Matteo Garcovich

Critical Illness-Related Corticosteroid Insufficiency in Patients With Cirrhosis and Variceal Bleeding

BACKGROUND & AIMSnRelative adrenal insufficiency (AI) occurs in patients with cirrhosis with sepsis, but not with variceal bleeding. We evaluated adrenal function in cirrhotic patients with and without bleeding.nnnMETHODSnTwenty cirrhotic patients with variceal bleeding were evaluated using the short synacthen test (SST) and 10 using the low-dose synacthen test (LDSST) followed by SST. The control group included 60 stable cirrhotic patients, assessed by LDSST (n = 50) or SST (n = 10), and 14 healthy volunteers. AI was diagnosed using SST, based on peak cortisol levels ≤ 18 μg/dL in nonstressed patients or Δmax <9 μg/dL or a total cortisol level <10 μg/dL in stressed patients with variceal bleeding-the current criteria for critical illness-related corticosteroid insufficiency. Using LDSST, diagnosis was based on peak concentrations of cortisol ≤ 18 μg/dL in nonstressed patients and <25 μg/dL (or Δmax <9 μg/dL) in patients with variceal bleeding. We evaluated patients with levels of serum albumin >2.5 g/dL, to indirectly assess cortisol binding.nnnRESULTSnAll healthy volunteers had normal results from LDSSTs and SSTs. Patients with variceal bleeding had higher median baseline concentrations of cortisol (15.4 μg/dL) than stable cirrhotic patients (8.7 μg/dL, P = .001) or healthy volunteers (10.1 μg/dL, P = .01). Patients with variceal bleeding had higher median peak concentrations of cortisol than stable cirrhotic patients (SST results of 32.7 vs 21 μg/dL, P = .001; LDSST results of 9.3 vs 8.1 μg/dL; nonsignificant), with no differences in Δmax in either test. These differences were greater with variceal bleeding than in stable cirrhotic patients with AI. Subanalysis of patients with albumin levels >2.5 g/dL did not change these differences.nnnCONCLUSIONSnCirrhotic patients with variceal bleeding have AI. Despite higher baseline concentrations of serum cortisol and subnormal Δmax values, they did not have adequate responses to stress, and therefore had critical illness-related corticosteroid insufficiency.

Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: The royal free hospital cirrhosis glomerular filtration rate.

Current expressions based on serum creatinine concentration overestimate kidney function in cirrhosis, leading to significant differences between “true” and calculated glomerular filtration rate (GFR). We compared the performance of the four‐variable and six‐variable Modification of Diet in Renal Disease and chronic kidney disease epidemiology with “true,” or measured, GFR (mGFR) and the impact of this difference on Model for End‐Stage Liver Disease (MELD) calculation. We subsequently developed and validated a GFR equation specifically for cirrhosis and compared the performance of the new derived formula with existing GFR formulae. We included 469 consecutive patients who had a transplant assessment between 2011 and 2014. mGFR was measured using plasma isotope clearance according to a technique validated in patients with ascites. A corrected creatinine was derived from the mGFR after application of the Modification of Diet in Renal Disease formula. Subsequently, a corrected MELD was calculated and compared with the conventionally calculated MELD. Stepwise multiple linear regression was used to derive a GFR equation. This was compared with the mGFR in independent external and internal validation sets of 82 and 174 patients with cirrhosis, respectively. A difference >20 mL/minute/1.73 m2 between existing formulae and mGFR was observed in 226 (48.2%) patients. The corrected MELD score was ≥3 points higher in 177 (37.7%) patients. The predicted equation (r2 = 74.6%) was GFR = 45.9 × (creatinine–0·836) × (urea–0·229) × (international normalized ratio–0·113) × (age−0.129 [Corrected November 29, 2016: originally written as “age‐129.”]) × (sodium0·972) × 0.809 (if female) × 0.92 (if moderate/severe ascites). An online calculator is available at http://rfh-cirrhosis-gfr.ucl.ac.uk. The model was a good fit and showed the greatest accuracy compared to that of existing formulae. Conclusion: We developed and validated a new accurate model for GFR assessment in cirrhosis, the Royal Free Hospital cirrhosis GFR, using readily available variables; this remains to be tested and incorporated in prognostic scores in patients with cirrhosis. (Hepatology 2017;65:582‐591).

Evaluation of renal function in patients with cirrhosis

Renal function in patients with cirrhosis is an important prognostic factor, both before and following liver transplantation (LT). The importance of renal function is reflected by serum creatinine (Cr) being in the model for end stage liver disease (MELD) score, which predicts the likelihood of death within 3 months for patients on liver transplant waiting lists and is used for prioritization of recipients (sickest first). Creatinine is also part of the UKELD score which predicts waiting list mortality over 1 year. Cr is a routine laboratory test and is part of the definitions of acute kidney injury, and hepatorenal syndrome in patients with progressive liver disease. However, it is only an indirect marker of renal function, i.e. of glomerular filtration rate (GFR). Unfortunately, all methods currently in use for assessment of renal function have several limitations and also do not have a good correlation with true GFR. Creatinine estimations are readily available but affected by changes in creatinine generation rate, volume of distribution and assay interference that can affect their interpretation. For example, serum creatinine is dependent upon other factors, including dietary meat, the conversion rate of creatine to creatinine, renal tubular secretion of creatinine, urinary flow rate, hydration status, as well as the total pool of body creatine (total muscle mass). The latter can lead to different Cr concentration between individuals with the same renal function but of different age, race and sex.Creatinine assays are also subject to interference by chromogens: bilirubin (both conjugated and unconjugated) which typically reduces the creatinine numerical value. In patients with cirrhosis the interference of bilirubin with Cr measurement is a major problem leading to differences in MELD scores up to 7 points, particularly in patients with the highest priority for LT. Modifications to reduce bilirubin interference are used, including enzymatic methods, but these are mostly more expensive and still underestimate creatinine at high bilirubin concentrations. It is important to recognise that there is no universal reference standard for creatinine, and hence, laboratory standardisation of techniques and normal values would be necessary for all liver transplant units to avoid systematic biases in UKELD and MELD-based allocation systems, or others which incorporate Cr values. Unfortunately, other renal biomarkers, such as cystatin C also have limitations, as cystatin C production is not constant and varies with inflammation. Inulin clearances are impractical in clinical practice. Single bolus isotopic and iodinated radiocontrast methods tend to over estimate true GFR in volume expanded patients with ascites, and further inaccuracy is added when attempts are made to correct for body surface area. A recently published modified Tikhonov method may improve isotopic estimation. Further studies are needed in large series of cirrhotic patients to correlate true GFR with potential serum or urinary markers, which could result in the creation and validation of more specific mathematical formulae for GFR in patients with cirrhosis.

Monitoring of Haemostasis during Liver Transplantation

When end stage liver disease occurs, liver transplantation is the only effective treatment available. In the past, liver transplantation was frequently accompanied by considerable bleeding complications and massive transfusion requirements, while only in recent years advances in operative management and a better understanding of the pathophysiology of coagulation have determined a better outcome for this major surgery. In addition, accumulating evidence shows that the overall haemostatic function in patients with cirrhosis facing liver transplantation may not be shifted towards a bleeding diathesis as traditionally believed, but that both bleeding episodes and thrombotic events may take place as major peri- and post-operative complications in patients undergoing liver surgery. The aim of this review paper is to offer an overview of recent developments that have gradually improved our understanding about the changes that may occur in the haemostatic system of patients undergoing liver transplantation, taking into account the best way to monitor them.

Contrast-enhanced ultrasound patterns of hepatocellular adenoma: an Italian multicenter experience

PurposeHepatocellular adenoma (HCA) is a rare benign monoclonal neoplasm, recently categorized on genetic and histopathological basis into four subtypes with different biological behaviors. Since contrast-enhanced ultrasonography (CEUS) is nowadays a well-established technique for liver nodule characterization, the aim of our study was to assess CEUS features of HCAs to identify criteria that correlate with different HCA subtypes as compared to histopathologic examination and other imaging modalities.MethodsWe retrospectively analyzed data of patients with histology-proven HCA who underwent CEUS, computed tomography or magnetic resonance imaging (MRI) in seven different Italian ultrasound units.ResultsThe study enrolled 19 patients (16 females; 69% with concomitant/prior use of oral contraceptives): the mean size of all HCAs was 4.2xa0cm (range 1.6–7.1xa0cm); 14/19 had inflammatory HCAs (I-HCA), 1/19 β-catenin-activated HCA, and the others unclassified HCAs. On CEUS, during the arterial phase, all but one HCA displayed a rapid enhancement, with 89% of these showing centripetal and 11% centrifugal filling pattern, whereas during the portal and late venous phase 58% of HCA showed washout and the remaining 42% displayed persistent enhancement. In particular, among I-HCAs 7/14 showed no washout, 3/14 and 4/14 showed washout in the portal or late phase, respectively.ConclusionsThis dataset represents one of the few published experiences on HCAs and CEUS in Italy and shows that HCAs are hypervascularized in the arterial phase usually with a centripetal flow pattern and have a heterogeneous behavior in portal and late phase. In particular, occurrence of delayed washout on CEUS but not on MRI is frequently observed in the subtype of I-HCA.RiassuntoIntroduzioneL′adenoma epatico (HCA) rappresenta una rara neoplasia primitiva del fegato, recentemente classificata in quattro diversi sottotipi sulla base delle caratteristiche istopatologiche e del comportamento biologico. In considerazione dell’ampio e diffuso utilizzo dell’ecografia con mezzo di contrasto ecografico (CEUS) nella valutazione non-invasiva delle lesioni focali epatiche l’obiettivo di questo studio è stato quello di documentare in una casistica multicentrica le caratteristiche CEUS di lesioni focali epatiche già caratterizzate come HCA e di valutare le eventuali correlazioni con i diversi sottotipi istologici e con altre metodiche di imaging (CT/MRI).MetodiSono stati raccolti retrospettivamente le informazioni su pazienti con diagnosi istologica di HCA sottoposti a CEUS e CT ± MR in sette diversi centri italiani di ecografia.RisultatiSono stati inclusi nello studio 19 pazienti con diagnosi istologica di HCA (16 donne; 69% con storia attuale e/o pregressa di utilizzo di farmaci estroprogestinici): 14/19 adenomi sottotipo “infiammatori” (IHCA), 1/19 β-catenin-activated HCA e i restanti erano HCA non classificabili. L’esame CEUS ha mostrato nella quasi totalità dei casi (18/19) un rapido enhancement arterioso di tipo centripeto (89%) o centrifugo (11%). Durante la fase portale e tardiva si è dimostrato un wash-out contrastografico rispettivamente nel 58% degli HCA; invece nel 42% dei rimanenti casi non è stato osservato wash-out in nessuna delle fasi contrastografiche. In particolare è stato evidenziato che nel sottotipo I-HCA 7/14 non presentavano washout in nessuna delle fasi contrastografiche, mentre 3/14 e 4/14 mostravano rispettivamente un washout nelle fasi portali o tardive.ConclusioniLa nostra casistica rappresenta una delle poche esperienze italiane presenti in letteratura riguardo all’utilizzo della CEUS negli adenomi epatici, confermando l’aspetto di ipervascolarizzazione nella fase arteriosa (soprattutto con un flusso centripeto) ed il comportamento eterogeneo nelle fasi portali e tardive. In particolare, nel caso di I-HCA un comportamento contrastografico caratterizzato da washout in fase tardiva è frequente con l’utilizzo della CEUS ma non con l’utilizzo della MRI.

Diffuse liver infiltration by lobular breast carcinoma: Shear wave elastography as gold standard imaging study

F IGURE 1 Imaging studies performed after the admission to the Hospital (January 2015). Ultrasound with color-Doppler study with reversal flow in portal vein and a small hypoechoic liver lesion in the III segment of the liver (arrow) (A); CT-scan (B), MRI (C), and FDG PETTC (D) do not show focal liver lesions; Supersonic Shear Wave Elastography shows a diffuse increase in tissue stiffness in the whole liver parenchyma, displaying a mean value of 62.5 kPa (E) [Color figure can be viewed at wileyonlinelibrary.com] Received: 29 November 2016 | Revised: 6 December 2016 | Accepted: 13 December 2016 DOI: 10.1111/tbj.12989

Sa1007 The Role of Dynamic Contrast Enhanced Ultrasound in Focal Liver Lesion Characterization: Preliminary Results

Background: Recent publications have shown that performing fibroscan of the spleen (fibrospleen) can predict the development of esophageal varices in patients with cirrhosis of the liver. The aim of the present study was to evaluate the fibrospleen as a diagnostic tool in a broader cohort of patients with liver diseases with and without cirrhosis. Methods: 182 consecutive patients [80 female and 102 male, median age 51.8 years] who underwent a fibroscan test at the University Hospital of Essen, Germany, from September 1st to October 10th received a fibroscan of the spleen after obtaining informed consent. The test was performed using Fibroscan touch™ (Echosens™, France). 46 patients were liver transplant recipients, 57 had a viral hepatitis, 28 an autoimmune and 26 a fatty liver disease, further 19 patients suffered from vascular or genetic liver diseases. The patients were further divided in 3 groups regarding their fibroscan of the liver ( 14 kPa n=63). The fibrospleen was correlated to the flow velocity of the portal vein and spleen size. Statistical analyses were performed using GraphPad Prism v 6.0. Results: In a total of 108 patients a valid fibrospleen was possible. The fibrospleen resulted in generally higher values than the fibroscan of the liver. Between the three groups the mean value increased from 28.8 to 33.4 to 52.2 kPa, respectively. The ratio between fibroscan of the liver and fibrospleen increased from 0.33 to 0.44 to 1.15 between the three groups. These differences were statistically significant. The fibrospleen correlated significantly with fibroscan of the liver (pearson coefficient 0.49; p=0.0001) and the size of the spleen (pearson coefficient 0.57; p<0.0001). There was no correlation to the portal flow velocity. The strongest correlation was seen in patients with viral hepatitis, the weakest correlation was seen in patients with a fibroscan of the liver between 7-14 kPa. Conclusion: The fibrospleen shows a linear correlation to liver stiffness in all stages of liver diseases. It correlates to the size of the spleen and is independent of the portal flow velocity. This suggests that fibrospleen may offer further information in the staging of liver disease and a valuable addition to the fibroscan. Prospective analyses are required to evaluate the potential of the fibrospleen in the diagnosis of liver diseases and its complications.

Mo2030 Treatment of Portal Vein Tumor Thrombosis (PVTT) Can Impact Survival of Patients With Advanced HCC

Background/Aims: Hepatolithiasis is a well known risk factor of cholangiocarcinoma. Despite advances in diagnostic modalities, diagnosing cholangiocarcinoma in patients with hepatolithiasis still challenging and there are not enough reports on the incidence of cholangiocarcinoma in patient with hepatolithiasis after treatment. We aimed to evaluate the incidence and clinical characteristics of cholangiocarcinoma in patients with hepatolithiasis who underwent liver resection or non-resection. Methods: Among a total of 257 patients who received treatment for hepatolithiasis from 2002 to 2011 at Korea University Anam and Guro Hospital, 236 patients were eligible for analysis; 92 patients underwent liver resection (resection group) and 144 patients did not (non-resection group). The data were retrospectively collected and analyzed. Results: The incidence of cholangiocarcinoma was 6.8% (16/236) during follow-up period (mean 41±41 months). The median tumor occurrence time was 28 (13-111) months. Cholangiocarcinoma occurred 6.5% (6/92) and 6.9% (10/144) in resection and non-resection group respectively (P=0.425). In resection group, cholangiocarcinoma occurred in 3.6% (2/56) of patients with complete stone removal, and in 13.3% (4/ 30) of patients with incomplete stone removal (p=0.591). In non-resection group, cholangiocarcinoma occurred in 5.7% (3/53) of patients with complete stone removal, and in 8.9% (7/79) of patient with incomplete stone removal (p=0.738). When analyzed according to completeness of stone removal regardless of treatment modality, cholangiocarcinoma occurred in 4.6% (5/109) of patients with complete stone removal, and in 10.1% (11/109) of patients with incomplete stone removal (p=0.429). Although the site of stone and tumor occurrence concurred in 10/16 patients (3/6 patients in the resection group, 7/10 patient in the non-resection group), it did not match in 6 patients. On univariate analysis, none of the factors (age, gender, abdominal pain, bile duct stenosis, bile duct dilatation, liver atrophy, residual stone, stone recurrence and liver resection) showed relationship with the incidence of cholangiocarcinoma. Conclusion: There was no difference in the incidence of cholangiocarcinoma according to the treatment modality or completeness of stone removal. Therefore, patients with hepatolithiasis should carefully be followed-up to detect cholangiocarcinoma even after treatment.