Increased nociceptin/orphanin FQ plasma levels in hepatocellular carcinoma

AIM: The heptadecapeptide nociceptin alias orphanin FQ is the endogenous agonist of opioid receptor-like1 receptor. It is involved in modulation of pain and cognition. High blood level was reported in patients with acute and chronic pain, and in Wilson disease. An accidental observation led us to investigate nociceptin in hepatocellular carcinoma. METHODS: Plasma nociceptin level was measured by radioimmunoassay, aprotinin was used as protease inhibitor. Hepatocellular carcinoma was diagnosed by laboratory, ultrasound, other imaging, and confirmed by fine needle biopsy. Results were compared to healthy controls and patients with other chronic liver diseases. RESULTS: Although nociceptin levels were elevated in patients with Wilson disease (14.0 +/- 2.7 pg/mL, n = 26), primary biliary cirrhosis (12.1 +/- 3.2 pg/mL, n = 21) and liver cirrhosis (12.8 +/- 4.0 pg/mL, n = 15) compared to the healthy controls (9.2 +/- 1.8 pg/mL, n = 29, P < 0.001 for each), in patients with hepatocellular carcinoma a ten-fold increase was found (105.9 &PLUSMN; 14.4 pg/mL, n = 29, P < 0.0001). High plasma levels were found in each hepatocellular carcinoma patient including those with normal alpha fetoprotein and those with pain (104.9 +/- 14.9 pg/mL, n = 12) and without (107.7 +/- 14.5 pg/mL, n = 6). CONCLUSION: A very high nociceptin plasma level seems to be an indicator for hepatocellular carcinoma. Further research is needed to clarify the mechanism and clinical significance of this novel finding

Autonomic and sensory nerve dysfunction in primary biliary cirrhosis

AIM: Cardiovascular autonomic and peripheral sensory neuropathy is a known complication of chronic alcoholic and non-alcoholic liver diseases. We aimed to assess the prevalence and risk factors for peripheral sensory nerve and autonomic dysfunction using sensitive methods in patients with primary biliary cirrhosis (PBC). METHODS: Twenty-four AMA M2 positive female patients with clinical, biochemical and histological evidence of PBC and 20 age matched healthy female subjects were studied. Five standard cardiovascular reflex tests and 24-h heart rate variability (HRV) analysis were performed to define autonomic function. Peripheral sensory nerve function on median and peroneal nerves was characterized by current perception threshold (CPT), measured by a neuroselective diagnostic stimulator (Neurotron, Baltimore, MD). RESULTS: Fourteen of 24 patients (58%) had at least one abnormal cardiovascular reflex test and thirteen (54%) had peripheral sensory neuropathy. Lower heart rate response to deep breathing (P = 0.001), standing (P = 0.03) and Valsalva manoeuvre (P = 0.01), and more profound decrease of blood pressure after standing (P = 0.03) was found in PBC patients than in controls. As a novel finding we proved that both time domain and frequency domain parameters of 24-h HRV were significantly reduced in PBC patients compared to controls. Each patient had at least one abnormal parameter of HRV. Lower CPT values indicated hyperaesthesia as a characteristic feature at peroneal nerve testing at three frequencies (2000 Hz: P = 0.005; 250 Hz: P = 0.002; 5 Hz: P = 0.004) in PBC compared to controls. Correlation of autonomic dysfunction with the severity and duration of the disease was observed. Lower total power of HRV correlated with lower CPT values at median nerve testing at 250 Hz (P = 0.0001) and at 5 Hz (P = 0.002), as well as with those at peroneal nerve testing at 2000 Hz (P = 0.01). CONCLUSION: Autonomic and sensory nerve dysfunctions are frequent in PBC. Twenty-four-hour HRV analysis is more sensitive than standard cardiovascular tests for detecting of both parasympathetic and sympathetic impairments. Our novel data suggest that hyperaesthesia is a characteristic feature of peripheral sensory neuropathy and might contribute to itching in PBC. Autonomic dysfunction is related to the duration and severity of PBC

Rising plasma nociceptin level during development of HCC: A case report

AIM: Although liver cirrhosis is a predisposing factor for hepatocellular carcinoma (HCC), relatively few reports are available on HCC in primary biliary cirrhosis. High plasma nociceptin (N/OFQ) level has been shown in Wilson disease and in patients with acute and chronic pain. METHODS: We report a follow-up case of HCC, which developed in a patient with primary biliary cirrhosis. The tumor appeared 18 years after the diagnosis of PBC and led to death within two years. Alfa fetoprotein and serum nociceptin levels were monitored before and during the development of HCC. Nociceptin content was also measured in the tumor tissue. RESULTS: The importance and the curiosity of the presented case was the novel finding of the progressive elevation of plasma nociceptin level up to 17-fold (172 pg/mL) above the baseline (9.2 +/- 1.8 pg/mL) parallel with the elevation of alpha fetoprotein (from 13 ng/mL up to 3 480 ng/mL) during tumor development. Nociceptin content was more than 15-fold higher in the neoplastic tissue (0.16 pg/mg) than that in the tumor-free liver tissue samples (0.01 pg/mg) taken during the autopsy. CONCLUSION: Results are in concordance with our previous observation that a very high plasma nociceptin level may be considered as an indicator for hepatocellular carcinoma

Cholangiocarcinoma in Wilson's Disease - a Case Report

It has been suggested that hepatobiliary carcinomas are less frequent in Wilson's disease (WD) than in liver diseases of other etiology. However, the protective role of copper against malignancies is debated. Only a few cases of cholangiocarcinoma (CCC) in WD have been published. Here we report on a case of a 47-year-old male H1069Q homozygous, Kayser-Fleischer ring positive WD patient with a low ceruloplasmin level who was followed up and treated with chelating agents throughout nine years. The patient presented with neurological symptoms and liver cirrhosis at diagnosis. Clinical symptoms regressed after the treatment initiation. Rapidly developed tumour metastases were found in the bones, lung and liver (without jaundice). Autopsy revealed cholangiocarcinoma as the primary tumour confirmed by strong CK7 positivity and glypican-3 negativity. The curiosity of the presented case is the very rapid development of CCC despite continuous chelating agent therapy

Interobserver agreement and diagnostic accuracy of shearwave elastography for the staging of hepatitis C virus-associated liver fibrosis

Abstract PURPOSE: Our study aimed to evaluate the technical success rate, interobserver reproducibility, and accuracy of shearwave elastography (SWE) in the staging of hepatitis C virus (HCV)-associated liver fibrosis. METHODS: A total of 10 healthy controls and 49 patients with chronic liver disease were enrolled prospectively. Two examiners performed point shearwave elastography (pSWE) and two-dimensional shearwave elastography (2D-SWE) measurements with an RS85A ultrasound scanner using the S-Shearwave application (Samsung Medison, Hongcheon, Korea). The performance of S-Shearwave in the staging (METAVIR F0-F4) of liver fibrosis was compared with prior transient elastography (TE) with receiver operating characteristic (ROC) curve analysis. RESULTS: The interobserver reproducibility was excellent with pSWE (ICC = 0.92, 95% CI: 0.86-0.95, P < .001). A very good agreement was found between pSWE and TE measurements (ICC =0.85, 95% CI: 0.78-0.89, P < .001). The ROC analysis determined the optimal cut-off values of pSWE for the staging of chronic hepatitis C-associated fibrosis (F2, 1.46 m/s; F3, 1.63 m/s; F4, 1.95 m/s). Both observers achieved excellent diagnostic accuracy (AUROC: 94% vs 97%) in the detection of significant (≥F2) liver fibrosis. CONCLUSION: The interobserver agreement is excellent with S-Shearwave pSWE, and observers can diagnose significant liver fibrosis with a comparable accuracy to TE

Májátültetés Wilson-kóros betegekben, 1996–2017 = Liver transplantation in Wilson’s disease patients, 1996–2017

Absztrakt: Bevezetés: A Wilson-kór a rézanyagcsere ritka, kezelés nélkül fatális, öröklődő megbetegedése. Bár a diagnosztika és a kezelés jelentős fejlődésen ment át az elmúlt években, számos beteg esetében ma is májátültetésre van szükség. Célkitűzés: A vizsgálat célja a Magyarországon Wilson-kór miatt májátültetésen átesett betegek adatainak összegyűjtése és feldolgozása volt. Módszer: Retrospektív módon vizsgáltuk a Semmelweis Egyetemen 1996 és 2017 között Wilson-kór miatt májátültetésen átesett 24 beteg adatait. A Wilson-kór diagnózisa minden esetben a nemzetközi, lipcsei pontrendszeren alapult. A heveny májelégtelenség felállításához a King’s College-kritériumrendszert használtuk. A májátültetések a Semmelweis Egyetem Transzplantációs és Sebészeti Klinikáján történtek, első alkalommal 1996-ban. Eredmények: Az átlagéletkor 26 év volt, a nő/férfi arány 13/11. 12 beteg heveny májelégtelenség miatt, 12 beteg dekompenzált cirrhosis miatt esett át májátültetésen. Egy beteg krónikus rejekció miatt retranszplantációra került. Három heveny májelégtelen beteg az Eurotransplant segítségével kapott új májat. A várólistán eltöltött átlagos idő 3 nap volt a heveny májelégtelen betegek, míg 320 nap a dekompenzált májbetegek esetében. Az ötéves túlélés 66% volt, azonban a 2002 után transzplantáltak esetében 80%, ami a tanulási folyamatot és a májátültetés elérhetőségének javulását jelezheti. A diagnosztika nehézségei ellenére a betegek többségében (21/24 beteg) már a műtét előtt ismert volt a Wilson-kór. Következtetések: Bár a Wilson-kór diagnosztikája és kezelése jelentős fejlődésen ment át az elmúlt évek során, ma is számos esetben van szükség májátültetésre. A betegek megfelelő kiválasztása és a transzplantáció időzítése jelentősen javítja a betegek túlélését. Orv Hetil. 2019; 160(51): 2021–2025. | Abstract: Introduction: Wilson’s disease is a lethal-without-treatment inherited disorder of copper metabolism. Despite the increased focus on the diagnosis and treatment, liver transplantation is needed in a number of cases even nowadays. Aim: To collect and analyze the data of the Hungarian Wilson’s disease patients who underwent liver transplantation. Method: Data of 24 Wilson’s disease patients who underwent liver transplantation at the Semmelweis University have been analyzed retrospectively. The diagnosis of Wilson’s disease was based on the international score system. The diagnosis of acute liver failure corresponded to the King’s College criteria. All liver transplantations had been performed at the Department of Transplantation and Surgery of Semmelweis University, in 1996 for the first time. Results: The mean age was 26 years, F/M = 13/11. Twelve patients needed urgent liver transplantation for acute liver failure, and 12 underwent transplantation for decompensated liver cirrhosis. One patient had been retransplanted because of chronic rejection. Three patients with acute on chronic liver failure were transplanted via the Eurotransplant program. The mean time on the waiting list was 3 vs 320 days in acute liver failure and chronic liver disease groups, respectively. The overall 5-year survival was 66%, but it was 80% after 2002 indicating both the learning curve effect and the improvement of vigilance in Hungary. Despite difficulties of the diagnostic process, Wilson’s disease was identified in 21/24 patients prior to the transplantation. Conclusion: Liver transplantation is needed in a number of cases of Wilson’s disease. The ideal indication and timing of transplantation may improve the survival of the patients. Orv Hetil. 2019; 160(51): 2021–2025

Malignus solid tumorhoz társuló hypereosinophil szindróma

A hypereosinophil szindróma tartós eosinophil-túltermeléssel járó, a következményes eosinophilinfiltráció és mediá- torfelszabadulás miatt többszervi károsodást okozó kórkép. Etiológia szerint megkülönböztetünk myeloproliferativ eredetű, parazitafertőzéshez, solid tumorhoz és T-sejtes lymphomához társuló, valamint idiopathiás formát. Esetis- mertetésünkben a 49 éves férfit fogyás, alszári oedema, tachycardia miatt vettük fel osztályunkra. Laborjából jelentősen emelkedett epeúti obstrukciós paraméterek, valamint extrém leukocytosis, eosinophilia volt kiemelhető. Hematológiai malignus betegség erős gyanújával kezdtük vizsgálni. Az elvégzett mellkasi, hasi és kismedencei CT hepatosplenomegaliát, multiplex intrahepaticus laesiókat és egy bizonytalan solitaer cystosus képletet írt le a pancreas farki részében, kóros nyirokcsomókkal és pleuralis folyadékgyülemmel. A leírt CT-kép a klinikum ismeretében elsősorban krónikus myeloid leukaemia manifesztációjának volt megfeleltethető, de a diagnózist a perifériás kenet, az áramlási citometria, a csontvelő-biopszia és a genetikai vizsgálat sem igazolta. Mindezek fényében solid tumorhoz társuló leukaemoid reakció irányába folytattuk a kivizsgálást, a májlaesiók pontos verifikálása érdekében vastagtűbiopszia történt. A szövettani eredmény pancreatobiliaris carcinoma áttétének megfeleltethető, alacsonyan differenciált hámtumor infiltrációját mutatta. A diagnózis felállításának másnapján kezelésünk ellenére a beteg exitált. A gastrointestinalis solid tumorokhoz kapcsolódó hypereosinophil szindróma rendkívül ritka kórkép. Tudomásunk szerint ez a magyar orvosi irodalomban közölt első ilyen eset, mely felhívja a figyelmet a magas fehérvérsejtszám és eosinophilarány differenciáldiagnosztikai kérdéseire, valamint arra, hogy nem korreláló hematológiai leletek esetén nem késlekedhetünk a solid eltérések szövettani mintavételével