William J H Griffiths

Cambridge University Hospitals NHS Foundation Trust, Cambridge, England, United Kingdom

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Publications (30)199.83 Total impact

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    ABSTRACT: Fully covered self-expanding metal stents (FCSEMS) constitute the first type of metal stent that can easily be removed endoscopically and/or intraoperatively, which may be advantageous in the management of distal malignant biliary strictures (DMBS). To assess the efficacy of FCSEMS as first-line treatment for DMBS, we compared patency, survival and complication rates between FCSEMS, uncovered self-expanding metal stents (USEMS) and plastic stents (PS). This was a multicentre retrospective study of 315 consecutive patients with DMBS, who underwent endoscopic retrograde cholangiopancreatography and stenting (FCSEMS, USEMS or PS) at two hospitals between 1 January 2007 and 31 December 2013. Stent patency and patient survival were compared using the Kaplan-Meier method; complication rates were compared using Fisher's exact test; and Cox regression analysis was used to screen for confounding factors. FCSEMS were associated with prolonged stent patency (median=145 days) compared with USEMS (median=110 days, P<0.003) and PS (median=34 days, P<0.001). Biliary sepsis rates were lower for FCSEMS compared with PS (4.7 vs. 17.8%, P=0.02), whereas pancreatitis rates were higher for FCSEMS compared with USEMS (7.8 vs. 1.0%, P=0.04), but not PS (2.6%, P=NS). The use of FCSEMS as first-line management for DMBS is associated with longer patency and reduced complication rates compared with the use of PS. However, the higher rate of pancreatitis compared with USEMS requires further evaluation in a large randomized controlled trial.
    European journal of gastroenterology & hepatology 08/2015; DOI:10.1097/MEG.0000000000000455 · 2.15 Impact Factor
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    ABSTRACT: Mutations in the only known mammalian iron exporter ferroportin cause a rare iron overload disorder termed ferroportin disease. Two distinct clinical phenotypes are caused by different disease mechanisms: mutations in ferroportin either cause loss of iron export function or gain of function due to resistance to hepcidin, the peptide hormone that normally downregulates ferroportin. The aim of the present study was to examine the disease mechanisms of the thus far unclassified A69T and D181V ferroportin mutations. We overexpressed wild-type and mutant ferroportin fused to green fluorescent protein in human embryonic kidney cells and used a 59Fe-assay, intracellular ferritin concentrations, confocal microscopy and flow cytometry to study iron export function, subcellular localization and the responsiveness to hepcidin. While the A69T ferroportin mutation seems not to affect the iron export function it causes dose-dependent hepcidin resistance. We further found that D181V mutated ferroportin is iron export defective and hepcidin resistant, similar to the loss of function control mutation A77D and C367X. This indicates that intact iron export might be necessary for hepcidin induced downregulation of ferroportin. This hypothesis was investigated by studying the hepcidin response under modulation of iron availability. Incubation of wild-type ferroportin overexpressing cells with holo-transferrin increases the hepcidin effect whereas chelating extracellular ferrous iron causes hepcidin resistance. In this study we present data that postulates to classify the D181V ferroportin mutation as loss of function and the A69T mutation as dose-dependent hepcidin resistant and outline a possible causal link between iron export function and the hepcidin effect.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 09/2014; 88(5). DOI:10.1016/j.bbadis.2014.05.011 · 5.09 Impact Factor
  • Hepatology 05/2014; 59(5). DOI:10.1002/hep.26676 · 11.19 Impact Factor
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    ABSTRACT: The degree to which heterozygous forms of alpha-1 antitrypsin (A1AT), principally MZ, causes liver disease is uncertain. If heterozygosity is a relevant cofactor, over-representation in patients with end-stage liver disease would be predicted. We therefore assessed the prevalence and disease-related distribution of A1AT heterozygosity in the largest cohort to date for this purpose. We retrospectively analysed 1036 patients assessed for liver transplantation at our unit between 2003 and 2010. A1AT heterozygotes were identified on the basis of isoelectric focusing and/or histology, showing A1AT globule deposition consistent with an abnormal phenotype. Z-allele frequency was the highest in patients with nonalcoholic steatohepatitis (NASH) cirrhosis (20.3%), followed by patients with 'other parenchymal' diseases (11.9%), alcohol-related liver disease (9.9%), autoimmune disease (8.6%), hepatitis C (6.1%), hepatitis B (3.0%) and biliary disease (1.9%). Compared with the heterozygote frequency in the general European population of 9.0%, the heterozygote frequency was significantly higher among patients with NASH cirrhosis (P≤0.0001) and lower in the biliary subgroup (P=0.004). The prevalence of MZ heterozygosity was significantly increased in cirrhosis because of both alcohol (9.9%) and NASH (17.3%) compared with the general European population (2.8%; P<0.0001). Accumulation of misfolded A1AT aggregates appears to accelerate progression, in which the hepatocyte is the key injured cell. Heterozygous A1AT states worsen prognosis, particularly in NASH and alcohol-related cirrhosis, and should be identified at presentation. In cases in which genetic screening is not readily available, a low threshold for isoelectric focusing and routine specific histochemical staining of liver biopsy specimens are warranted to identify these patients.
    European journal of gastroenterology & hepatology 02/2014; 26(4). DOI:10.1097/MEG.0000000000000061 · 2.15 Impact Factor
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    ABSTRACT: Cholesterol ester storage disease (CESD) is a rare autosomal recessive lipid storage disorder associated with mutations of the gene encoding lysosomal acid lipase, manifestations of which include chronic liver disease and early atherosclerosis. Although normally presenting in childhood, severity is variable and the condition can occasionally remain undetected until middle age. Typical presentation is with asymptomatic hepatosplenomegaly and hyperlipidaemia, though the condition is probably underdiagnosed. Treatment is supportive and may include attention to cardiovascular risk factors. Phase I/II trials of enzyme replacement therapy are ongoing, but this approach remains experimental. We present the case of a 42-year-old woman diagnosed with CESD in childhood who ran an indolent course until re-presentation with cirrhotic hydrothorax. She underwent orthotopic liver transplantation but required re-transplantation for hepatic artery thrombosis. She remains well with excellent graft function 2 years later. Although atherosclerosis was apparent at assessment, and may have contributed to hepatic artery thrombosis, partial correction of the metabolic defect and restoration of liver function by transplantation together with ongoing medical therapy should permit reasonable survival over the longer term from both a liver and a vascular perspective. This is the first reported case of orthotopic liver transplantation for CESD in an adult, which was the only available option to improve survival. The case highlights the importance of monitoring patients with CESD through adulthood and suggests that liver replacement at a later stage may yet be indicated and remain of benefit.
    01/2013; 8:41-6. DOI:10.1007/8904_2012_155
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    ABSTRACT: RATIONALE: Alpha-1-antitrypsin deficiency is one of the commonest heritable human diseases, predisposing to liver and lung injury. Significant heterogeneity in phenotypic expression is well documented, but less is known of the prevalence, severity and correlates of chronic liver disease among individuals presenting with lung disease. METHODS: A well-characterized cohort of 57 PiZZ adults attending a tertiary referral chest clinic was screened prospectively for clinical, biochemical, radiological and (when appropriate) histological evidence of chronic liver disease. MEASUREMENTS AND MAIN RESULTS: 36 of 57 (63.2%) had one or more abnormality of liver function, liver ultrasound or risk factors for chronic liver disease and 24 of these underwent liver biopsy. Ten (17.5%) had evidence of severe fibrosis or cirrhosis and were more likely to have higher body mass index (p=0.04), alanine transaminase (p=0.0001), alkaline phosphatase (p=0.0009), prothrombin time (p=0.0005) and maximal vital capacity (VCmax, p=0.04); lower platelet count (p=0.007); and abnormal liver echogenicity (p<0.001) and/ or splenomegaly  (p=0.001) at ultrasound. Screening with liver ultrasound provided a sensitivity and negative predictive value for severe fibrosis or cirrhosis of 100% as were the specificity and positive predictive value for platelet count ≤174,000 per mm3 and splenomegaly. Among individuals undergoing liver biopsy, fibrosis stage correlated with increasing VCmax (p=0.02) and % predicted VCmax (p=0.05), and decreasing RV/TLC (p=0.02) and % predicted RV/TLC (p=0.05). CONCLUSION: Significant chronic liver disease is common in PiZZ individuals with lung disease and can be screened effectively by a combination of conventional tests of liver function, platelet count and liver ultrasound.
    American Journal of Respiratory and Critical Care Medicine 12/2012; 187(5). DOI:10.1164/rccm.201204-0739OC · 11.99 Impact Factor
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    ABSTRACT: Objectives Conventional imaging techniques are insensitive to liver fibrosis. This study assesses the diagnostic accuracy of MR elastography (MRE) stiffness values and the ratio of phosphomonoesters (PME)/phosphodiesters (PDE) measured using 31P spectroscopy against histological fibrosis staging. Methods The local research ethics committee approved this prospective, blinded study. A total of 77 consecutive patients (55 male, aged 49 ± 11.5 years) with a clinical suspicion of liver fibrosis underwent an MR examination with a liver biopsy later the same day. Patients underwent MRE and 31P spectroscopy on a 1.5 T whole body system. The liver biopsies were staged using an Ishak score for chronic hepatitis or a modified NAS fibrosis score for fatty liver disease. Results MRE increased with and was positively associated with fibrosis stage (Spearman’s rank = 0.622, P p = 0.741). Area under receiver operating curves for MRE stiffness values were high (range 0.75–0.97). The diagnostic utility of PME/PDE was no better than chance (range 0.44–0.58). Conclusions MRE-estimated liver stiffness increases with fibrosis stage and is able to dichotomise fibrosis stage groupings. We did not find a relationship between 31P MR spectroscopy and fibrosis stage. Key Points • Magnetic resonance elastography (MRE) and MR spectroscopy can both assess the liver. • MRE is superior to 31 P MR spectroscopy in staging hepatic fibrosis. • MRE is able to dichotomise liver fibrosis stage groupings. • Gradient-echo MRE may be problematic in genetic haemochromatosis.
    European Radiology 12/2012; 22(12). DOI:10.1007/s00330-012-2527-x · 4.34 Impact Factor
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    Fotios Sampaziotis · William J H Griffiths
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    ABSTRACT: Aims: We report two cases of patients with end stage primary sclerosing cholangitis and intractable pruritus. Rifampicin was used as a second line agent for symptom control. Both patients developed severe coagulopathy with prothrombin time prolongation. Methods: Serum liver function tests were performed to rule out toxic hepatitis secondary to rifampicin as a cause for the coagulopathy. The patients' coagulation profile was further characterized by clotting factors quantification. Results: Low levels of the vitamin K dependent factors (II, VII, IX, X) were detected. The coagulopathy resolved fully with administration of parenteral vitamin K, suggesting that rifampicin induced hypoprothrombinaemia is mediated by vitamin K deficiency. Conclusion: To the best of our knowledge, this adverse effect has never before been described with the use of rifampicin in primary sclerosing cholangitis. We review the pathophysiology and discuss the need for vitamin K replacement in severely cholestatic patients prior to treatment with rifampicin.
    British Journal of Clinical Pharmacology 11/2011; 73(5):826-7. DOI:10.1111/j.1365-2125.2011.04158.x · 3.69 Impact Factor
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    Journal of Hepatology 09/2011; 55(3):734-736. DOI:10.1016/j.jhep.2011.05.002 · 10.40 Impact Factor
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    ABSTRACT: Liver transplantation in the presence of cholangiocarcinoma (CCA) generally carries a poor prognosis. However, the outcome of patients found to have incidental CCA (iCCA) on explanted liver histology is less clear. We have evaluated the outcomes of iCCA in our liver transplant population. A retrospective search was made of the transplantation and histopathology databases for patients fulfilling our definition for iCCA. All records, including archived histopathologic slides were retrieved and analyzed. Of 1288 patients undergoing liver transplantation over the 20-year period 1988-2008, nine were found to have iCCA (0.70%). Seven of the nine patients underwent liver transplantation for primary sclerosing cholangitis. Three additional patients who were transplanted for presumed hepatocellular carcinoma that subsequently turned out to be CCA were identified, but excluded from survival analysis. The majority of tumors were early stage (T2 or below), but five (55.6%) had positive biliary transection margins. Median follow-up was 51 months. Five patients (55.6%) developed recurrence of CCA after a median interval of 25.8 months, giving a disease-free survival of 100% at 1 year and 66.7% at 3 years. Three patients have died of recurrence, with a median interval from transplantation of 25 months. The overall 3-year survival was 66.7%. Patients found to have iCCA after liver transplantation have a relatively poor prognosis. Prospective liver transplant recipients, especially those with primary sclerosing cholangitis, should be investigated rigorously to exclude CCA.
    Transplantation 06/2011; 91(12):1392-7. DOI:10.1097/TP.0b013e31821aba57 · 3.78 Impact Factor
  • Archives of surgery (Chicago, Ill.: 1960) 04/2011; 146(4):483-4. DOI:10.1001/archsurg.2011.54-a · 4.30 Impact Factor
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    ABSTRACT: Patients with ferroportin iron overload due to loss-of-function mutations in SLC40A1 have macrophage iron overload, hyperferritinemia, and normal transferrin saturation. In contrast, hepatocellular iron storage, hyperferritinemia, and increased saturation of transferrin are a distinct clinical presentation of ferroportin iron overload that results from SLC40A1 mutations that confer resistance of ferroportin to hepcidin-mediated inactivation. SLC40A1 was sequenced in patients from 2 independent pedigrees affected by hepatic iron overload unrelated to HFE. Functions of the ferroportin variants were tested in vitro. A patient heterozygous for the variant p.W158C in SLC40A1 presented with macrophage iron overload, hyperferritinemia, and normal transferrin saturation. A patient with hepatocellular iron storage, hyperferritinemia, and increased transferrin saturation was heterozygous for p.H507R. Expression of the p.W158C form of ferroportin in 293T cells resulted in defective trafficking to the plasma membrane and reduced iron export activity; the iron export activity of cells that expressed the p.H507R form of ferroportin did not differ from cells that expressed ferroportin without this mutation. The p.H507R of ferroportin localizes normally to the plasma membrane but is resistant to hepcidin-mediated inactivation. Addition of a synthetic peptide derived from ferroportin without these mutations (amino acids 500-518) decreased the inhibitory activity of hepcidin in cells, whereas a peptide from the same region, with p.H507R, had no effect on hepcidin activity. The variant p.W158C in SLC40A1 impairs intracellular trafficking of ferroportin, resulting in reduced iron export. The variant p.H507R does not bind hepcidin in vitro and results in apparent hepcidin resistance.
    Gastroenterology 03/2011; 140(7):2056-63, 2063.e1. DOI:10.1053/j.gastro.2011.02.064 · 13.93 Impact Factor
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    ABSTRACT: Classical ferroportin disease is characterized by hyperferritinemia, normal transferrin saturation, and iron overload in macrophages. A non-classical form is characterized by additional hepatocellular iron deposits and a high transferrin saturation. Both forms demonstrate autosomal dominant transmission and are associated with ferroportin gene (SLC40A1) mutations. SLC40A1 encodes a cellular iron exporter expressed in macrophages, enterocytes, and hepatocytes. The aim of the analysis is to determine the penetrance of SLC40A1 mutations and to evaluate in silico tools to predict the functional impairment of ferroportin mutations as an alternative to in vitro studies. We conducted a systematic review of the literature and meta-analysis of the biochemical presentation, genetics, and pathology of ferroportin disease. Of the 176 individuals reported with SLC40A1 mutations, 80 were classified as classical phenotype with hyperferritinemia and normal transferrin saturation. The non-classical phenotype with hyperferritinemia and elevated transferrin saturation was present in 53 patients. The remaining patients had normal serum ferritin or the data were reported incompletely. Despite an increased hepatic iron concentration in all biopsied patients, significant fibrosis or cirrhosis was present in only 11%. Hyperferritinemia was present in 86% of individuals with ferroportin mutations. Bio-informatic analysis of ferroportin mutations showed that the PolyPhen score has a sensitivity of 99% and a specificity of 67% for the discrimination between ferroportin mutations and polymorphisms. In contrast to HFE hemochromatosis, ferroportin disease has a high penetrance, is genetically heterogeneous and is rarely associated with fibrosis. Non-classical ferroportin disease is associated with a higher risk of fibrosis and a more severe overload of hepatic iron.
    Journal of Hepatology 11/2010; 53(5):941-9. DOI:10.1016/j.jhep.2010.05.016 · 10.40 Impact Factor
  • R Mayr · T Hochgruber · W Griffiths · M Hermann · N Baumgartner · T Cox · W Vogel · H Zoller
    Zeitschrift für Gastroenterologie 05/2010; 48(05). DOI:10.1055/s-0030-1254610 · 1.67 Impact Factor
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    ABSTRACT: Mutations in the SLC40A1 gene, which encodes ferroportin, are associated with autosomal dominant hemochromatosis. Ferroportin is inhibited directly by hepcidin, a key iron-regulatory peptide, and functional consequences of SLC40A1 mutations account for observed phenotypic differences in patients with ferroportin disease. We describe a large pedigree with a novel SLC40A1 mutation and, through in vitro analysis, elucidate the associated molecular mechanism of iron overload. The entire coding sequence of the SLC40A1 gene was sequenced in a pedigree, presenting with autosomal dominant hyperferritinemia. The functional effects of a novel SLC40A1 mutation were studied by overexpression of wild-type and mutant ferroportin fusion proteins in human embryonic kidney cells. Iron export was studied in these cells using (59)Fe transport assays; subcellular localization of ferroportin was examined by way of confocal microscopy. A novel SLC40A1 mutation p.R489K segregated with iron overload in a family with clinical and histopathological signs of macrophage-type ferroportin disease. Human embryonic kidney cells overexpressing p.R489K ferroportin showed decreased iron export capacity when compared with wild-type ferroportin overexpressing cells. Subcellular localization studies demonstrated that p.R489K ferroportin was retained abnormally within an intracellular compartment. Conclusion: We report a novel pathological SLC40A1 variant associated with abnormal cell surface expression of ferroportin due to intracellular retention of the mutant protein. These findings predict macrophage-type ferroportin disease, the phenotype observed in this kindred. Study of the molecular cell biology of ferroportin and its mutants is key to understanding the pathogenesis of this increasingly recognized form of hemochromatosis, which responds poorly to conventional therapy.
    Hepatology 03/2010; 51(3):788-95. DOI:10.1002/hep.23377 · 11.19 Impact Factor
  • S Sen · S M Rushbrook · T C See · W J H Griffiths
    Gut 02/2009; 58(1):59, 144. DOI:10.1136/gut.2008.161505 · 13.32 Impact Factor
  • G M Hirschfield · P Gibbs · W J H Griffiths
    BMJ (online) 02/2009; 338:b1670. DOI:10.1136/bmj.b1670 · 16.38 Impact Factor
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    ABSTRACT: Percutaneous aspiration and drainage of post-operative abdominal fluid collections is a well established standard technique. However, some fluid collections are not amenable to percutaneous drainage either due to location or the presence of surrounding visceral structures. Endoscopic Ultrasound (EUS) has been widely used for the drainage of pancreatitis-related abdominal fluid collections. However, there are no reports on the use of this technique in the post-operative setting. We report a case where the EUS-guided technique was used to drain a percutaneously inaccessible post-operative collection which had developed after Whipple's resection.
    World Journal of Gastroenterology 12/2008; 14(44):6867-8. DOI:10.3748/wjg.14.6867 · 2.43 Impact Factor
  • K L Nash · T M Yeung · P J Lehner · P Gibbs · W J H Griffiths
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    ABSTRACT: The management of patients with pre-existing tuberculosis (TB) undergoing liver transplantation is challenging. Cautious immunosuppression is required to prevent reactivation of disease, and second-line anti-tuberculous treatment may be necessary to prevent graft hepatotoxicity. Furthermore, liver transplantation in the context of isoniazid-resistant TB has seldom been reported. We report on a 44-year-old man with recent isoniazid-resistant extra-pulmonary TB who developed subacute hepatic failure requiring emergency liver transplantation and treatment with second-line anti-tuberculous therapy. We demonstrate that patients who have pre-existing TB can be successfully treated with alternative anti-tuberculous medication while under immunosuppression post transplantation. Pre-existing TB, including resistant strains, should not be an absolute contraindication to liver transplantation.
    Transplant Infectious Disease 10/2007; 10(4):272-5. DOI:10.1111/j.1399-3062.2007.00277.x · 1.98 Impact Factor
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    W J H Griffiths
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    ABSTRACT: Since the seminal discovery of the HFE gene a decade ago, considerable further progress in unravelling the genetic basis of haemochromatosis has been made. Novel genes and iron overload phenotypes have been described with potential insights into the molecular pathophysiology of human iron metabolism. To review recent key advances in the field of inherited iron overload and assess their impact on clinical practice and on our understanding of iron regulation. A PubMed search was undertaken predominantly using 'haemochromatosis', 'HFE', 'hepcidin' and 'ferroportin'. Illustrative cases were sought. The impact of HFE mutation analysis on the management of haemochromatosis is significant and allows early accurate diagnosis. HFE is also implicated in the siderosis associated with other liver pathologies. Non-HFE genes underpinning other forms of haemochromatosis are now recognized and genotype-phenotype interactions result in a spectrum of disease. These novel gene products interact with HFE in a common pathway for iron homeostasis. Further identification of non-HFE genes associated with iron homeostasis will enhance our diagnostic certainty of primary haemochromatosis and may explain the variable expression seen in HFE-related disease. Improving our understanding of the mechanisms of iron regulation may lead to novel therapeutic strategies for the management of iron overload.
    Alimentary Pharmacology & Therapeutics 09/2007; 26(3):331-42. DOI:10.1111/j.1365-2036.2007.03387.x · 5.48 Impact Factor

Publication Stats

338 Citations
199.83 Total Impact Points

Institutions

  • 2008–2014
    • Cambridge University Hospitals NHS Foundation Trust
      • Department of Clinical Biochemistry
      Cambridge, England, United Kingdom
  • 1999–2014
    • University of Cambridge
      • • Department of Surgery
      • • Department of Medicine
      Cambridge, England, United Kingdom