Gerry MacQuillan

Validation of the FibroTest Biochemical Markers Score in Assessing Liver Fibrosis in Hepatitis C Patients

BACKGROUND Determining the stage of fibrosis by liver biopsy is important in managing patients with hepatitis C virus infection. We investigated the predictive value of the proprietary FibroTest score to accurately identify significant fibrosis in Australian hepatitis C patients. METHODS Serum obtained from 125 confirmed hepatitis C patients before antiviral therapy was analyzed for haptoglobin, alpha(2)-macroglobulin, apolipoprotein A1, bilirubin, and gamma-glutamyltransferase activity, and the FibroTest score was computed. Liver fibrosis pathology was staged according to a defined system on a scale of F0 to F4. We used predictive values and a ROC curve to assess the accuracy of FibroTest scores. RESULTS The prevalence of significant fibrosis defined by liver biopsy was 0.38. The most useful single test for predicting significant fibrosis was serum alpha(2)-macroglobulin (cutoff value, 2.52 g/L; sensitivity, 75%; specificity, 67%). The negative predictive value of a FibroTest score <0.1 was 85%, and the positive predictive value of a score >0.6 was 78%. Although 33 of the 125 patients had FibroTest scores <0.1 and were therefore deemed unlikely to have fibrosis, 6 (18%) had significant fibrosis. Conversely, of the 24 patients with scores >0.6 who were likely to have significant fibrosis, 5 (21%) had mild fibrosis. Of the 125 patients in the cohort, 57 (46%) could have avoided liver biopsy, but discrepant results were recorded in 11 of those 57 (19%). CONCLUSION The FibroTest score could not accurately predict the presence or absence of significant liver fibrosis.

Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by mucocutaneous and visceral telangiectasia. Hepatic involvement with vascular malformations may lead to portal hypertension, biliary ischemia, and high‐output cardiac failure. Liver transplantation is indicated for life‐threatening disease but carries significant risk from surgery and chronic immunosuppression. We report a case of a 47‐year‐old woman with HHT successfully treated with the vascular endothelial growth factor (VEGF) antibody bevacizumab. The patient was referred for consideration of liver transplantation because of hepatic HHT leading to high‐output cardiac failure, diuretic resistant ascites, cholestasis, and malnutrition. As she was considered a high‐risk candidate for transplantation, she underwent 6 courses of bevacizumab (5 mg/kg) over 12 weeks. A dramatic improvement in her clinical state was observed after 3 months with reversal of cholestasis, resolution of cardiac failure and ascites, and improvement in nutritional status with a 10% dry weight increase. Treatment induced a marked reduction in liver vascularity and halving of her liver volume from 4807 to 2269 mL over 6 months. This was associated with normalization of her cardiac output from 10.2 to 5.1 L/minute. Correspondingly, she ceased diuretic medications, returned to full‐time work, and was delisted as a transplant candidate. She remains well 6 months after completing treatment. In conclusion, antagonism of VEGF receptors led to a dramatic regression of hepatic vascular malformations and reversal of high‐output cardiac failure and complications of portal hypertension in this patient with HHT. Bevacizumab may potentially alleviate the need for liver transplantation in this group of patients. Liver Transpl 14:210–213. 2008.

Hepatitis C virus eradication in intravenous drug users maintained with subcutaneous naltrexone implants

The effectiveness of HCV antiviral therapy in patients who have undergone recent drug dependency treatment and continue to inject drugs sporadically is presently not clear. Patients attending a community‐based drug rehabilitation and naltrexone implant clinic from October 2002 until March 2005 were screened for HCV infection and if positive offered further assessment and treatment with interferon and ribavirin therapy. The first 50 patients to commence HCV therapy and complete at least 6 months follow‐up were prospectively studied. ETR response (HCV PCR negative) was 34/50 (68%) and SVR 6 months post‐treatment was 31/50 (62%). Viral eradication was maintained in those 22 patients that have had 12 months or more post‐treatment follow‐up. Eleven (22%) patients stopped therapy early due to side effects or poor compliance. Only two patients with an ETR likely reinfected due to unsafe injection practices. One was re‐treated and achieved an SVR. Of the patients achieving a 6‐month SVR, 17 of 31 patients reported no further IDU and 13 of 31 patients occasional IDU during treatment and this was maintained after HCV treatment cessation. 46% of patients received antidepressant and/or antipsychotic medication during treatment. Conclusion: This study of HCV treatment in a community‐based subcutaneous naltrexone implant clinic found antiviral therapy resulted in a 62% SVR. This result is comparable to that reported in hospital‐based clinics in non‐IDU patients. The side effect profile and compliance was also similar. HCV antiviral therapy should be offered to this large and currently under treated group. (HEPATOLOGY 2007;45:111–117.)

The impact of phlebotomy in nonalcoholic fatty liver disease: A prospective, randomized, controlled trial

Iron is implicated in the pathogenesis of liver injury and insulin resistance (IR) and thus phlebotomy has been proposed as a treatment for nonalcoholic fatty liver disease (NAFLD). We performed a prospective 6‐month randomized, controlled trial examining the impact of phlebotomy on the background of lifestyle advice in patients with NAFLD. Primary endpoints were hepatic steatosis (HS; quantified by magnetic resonance imaging) and liver injury (determined by alanine aminotransaminase [ALT] and cytokeratin‐18 [CK‐18]). Secondary endpoints included insulin resistance measured by the insulin sensitivity index (ISI) and homeostasis model of assessment (HOMA), and systemic lipid peroxidation determined by plasma F2‐isoprostane levels. A total of 74 subjects were randomized (33 phlebotomy and 41 control). The phlebotomy group underwent a median (range) of 7 (1‐19) venesection sessions and had a significantly greater reduction in ferritin levels over 6 months, compared to controls (−148 ± 114 vs. −38 ± 89 ng/mL; P < 0.001). At 6 months, there was no difference between phlebotomy and control groups in HS (17.7% vs. 15.5%; P = 0.4), serum ALT (36 vs. 46 IU/L; P = 0.4), or CK‐18 levels (175 vs. 196 U/L; P = 0.9). Similarly, there was no difference in end‐of‐study ISI (2.5 vs. 2.7; P = 0.9), HOMA (3.2 vs. 3.2; P = 0.6), or F2‐isoprostane levels (1,332 vs. 1,190 pmmol/L; P = 0.6) between phlebotomy and control groups. No differences in any endpoint were noted in patients with hyperferritinemia at baseline. Among patients undergoing phlebotomy, there was no correlation between number of phlebotomy sessions and change in HS, liver injury, or IR from baseline to end of study. Conclusion: Reduction in ferritin by phlebotomy does not improve liver enzymes, hepatic fat, or IR in subjects with NAFLD. (Hepatology 2015;61:1555–1564)

Image analysis of liver biopsy samples measures fibrosis and predicts clinical outcome

BACKGROUND & AIMS Histopathological scoring of liver fibrosis mainly measures architectural abnormalities and requires a minimum biopsy size (⩾ 10 mm). Liver collagen quantification may allow use of small size biopsies and improve the prediction of clinical outcomes. This study evaluated the ability of the collagen proportional area (CPA) measurement to predict clinical outcomes. METHODS Clinical outcomes were determined using population based data-linkage for chronic hepatitis C (CHC) patients from 1992 to 2012. Quantitative digital image analysis of liver biopsies was used for CPA measurement. RESULTS 533 patients with a biopsy size ⩾ 5 mm were included. Median follow up was 10.5 years. 26 developed hepatocellular carcinoma (HCC), 39 developed liver decompensation and 33 had liver related death. 453 had Metavir F0-F2 and 80 had F3-F4. CPA ranged from 1.3% to 44.6%. CPA and Metavir stage were independently associated with liver related death. Metavir stage, CPA stage and age were independently associated with HCC. CPA stage (C1: 0%-5%, C2: 5%-10%, C3: 10%-20%, C4: >20%) stratified risk and a significant difference in outcomes was present between all CPA stages for HCC and between C2-C3 and C3-C4 for decompensation and liver related death. The 15 year composite endpoint-free survival was 97% for C1, 89% for C2, 60% for C3, 7% for C4. C4 had significantly worse survival than ⩽ C3 (p<0.001) in cirrhotic patients. CONCLUSIONS CPA stage gave additional information regarding risk stratification for adverse clinical outcomes independent of Metavir stage.

Acute graft-versus-host disease after liver transplant: Novel use of etanercept and the role of tumor necrosis factor α inhibitors

Acute graft‐versus‐host disease following orthotopic liver transplantation is a rare but feared complication arising in 1% to 2% of cases with a dismal prognosis. It most often presents as fever, rash, and diarrhea with or without pancytopenia. Patients die from complications of marrow failure such as sepsis or bleeding. Because of its low incidence, there is no clear treatment protocol for this complication. Both increasing and withdrawing immunosuppression have been attempted with variable success. Although anti–tumor necrosis factor α therapy has been widely used for the treatment of steroid‐resistant acute graft‐versus‐host disease in the hematopoietic stem cell transplant setting, there previously have been no reported cases of its use in liver transplantation. The aim of this report is to review a case of acute graft‐versus‐host disease and the use of etanercept to manage this complication. Etanercept has never previously been used in liver transplantation complicated by acute graft‐versus‐host disease. In the hematology literature, the success of its use is offset by significant rates of serious infectious (especially fungal) complications. However, preliminary results are encouraging and offer insight into its use as a potentially viable therapeutic option. We report the first successful use of etanercept in liver transplantation–associated graft‐versus‐host disease, albeit complicated by invasive aspergillosis, and recommend concurrent antifungal prophylaxis when the drug is used in this setting. Liver Transpl 15:421–426, 2009.

LEVETIRACETAM AS A POSSIBLE CAUSE OF FULMINANT LIVER FAILURE

A 21-year-old man presented to the hospital following a generalized seizure preceded by a 6-day history of pale stools, dark urine, and jaundice. His relevant past medical history included neurocysticercosis diagnosed 12 months previously and treated with a short course of albendazole. He developed post-neurocysticercosis epilepsy and was treated with a stable dose of oxcarbazepine. A month prior to this current presentation he was switched from oxcarbazepine to levetiracetam to improve seizure control. His liver function tests (LFTs) were normal then. He has no history of significant alcohol intake. Initial assessment revealed a markedly icteric man with moderate hepatic encephalopathy (confusion, disorientation, somnolence, and a Glasgow Coma Scale of 13/15) but no focal neurologic deficits. Initial results were as follows: LFTs: bilirubin 591 μmol/L, alanine aminotransferase (ALT) 1,610 U/L, alkaline phosphatase (ALP) 246 U/L, INR was 3.6. A cerebral CT scan revealed multiple ring enhancing lesions consistent with the previously documented neurocysticercosis. Autoimmune, viral, and metabolic liver screens were negative. A triphasic liver CT scan revealed a reduced liver volume. A transjugular liver biopsy demonstrated massive confluent …

Immunological markers predicting outcome in patients with hepatitis C treated with interferon-α and ribavirin

Type 1 (T1) cytokine responses are required for the clearance of hepatitis C virus by cytotoxic T lymphocytes, but can promote liver damage. Interferon‐α (IFNα) can be expected to promote T1 cytokine responses, so treatment outcome may depend on the T1/T2 cytokine environment and levels of immune activation at baseline. This model was tested by monitoring immunological markers in a pilot study of treatment naïve patients given IFNα2b and ribavirin, with the aim of finding markers that predict virological outcome. Soluble (s) CD26/dipeptidyl peptidase IV enzyme activity and levels of sCD30, bioavailable IL‐6, sTNF‐RI, IL‐1ra and nitrite/nitrate (NO2 −/NO3 −) were measured. Levels of IL‐1ra and bioavailable IL‐6 were lower in patients than controls and did not change with therapy. Treatment decreased sCD26/dipeptidyl peptidase IV enzyme activities and sCD30 levels and increased NO2 −/NO3 − levels. High baseline sCD30 levels predicted an early (P = 0.008) and sustained (P = 0.03) virological response to therapy, suggesting treatment may be more effective in patients with a predominant T2 profile.

Does sequencing the PKRBD of hepatitis C virus NS5A predict therapeutic response to combination therapy in an Australian population

Background and Aim:  The presence of four or more amino acid substitutions within the interferon sensitivity determining region (ISDR) of the hepatitis C virus (HCV) genotype 1b NS5A gene determines sensitivity to interferon (IFN) monotherapy in Japanese patients. Resistance of HCV genotype 1 to IFN‐alpha has been attributed to the functional inhibition of a RNA dependent protein kinase (PKR) by the HCV NS5A PKR binding domain (PKRBD), which includes the ISDR. The ability of the ISDR and PKRBD sequence to predict a response to IFN‐alpha and ribavirin combination therapy was investigated in an Australian population.

High biological variation of serum hyaluronic acid and Hepascore, a biochemical marker model for the prediction of liver fibrosis

Abstract Background: Serum hyaluronic acid and biochemical models which require hyaluronic acid analysis are commonly used as predictors of liver fibrosis in patients with chronic liver disease, however biological variation data for hyaluronic acid are deficient. Methods: Four serial serum samples were obtained at weekly intervals from healthy volunteers and patients with chronic hepatitis B, chronic hepatitis C and non- alcoholic fatty liver disease (NAFLD; 20 in each group). The within-individual week-to-week variation (CVI) and reference change values for hyaluronic acid, α2-macroglobulin and Hepascore were obtained. Hepascore is calculated from hyaluronic acid, α2-macroglobulin, bilirubin and γ-glutamyltransferase activity. Results: Hyaluronic acid displayed large within-individual variation, the CVI values were 62% in healthy subjects, 38% in hepatitis C, 37% in hepatitis B and 36% in NAFLD patients. Hepascore CVIs were 43% in healthy subjects, 24% in hepatitis C, 28% in hepatitis B and 39% in NAFLD patients. α2-Macroglobulin was much less variable with CVIs ranging from 4.4% to 7.6%. Bland-Altman plots of week-to-week variations showed rates of significant disagreement for samples collected in any 2 successive weeks varied from 5% in NAFLD patients to 8.3% in healthy subjects. Conclusions: When using non-fasting serum samples, hyaluronic acid and to a lesser extent, the Hepascore model display large within-individual variations in both health and chronic liver disease. This information is critical for interpreting the significance of both single measurements and changes in serial measurements.