rs80047338) conferred a highly significant risk for liver disease. Functional studies found no effect of this SNP on A1AT activity, suggesting another mechanism yet to be determined must account for this observation.
39. 1-ATZ mutation revealed increased susceptibility to fibrosis formation and stellate cell activation compared with wild-type mice after BDL.
40. Perlmutter DH, Brodsky JL, Balistreri WF, Trapnell BC. Molecular pathogenesis of alpha-1-antitrypsin deficiency-associated liver disease: a meeting review. Hepatology 2007; 45:1313-1323.