Darrell H G Crawford

University of South Australia , Adelaide, South Australia, Australia

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Publications (46)355.87 Total impact

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    ABSTRACT: BACKGROUND & AIMS: The relationship between vitamin D status and response to antiviral therapy and liver histology in hepatitis C virus genotype 1 (HCV-1) infection remains unclear with studies to date yielding inconsistent results and failing to use reference assay methodology. We therefore analyzed pre-treatment 25-hydroxyvitamin D [25(OH)D] level using reference liquid chromatography-tandem mass spectrometry methodology in a cohort of treatment-naïve patients with HCV-1 to evaluate the association between vitamin D status, virologic response, and liver histology. METHODS: 274 patients with pre-treatment liver biopsy and up to 48 weeks of pegylated interferon alfa-2a plus ribavirin therapy were tested for serum 25(OH)D level. Predictors of sustained virologic response (SVR), and variables associated with fibrosis stage, activity grade and 25(OH)D status were identified using multivariate analysis. RESULTS: Mean 25(OH)D level was 79.6 nmol/L, with a prevalence of 25(OH)D <75 nmol/L and <50 nmol/L of 48% and 16% respectively. Season, race and geographic latitude were independent predictors of 25(OH)D status, while vitamin D deficiency was more prevalent in those with high activity grade (21% vs 11%; P=0.03). Mean 25(OH)D level was lower (76.6 vs 84.7 nmol/L; P=0.03) and 25(OH)D <75 nmol/L more prevalent (53% vs 40%; P=0.03) in patients with an SVR, but no association between 25(OH)D status and SVR was found on multivariate analysis. Mean 25(OH)D level did not vary between fibrosis stage or activity grade. CONCLUSIONS: Baseline 25(OH)D level is not independently associated with SVR or fibrosis stage in HCV-1, but vitamin D deficiency is associated with high activity grade.
    Journal of Hepatology 11/2012; · 9.86 Impact Factor
  • Hepatology 09/2012; · 12.00 Impact Factor
  • Daniel F Wallace, Darrell H G Crawford, V Nathan Subramaniam
    Gastroenterology 07/2012; 143(3):862-5. · 12.82 Impact Factor
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    ABSTRACT: Serum hepcidin concentration is potentially affected by inflammation and iron stores in chronic liver disease (CLD), but little is known about the relationship between hepcidin and the degree of hepatic fibrosis. We investigated the potential role of serum hepcidin as a biomarker of advanced liver disease. Serum hepcidin was measured in 332 adults with CLD of varying aetiologies, 45 healthy and 50 non-liver disease patient controls. Liver biopsy data were available for 228 CLD subjects. Hepcidin was decreased in CLD patients compared with non-liver disease patient controls (P < 0.0001) but not healthy controls, and was lowest in those with cirrhosis (P < 0.0001). Serum hepcidin correlated with hepatic hepcidin mRNA expression in 91 biopsy samples available for genetic analysis (r = 0.68, P < 0.0001). Hepcidin also correlated positively with serum ferritin concentration, transferrin saturation, ALT, serum albumin and haemoglobin, but negatively with serum bilirubin. The hepcidin:ferritin ratio was significantly lower in CLD subjects compared with healthy and disease controls, and decreased with each increase in the stage of fibrosis and siderosis. The hepcidin:ferritin ratio was associated with progressive fibrosis on linear regression, and a value of less than 0.1 was independently associated with cirrhosis on logistic regression analyses (OR 5.54, P < 0.001). Receiver operating characteristic analysis showed the hepcidin:ferritin ratio was able to distinguish between F0 and F4 stages of fibrosis (area under receiver operating characteristic curve = 0.86). The hepcidin:ferritin ratio is reduced in relation to increasing fibrosis in CLD and the use of this ratio may have potential future diagnostic implications as a marker of cirrhosis.
    Liver international: official journal of the International Association for the Study of the Liver 06/2012; 32(9):1391-9. · 3.87 Impact Factor
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    ABSTRACT: To explore how liver damage arising from cardio-hepatic syndromes in RHF affect the hepatic pharmacokinetics of basic drugs. The hepatic pharmacokinetics of five selected basic drugs with different physicochemical properties were studied in IPRL from control rats and rats with RHF. Hepatic pharmacokinetic modelling was performed with a two-phase physiologically-based organ pharmacokinetic model with the vascular space and dispersion evaluated with the MID technique. The liver damage arising from RHF was assessed by changes in liver biochemistry and histopathology. The expression of various CYP isoforms was evaluated by real-time RT-PCR analysis. Four of the five basic drugs had a significantly lower E in RHF rat livers compared to the control rat livers. Hepatic pharmacokinetic analysis showed that both the CL int and PS were significantly decreased in the RHF rat livers. Stepwise regression analysis showed that the alterations in the pharmacokinetic parameters (E, CL int and PS) can be correlated to the observed histopathological changes (NI, CYP concentration and FI) as well as to the lipophilicity of the basic drugs (logP app). Serious hepatocellular necrosis and fibrosis induced by RHF affects both hepatic microsomal activity and hepatocyte wall permeability, leading to significant impairment in the hepatic pharmacokinetics of basic drugs.
    Pharmaceutical Research 02/2012; 29(6):1658-69. · 4.74 Impact Factor
  • Daniel F Wallace, Darrell H G Crawford, V Nathan Subramaniam
    Gastroenterology 08/2011; 141(4):1520-2. · 12.82 Impact Factor
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    ABSTRACT: Anemia may increase the likelihood of achieving a sustained virological response (SVR) during pegylated interferon and ribavirin treatment of hepatitis C virus (HCV) infection. To determine whether hemoglobin decline is associated with SVR, we retrospectively evaluated the CHARIOT study of 871 treatment-naïve HCV genotype 1 patients. Anemia (serum hemoglobin <100 g/L) occurred in 137 (16%) patients, of whom only 14 (10%) received erythropoietin. Hemoglobin decline >30g/L from baseline occurred in 76% of patients overall, including 526 patients who did not become anemic. Virological responses were higher in anemic patients compared with those who did not develop anemia (end of treatment, 80% versus 65%, P = 0.003; SVR, 61% versus 50%, P = 0.02); these differences remained significant when patients receiving erythropoietin were excluded from analysis. SVR was also higher in patients with hemoglobin decline >30 g/L compared with patients without a similar decline. In multiple logistic regression analyses with treatment group and baseline characteristics, the odds ratio for SVR was 1.97 (95% confidence interval, 1.08-3.62) for anemia and 2.17 (95% confidence interval, 1.31-3.62) for hemoglobin decline >30 g/L. Patients who first developed a hemoglobin decline >30 g/L during weeks 5-12 and 13-48 were more likely to achieve SVR than those who first developed such changes in weeks 0-4 or who never experienced them. CONCLUSION: Patients with HCV genotype 1 infection who develop anemia or experience a hemoglobin decline >30 g/L during weeks 5-48 of therapy achieve higher virological responses to pegylated interferon and ribavirin therapy that are unrelated to erythropoietin use.
    Hepatology 04/2011; 53(4):1109-17. · 12.00 Impact Factor
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    ABSTRACT: We examined the detection of low-level viraemia at week 24 as a predictor of sustained virological response (SVR) and viral relapse/breakthrough, and the agreement between the Roche Cobas TaqMan™ HCV RNA assay (TaqMan) and Roche Cobas(®) Amplicor HCV qualitative assay (Amplicor; both Roche Molecular Diagnostics, Pleasanton, CA, USA) for detection of low-level viraemia. A total of 871 treatment-naive HCV genotype 1 patients participating in an induction-dose pegylated interferon therapy study had virological responses assessed using TaqMan. A total of 151 patients with HCV RNA levels ≤500 IU/ml had samples tested in parallel using the Amplicor and TaqMan assays. SVR was significantly lower and relapse/breakthrough significantly higher in patients with low-level residual viraemia at week 24 compared with those who had undetectable viraemia: SVR was 72%, 29% and 14% (P<0.0001) and relapse/breakthrough 28%, 71% and 86% (P<0.0001) in patients with viraemia that was undetectable, detectable <15 IU/ml and detectable 15-<50 IU/ml, respectively, at week 24. The negative predictive value (NPV) for a week-24 virological response for SVR was 86%, 90% and 90% using TaqMan cutoffs of undetectable, <15 IU/ml and <50 IU/ml, respectively. The percentage agreement between Amplicor and TaqMan was similarly high for TaqMan cutoffs of 50 IU/ml and 15 IU/ml, but lower for undetectable viraemia (83%, 83% and 70%, respectively). These data emphasize the importance of achieving undetectable HCV RNA during pegylated interferon therapy to maximize SVR; however, the current 24-week stopping rule of undetectable HCV RNA appears too stringent when using sensitive PCR assays given the observed lower NPV for SVR using the TaqMan undetectable cutoff. Our data also suggest that a TaqMan <15 IU/ml result is comparable to an Amplicor-negative result (that is, below the assay cutoff value) when monitoring viral response.
    Antiviral therapy 01/2011; 16(2):173-80. · 3.07 Impact Factor
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    ABSTRACT: The hepatic pharmacokinetics of five selected cationic drugs (propranolol, labetalol, metoprolol, antipyrine, and atenolol) was studied in the liver from control rats and from those with high-fat emulsion-induced nonalcoholic steatohepatitis (NASH). Studies were undertaken using an in situ-perfused rat liver and multiple indicator dilution, and outflow data were analyzed with a physiologically based organ pharmacokinetic model. Hepatic extraction (E) was significantly lower in the NASH model, and lipophilicity was the main solute structural determinant of the observed differences in intrinsic elimination clearance (CL(int)) and permeability-surface area product (PS) with pK(a) defining the extent of sequestration in the liver [apparent distribution ratio (K(v))]. The main pathophysiological determinants were liver fibrosis, leading to a decreased PS, liver fat causing an increase in K(v), and an increase in both total liver cytochrome P450 (P450) concentration and P450 isoform expression for Cyp3a2 and Cyp2d2, causing an increase CL(int) in NASH rat livers compared with control livers. Changes in hepatic pharmacokinetics (PS, K(v), CL(int), and E ratio) as a result of NASH were related to the physicochemical properties of drugs (lipophilicity or pK(a)) and hepatic histopathological changes (fibrosis index, steatosis index, and P450 concentration) by stepwise regression analysis. Thus, it appears that in NASH, counteracting mechanisms to facilitate hepatic removal are created in NASH-induced P450 expression, whereas NASH-induced fibrosis and steatohepatitis inhibit E by decreasing hepatocyte permeability through fibrosis and hepatic sequestration.
    Drug metabolism and disposition: the biological fate of chemicals 01/2011; 39(4):571-9. · 3.74 Impact Factor
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    ABSTRACT: The impact of fibrosis stage on chronic hepatitis C virus (HCV) treatment response was explored in CHARIOT, a study of high dose peginterferon alfa-2a (PEG-IFNalpha-2a) induction therapy in treatment naïve genotype 1 infection. Eight hundred and ninety-six patients were randomised 1:1 to 360 microg (n=448) or 180 microg (n=448) PEG-IFNalpha-2a weekly with RBV 1000-1200 mg/day for 12 weeks followed by 36 weeks of 180 microg PEG-IFNalpha-2a weekly plus RBV 1000-1200 mg/day. Virological responses were assessed at week 4, 8, 12, 24, 48 (end of therapy), and 24 weeks following therapy (sustained virological response, SVR). As previously reported, there was no significant difference in SVR in the induction (53%) and standard (50%) arms, therefore the pooled study population was used for analysis of SVR and relapse. A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0-2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001). Cumulative PEG-IFNalpha-2a and ribavirin doses were similar among patients with F3/4 and F0-2 within treatment arms through week 4, 8, 12, and week 24. Low virological response in hepatitis C genotype 1 patients with advanced fibrosis is not explained by inadequate cumulative PEG-IFN and ribavirin doses.
    Journal of Hepatology 10/2010; 53(4):616-23. · 9.86 Impact Factor
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    ABSTRACT: This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl(4)-induced fibrotic perfused rat livers and the results were compared to those in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single-pass-perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl(4)-treated rats compared to controls (p<0.05). The extraction ratios (E) for all drugs were significantly lower (p<0.05) in fibrotic than in normal livers and the decrease in E was consistent with the decrease in intrinsic clearance and permeability-surface area product. In addition, other than for furosemide, the mean transit times for all drugs were significantly longer (p<0.01) in the fibrotic livers than in normal livers. Pharmacokinetic model and stepwise regression analyses suggest that these differences arise from a reduction in both the transport of drugs across the basolateral membrane and their metabolic clearance and were in a manner similar to those previously found for another group of drugs.
    Drug Metabolism and Pharmacokinetics 09/2010; 25(5):442-9. · 2.07 Impact Factor
  • Darrell H G Crawford, Linda M Fletcher, Katherine A. Stuart
    Hepatology 05/2010; 52(1):393. · 12.00 Impact Factor
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    ABSTRACT: Additional markers are required to identify patients on the orthotopic liver transplant (OLT) waiting list at increased risk of death and adverse clinical events. Serum ferritin concentration is a marker of varied pathophysiological events and is elevated with increased liver iron concentration, hepatic necroinflammation, and systemic illness, all of which may cause a deterioration in liver function and clinical status. The aim of this study was to determine whether serum ferritin concentration is an independent prognostic factor in subjects awaiting OLT. This is a dual-center retrospective study. The study cohort consisted of 191 consecutive adults with cirrhosis accepted by the Queensland (Australia) Liver Transplant Service between January 2000 and June 2006 and a validation cohort of 131 patients from University of California Los Angeles (UCLA) Transplant Center. In the study cohort, baseline serum ferritin greater than 200 microg/L was an independent factor predicting increased 180-day and 1-year waiting list mortality. This effect was independent of model for end-stage liver disease (MELD), hepatocellular carcinoma, age, and sex. Subjects with higher serum ferritin had increased frequency of liver-related clinical events. The relationship between serum ferritin and waiting list mortality was confirmed in the UCLA cohort; all deceased patients had serum ferritin greater than 400 microg/L. Serum ferritin greater than 500 microg/L and MELD were independent risk factors for death. CONCLUSION: Serum ferritin concentration is an independent predictor of mortality-related and liver-related clinical events. Baseline serum ferritin identifies a group of "higher-risk" patients awaiting OLT and should be investigated as an adjunct to MELD in organ allocation.
    Hepatology 01/2010; 51(5):1683-91. · 12.00 Impact Factor
  • Darrell H G Crawford, Katherine Stuart
    Journal of Gastroenterology and Hepatology 12/2009; 24(12):1804-6. · 3.33 Impact Factor
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    ABSTRACT: Hepatic stellate cell transdifferentiation, epithelial-mesenchymal cell transition, and the ductular reaction each contribute to the development of hepatic fibrosis in cholestatic liver diseases. Inhibitors of mammalian target of rapamycin have antifibrotic properties. We evaluated the hypothesis that the antifibrotic action of rapamycin is due to attenuated myofibroblast proliferation in addition to an inhibitory effect on epithelial-mesenchymal transition and the ductular reaction. Hepatic fibrosis was induced by bile duct ligation, and rodents received 1.5 mg/kg/day rapamycin by subcutaneous infusion for 21 days. The expression of various markers of hepatic fibrosis, stellate cell transactivation, epithelial-mesenchymal transition, and the ductular reaction was compared between treated and untreated animals. Hepatic fibrosis, hepatic procollagen type 1 messenger RNA, and alpha-smooth muscle actin expression were significantly reduced in treated animals. Hepatic stellate cell procollagen expression and proliferation were also reduced by rapamycin. The following markers of epithelial-mesenchymal transition--vimentin protein expression, S100 calcium binding protein A4 and transforming growth factor beta 1 messenger RNA, and the mothers against decapentaplegic homolog signaling pathway--were all reduced after rapamycin treatment. The intensity of the ductular reaction was reduced by rapamycin as assessed by histopathological scoring and by reduced cytokeratin 19 expression. Rapamycin caused a reduction in hepatic progenitor cell proliferation. Together, these data show that multiple profibrogenic pathways are activated in an animal model of cholestasis and that rapamycin attenuates epithelial-mesenchymal transition and the ductular reaction as well as hepatic stellate cell activation.
    Liver Transplantation 10/2009; 15(10):1315-24. · 3.94 Impact Factor
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    ABSTRACT: This study tested the hypothesis that high-dose peginterferon alfa-2a (PEG-IFNalpha-2a) for the first 12 weeks would increase early and sustained virological response (SVR) rates in patients with chronic hepatitis C genotype 1. Eight hundred ninety-six patients were randomized 1:1 to 360 microg (n = 448) or 180 microg (n = 448) PEG-IFNalpha-2a weekly plus ribavirin at 1000-1200 mg/day for 12 weeks, followed by 36 weeks of 180 microg PEG-IFNalpha-2a weekly plus ribavirin at 1000-1200 mg/day with 871 patients evaluable for the intention-to-treat analysis. Virological responses were assessed by TaqMan (limit of detection 15 IU/mL) at week 4, 8, 12, 24, 48 (end of therapy), and 24 weeks following therapy (SVR). Undetectable hepatitis C virus RNA rates were significantly higher among patients receiving high-dose induction therapy at week 4 (36% versus 26%, P < 0.005), week 8 (61% versus 50%, P < 0.005), and week 12 (74% versus 62%, P < 0.005). However, SVR was not significantly different between patients receiving high-dose (53%) and standard (50%) therapy. Significant baseline prognostic factors for SVR included age, sex, race, histological stage, and viral load. SVR was considerably higher among patients with no or minimal fibrosis (64% and 60%, respectively) compared to those with severe fibrosis/cirrhosis (28% and 24%, respectively). The frequency of serious adverse events and drug discontinuations were similar in both groups, whereas PEG-IFN dose modification, weight and appetite reduction, and grade IV neutropenia were significantly higher in the induction arm. CONCLUSION: Induction dosing with 360 microg/week PEG-IFNalpha-2a for 12 weeks was well tolerated and enhanced early virological response but not SVR rates. The high SVR rates in patients with minimal fibrosis highlight the benefit of early treatment in patients with hepatitis C virus genotype 1.
    Hepatology 07/2009; 50(4):1045-55. · 12.00 Impact Factor
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    ABSTRACT: Expression of Hamp1, the gene encoding the iron regulatory peptide hepcidin, is inappropriately low in HFE-associated hereditary hemochromatosis and Hfe knockout mice (Hfe(-/-)). Since chronic alcohol consumption is also associated with disturbances in iron metabolism, we investigated the effects of alcohol consumption on hepcidin mRNA expression in Hfe(-/-) mice. Hfe(-/-) and C57BL/6 (wild-type) mice were pair-fed either an alcohol liquid diet or control diet for up to 8 weeks. The mRNA levels of hepcidin and ferroportin were measured at the mRNA level by RT-PCR and protein expression of hypoxia inducible factor-1 alpha (HIF-1alpha) was measured by western blot. Hamp1 mRNA expression was significantly decreased and duodenal ferroportin expression was increased in alcohol-fed wild-type mice at 8 weeks. Time course experiments showed that the decrease in hepcidin mRNA was not immediate, but was significant by 4 weeks. Consistent with the genetic defect, Hamp1 mRNA was decreased and duodenal ferroportin mRNA expression was increased in Hfe(-/-) mice fed on the control diet compared with wild-type animals and alcohol further exacerbated these effects. HIF-1alpha protein levels were elevated in alcohol-fed wild-type animals compared with controls. Alcohol may decrease Hamp1 gene expression independently of the HFE pathway possibly via alcohol-induced hypoxia.
    Alcoholism Clinical and Experimental Research 06/2009; 33(8):1391-400. · 3.42 Impact Factor
  • Darrell H G Crawford, Grant A Ramm
    Hepatology 05/2009; 49(5):1781-1782. · 12.00 Impact Factor
  • The Journal of pediatrics 11/2008; 153(4):588. · 4.02 Impact Factor
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    ABSTRACT: Diagnosing the presence of cirrhosis is crucial for the management of patients with C282Y hereditary hemochromatosis (HH). HH patients with serum ferritin >1,000 microg/L are at risk of cirrhosis; however, the majority of these patients do not have cirrhosis. Noninvasive markers of hepatic fibrosis may assist in determining which patients with a serum ferritin >1,000 microg/L have cirrhosis and require liver biopsy. This study evaluated the utility of current diagnostic algorithms for detecting cirrhosis, including serum ferritin concentration, platelet counts, and aspartate aminotransferase (AST) levels, in combination with serum markers of fibrosis, hyaluronic acid and collagen type IV (CLIV), in predicting cirrhosis in HH patients. Stage of fibrosis, serum hyaluronic acid and CLIV levels, were measured in 56 patients with HH. No patient with a serum ferritin <1,000 microg/L had cirrhosis, but only 40% of patients with serum ferritin >1,000 microg/L were cirrhotic. A combination of platelet count (<200 x 10(9)/L), elevated AST, and serum ferritin >1,000 microg/L did not detect 30% of cirrhotic subjects. Serum hyaluronic acid was increased in HH compared with controls (42.0 +/- 9.8 ng/mL versus 19.3 +/- 1.8 ng/mL; P = 0.02). A hyaluronic acid concentration >46.5 ng/mL was 100% sensitive and 100% specific in identifying patients with cirrhosis. In patients with serum ferritin >1,000 microg/L, hyaluronic acid levels were significantly elevated in patients with cirrhosis versus those without cirrhosis (137 +/- 34.4 ng/mL versus 18.6 +/- 1.5 ng/mL, respectively; P = 0.006). CLIV >113 ng/mL was 100% sensitive but only 56% specific for cirrhosis (area under the curve = 0.78; P = 0.01). Conclusion: In HH, the measurement of hyaluronic acid in patients with serum ferritin >1,000 microg/L is a noninvasive, accurate, and cost-effective method for the diagnosis of cirrhosis. (HEPATOLOGY 2009;49:418-425.).
    Hepatology 09/2008; 49(2):418-25. · 12.00 Impact Factor

Publication Stats

1k Citations
332 Downloads
2k Views
355.87 Total Impact Points

Institutions

  • 2012
    • University of South Australia 
      • School of Pharmacy and Medical Sciences
      Adelaide, South Australia, Australia
  • 1999–2011
    • Royal Brisbane Hospital
      • Department of Medicine
      Brisbane, Queensland, Australia
    • University of Queensland 
      • School of Medicine
      Brisbane, Queensland, Australia
  • 2001–2010
    • Princess Alexandra Hospital (Queensland Health)
      • Division of Medicine
      Brisbane, Queensland, Australia
  • 2002
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia