George Garas

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.

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)

Ganciclovir and the treatment of Epstein-Barr virus hepatitis.

Epstein‐Barr virus (EBV) is part of the herpesvirus family that infects up to 90% of the population. Initial infection is often subclincal in children but will generally result in symptomatic infectious mononucleosis in adolescents and adults. Ganciclovir has been utilized in immunocompromised patients with EBV encephalitis and post‐liver transplant for EBV fulminant hepatitis. Herein, the successful use of ganciclovir in two immunocompetent patients with severe EBV hepatitis is reported.

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.

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.

Tacrolimus‐induced thrombotic microangiopathy in orthotopic liver transplant patients: case series of four patients

Thrombotic microangiopathy (TMA) is a potentially fatal complication in solid organ and bone marrow transplant patients, with reported incidence of 0.5–3% and mortality of about 75%. To emphasise the importance of early diagnosis and prompt commencement of therapy results in improved clinical outcomes. A retrospective study of all patients who underwent orthotopic liver transplantation (OLTX) at the Western Australian Liver Transplantation Service from May 1994 to December 2010 was conducted to identify patients who developed tacrolimus‐induced TMA. We identified four patients with tacrolimus‐induced TMA post‐OLTX, derived from a cohort of 104 patients treated with tacrolimus in our institution. The mean age at diagnosis was 40 years, and the mean time of onset was 63 ± 7.5 weeks after OLTX. The indications for OLTX in the four patients were fulminant hepatic failure in three (Wilson disease, paracetamol overdose and post‐partum thrombotic thrombocytopenic purpura) and hepatitis C virus‐related cirrhosis. All patients had tacrolimus post‐OLTX. At diagnosis, tacrolimus was discontinued in all patients, and three of the four patients underwent plasma exchange and all patients improved clinically. Mean duration of follow up was 15 ± 7.5 months. There was no mortality 6 months post‐TMA. Early diagnosis with immediate discontinuation or conversion of calcineurin inhibitors and plasma exchange should be offered to OLTX patients with TMA as it results in good outcomes.

Outcome, tolerability and compliance of compassionate use interferon and ribavirin for hepatitis C infection in a shared care hospital clinic

Abstract

Ticlopidine-associated cholestatic hepatitis

A 60-year-old Chinese male was admitted with a 2-week history of deepening jaundice, pruritis and dark urine. Five weeks prior, he had been visiting family in Malaysia and had undergone gastroscopy for investigation of anorexia. Extensive gastric erosions secondary to aspirin were found. Omeprazole (20 mg daily) was commenced and the patient’s aspirin was changed to ticlopidine (250 mg b.i.d). There was no history of abdominal pain, fever or rash. The patient did not drink alcohol.

Nonalcoholic fatty liver disease-related cirrhosis is commonly unrecognized and associated with hepatocellular carcinoma

Determination of cirrhosis in nonalcoholic fatty liver disease (NAFLD) is important as it alters prognosis and management. We aimed to examine whether cirrhosis was diagnosed incidentally or intentionally in patients with NAFLD. We reviewed 100 patients with NAFLD cirrhosis to determine mode of cirrhosis diagnosis (incidental or by intent), severity of liver disease at diagnosis, diagnostician, and previous clinical imaging or laboratory evidence of unrecognized cirrhosis. The majority (66/100) of patients with NAFLD cirrhosis were diagnosed incidentally, with the majority of these (74%) diagnosed with NAFLD simultaneously. Those with incidental cirrhosis diagnoses had more deranged platelet and international normalized ratio levels (P < 0.05) and were more likely to have concomitant hepatocellular carcinoma (HCC) (12% versus 0%, P < 0.05). Incidental cirrhosis was diagnosed following imaging (32%) or liver tests (26%) performed for reasons unrelated to liver disease, following unexpected endoscopic finding of varices (21%) or an unexpected surgical finding (14%). Diagnoses by intent were predominantly made by gastroenterologists/hepatologists, whereas general practitioners, surgeons, and physicians tended to diagnose cirrhosis incidentally (P < 0.001). The majority of patients diagnosed incidentally (n = 48/66, 73%) had previous thrombocytopenia, splenomegaly, or high noninvasive fibrosis scores. Following diagnosis, patients diagnosed incidentally were less likely to undergo HCC screening. Conclusion: The majority of patients with NAFLD cirrhosis are diagnosed incidentally. These patients are more likely to have advanced liver disease and HCC. Increased awareness of screening for cirrhosis is needed in patients with NAFLD. (Hepatology Communications 2017;1:53–60)

Malignant peripheral nerve sheath tumour of the liver

Sir, Malignant peripheral nerve sheath tumour (MPNST) of the liver is extremely rare, especially in the absence of neurofibromatosis type 1 (NF-1). We report a case of MPNST of the liver. A 71-year-old male, otherwise well except for an inguinal hernia, presented with an 8 month history of right upper quadrant pain and abdominal distension as well as a 1 month history of fever and night sweats. Six months prior to presentation, he underwent a right hemicolectomy and omentectomy; histopathology revealed omental infarction of uncertain aetiology. At that time, the computed tomography (CT) scan also showed a 1.3 cm low attenuation subcapsular lesion in segment VII/VIII of the liver (Fig. 1). Physical examination revealed a soft abdomen with mild distension and tender hepatomegaly. There were no significant skin lesions, lymphadenopathy, ascites or splenomegaly. Initial laboratory data revealed a raised white cell count of 14.1 (4-11 10/L) and C-reactive protein 180 (<10mg/L). His liver function tests were abnormal with an alanine transaminase 187 (<40U/L), gamma glutamyl transferase 535 (<60U/L) and alkaline phosphatase 923 (35–135U/L). Computed tomography (CT) and magnetic resonance imaging (MRI) (Fig. 2) revealed a 21 cm complex solid and cystic right lobe liver lesion. An infectious screen including hydatid and Entamoeba serology as well as a liver and autoimmune screen were negative. Tumour markers, including alpha fetoprotein, as well as flow cytometry on blood were normal. He had ongoing temperature spikes despite being on broad spectrum antibiotics. Cultures of aspirates from the liver lesion were negative. Cytology showed degenerate neutrophil polymorphs only. He subsequently underwent an exploratory laparotomy and resection of the liver mass. Macroscopically the tumour was received piecemeal, composed of irregular fragments of firm to friable haemorrhagic tissue, associated with abundant blood (Fig. 3). Histopathology of the resected liver mass revealed a largely necrotic and haemorrhagic tumour with viable areas that exhibited morphological appearances of a high grade malignant spindle cell neoplasm. The spindle cells were plump and exhibited mild pleomorphism with irregular nuclear contours and coarsely granular chromatin, with moderate amounts of eosinophilic cytoplasm. They were mostly arranged in a sheetlike architecture (Fig. 4) with a background of thin-walled curvilinear vessels and focal areas of accentuated perivascular cellularity. A mitotic count numbered greater than 30 per 10 high power fields (HPF) (Fig. 5). A broad immunohistochemical staining panel was applied revealing patchy nuclear positivity for S100 (Fig. 6) with negative staining for a panel of epithelial markers (Cam5.2, AE1þ3, MNF116, CK7, CK20 and EMA), myoepithelial and smooth muscle markers (p63, desmin, myogenin, caldesmon and smooth muscle actin), melanoma markers (Melan A, HMB45 and MITF), vascular markers (CD31 and CD34), GIST markers (CD117 and DOG-1) and a hepatocyte marker (HepPar-1). Ultrastructural