Role of liver biopsy in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD), defined as abnormal accumulation (> 5%) of hepatic triglyceride without excess alcohol intake, is the most common form of chronic liver disease in adults and children in the United States. NAFLD encompasses a spectrum of histologic findings including uncomplicated steatosis, steatosis with inflammation and steatohepatitis [nonalcoholic steatohepatitis (NASH)]; the latter can advance to cirrhosis and hepatocellular carcinoma. NASH is currently accepted as the hepatic manifestation of the set of cardiovascular risk factors collectively known as metabolic syndrome. In 1999 a system for histologic grading and staging for NASH was proposed; this was revised by the NASH Clinical Research Network in 2005 for the entire spectrum of lesions in NAFLD, including the lesions and patterns of pediatric NAFLD, and for application in clinical research trials. Diagnosis remains distinct from grade and stage. A recent European proposal separates steatosis from activity to derive a numeric diagnosis of NASH. Even though there have been promising advancements in non-invasive testing, these tests are not yet detailed enough to replace the full range of findings provided by liver biopsy evaluation. Limitations of biopsy are acknowledged, but liver biopsy remains the “gold standard” for diagnosis and determination of amounts of necroinflammatory activity, and location of fibrosis, as well as remodeling of the parenchyma in NASH. This review focuses on the specific histologic lesions of NAFLD and NASH, grading and staging, differential diagnoses to be considered, and the continuing role of the liver biopsy in this important liver disease

Insulin resistance associates with hepatic lobular inflammation in subjects with obesity

Purpose: Obese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR. Objective: To assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent. Methods: This cross-sectional study included 78 obese subjects (mean age 46 +/- 11 years; BMI 42.2 +/- 4.7 kg/m(2)). Glucose levels were analysed by hexokinase method and insulin levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD. Results: A positive association between overall NAFLD Activity Score and HOMA-IR was found (r(s) = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, glucose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammatory foci or higher stage of fibrosis. These findings were independent of age, BMI, triglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR. Conclusion: In this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assessed, preventing or mitigating this inflammatory response in obesity might be of importance in controlling obesity-related metabolic disturbances

Bariatrik cerrahi sonrası viseral organ yağ infiltrasyon değişikliklerini izlemenin etkili yöntemi: İdeal IQ sekansı

Aim: The aim of this study is to demonstrate the efficiency of non-invasive imaging method-MR proton density fat fraction (PDFF); ideal IQ sequence- on detecting the effects of bariatric surgery on liver and pancreatic fatty infiltration. Materials and Methods: Thirty-nine patients (25 females, 14 males) who underwent bariatric surgery between May 2016 and April 2017 were analyzed retrospectively in this study. Body mass index (BMI) and body weight (BW) values of all patients were noted one week before and one month after bariatric surgery, and meanwhile an unenhanced upper abdominal MR imaging was performed. Liver fat fraction (LFF), pancreas fat fraction (PFF), liver volume (LV) and craniocaudal length of liver (LL) were measured with MR-PDFF and T2 weighted images. Changes in all parameters after the surgery were recorded and the correlation of these changes with the change in LFF was analyzed. Results: At the end of first month of bariatric surgery, a significant decrease on mean values of LFF and PFF has been observed along with a decrease of LV, LL, BW and BMI (p<0.0001). A moderate positive linear correlation was observed between LFF and PFF, LV, LL (r=0.69, 0.61, 0.49; respectively) while a weak positive linear correlation was noticed between LFF and BMI, BW (r=0.34, 0.21; respectively). Conclusion: Ideal IQ sequence enables quantitative analysis of fatty infiltration of the liver and pancreas and thus may be used as a non-invasive tool to monitor the positive effects of the bariatric surgery on fatty infiltration of these visceral organs in the postoperative period.Amaç: Bariatrik cerrahinin karaciğer ve pankreas yağ infiltrasyonu üzerindeki etkilerinin saptanmasında non-invaziv görüntüleme yönteminin-MR proton dansite yağ fraksiyonu (PDFF); ideal IQ sekansı-etkinliğini göstermeyi amaçladık. Gereç ve Yöntem: Bu çalışmada Mayıs 2016 ile Nisan 2017 tarihleri arasında obezite cerrahisi geçiren 39 hasta (25 kadın, 14 erkek) retrospektif olarak incelendi. Tüm hastaların vücut kitle indeksi (VKİ) ve vücut ağırlığı (VA) değerleri bariatrik cerrahiden bir hafta önce ve bir ay sonra kaydedildi ve bu esnada kontrastsız üst abdomen MR görüntülemesi yapıldı. MR-PDFF ve T2 ağırlıklı görüntülerle karaciğer yağ fraksiyonu (KYF), pankreas yağ fraksiyonu (PYF), karaciğer hacmi (KV) ve karaciğer kraniyokaudal uzunluğu (KKU) ölçüldü. Ameliyat sonrası tüm parametrelerdeki değişiklikler kaydedildi ve bu değişikliklerin KYF’deki değişiklik ile korelasyonu analiz edildi. Bulgular: Bariatrik cerrahinin 1. ayının sonunda KYF ve PYF ortalama değerlerinde anlamlı azalma ile birlikte KV, KKU, VA ve VKİ’de azalma gözlendi (p<0,0001). KYF ile PYF, KV, KKU arasında orta derecede pozitif bir doğrusal korelasyon gözlenirken (sırasıyla r=0,69, 0,61, 0,49), KYF ile VKİ, VA arasında (sırasıyla r=0,34, 0,21) zayıf bir pozitif doğrusal korelasyon fark edildi. Sonuç: İdeal IQ sekansı, karaciğer ve pankreasın yağ infiltrasyonunun kantitatif analizini sağlar ve bu nedenle postoperatif dönemde bariatrik cerrahinin bu viseral organların yağ infiltrasyonu üzerindeki olumlu etkilerini izlemek için non-invaziv bir araç olarak kullanılabilir

Análise de marcadores não-invasivos de fibrose em portadores de doença hepática gordurosa não alcoólica

Introdução: o diagnóstico da doença hepática gordurosa não alcoólica (DHGNA), é realizado pela biópsia hepática que direciona o seu tratamento. Como desvantagens da biópsia,têm-se o custo do procedimento, a possibilidade de erro amostral e a morbidade. Visando minimizar e/ou direcionar a indicação da biópsia hepática, marcadores não-invasivos têm sido propostos para avaliar fibrose em portadores de DHGNA. Objetivos: Analisar a eficácia dos escores não–invasivos de fibrose APRI e FIB-4 na avaliação de pacientes com DHGNA e verificar o seu benefício na prática clínica. Métodos: Estudo transversal incluindo pacientes com DHGNA submetidos à biópsia de fígado. Definiu-se como fibrose significante, o estádio maior ou igual a dois na biópsia, usada como padrão-ouro. Curvas ROC foram utilizadas para avaliar o desempenho diagnóstico dos escores em predizer a presença ou ausência de fibrose significativa. Resultados: Foram incluídos 33 pacientes adultos, com média de idade 46,4 ± 11,05 anos. Foram considerados como pontos de corte para fibrose não significativa, os valores iguais ou menores do que 0,33 e 1,3 para o APRI e o FIB-4, respectivamente. As AUROC foram 0,68 para o APRI e 0,63 para o FIB-4. A presença de cirrose foi considerada nos pontos de corte 1 e 2,67 para o APRI e FIB-4, respectivamente. Os VPP e VPN para excluir fibrose significativa foram: APRI 90% e 46,15% e para o FIB-4 de 85,18% e 66,66%, respectivamente. O procedimento poderia ter sido corretamente evitado em 54,5 % com o APRI e 66,7 % com o FIB-4, se restringíssemos a indicação de biópsia hepática aos indivíduos com valores intermediários de cada escore. Conclusão: Embora os modelos APRI e FIB-4 tenham apresentado sensibilidade e especificidade sub-ótimas para diferenciar fibrose significativa, para a maioria dos pacientes a biópsia poderia ter sido evitada com a aplicação dos escores, o que corrobora sua utilização na prática clínica

Efeito da mudança do estilo de vida no manejo da síndrome metabólica e do fígado gorduroso não alcoólico em adolescentes : revisão sistemática

Objetivo: Avaliar o impacto das intervenções relativas à mudança do estilo de vida no manejo da SM e do DFGNA em adolescentes. Metodologia: Revisão sistemática da literatura que englobou ensaios clínicos randomizados em indivíduos de 12 a 18 anos de idade, com diagnóstico de SM e/ou DFGNA, com período mínimo de intervenção de três meses. Os estudos foram identificados por meio de pesquisa nas bases de dados Pubmed, Embase e na base de dados de ensaios clínicos randomizados da Cochrane Library. A busca foi realizada através dos termos ‘Adolescente’, ‘Fígado Gorduroso não Alcoólico’, ‘Síndrome Metabólica’, ‘Dieta’, ‘Atividade Física’, ‘Estilo de Vida’ e seus termos correlatos. Foram considerados os estudos publicados em língua inglesa, espanhola, portuguesa, italiana, francesa, alemã e sueca. Resultados: Um total de 1.676 artigos foram encontrados durante a busca e, após adequada avaliação, cinco artigos foram considerados relevantes para o objetivo desta revisão sistemática. Intervenções dietéticas, se mostraram eficazes na redução de peso, IMC, perfil lipídico e gordura intra-hepática. As intervenções na atividade física, na forma de treino aeróbio associado ao treino de resistência mostraram-se efetivas na redução da prevalência de DFGNA, bem como, os treinos de alta e baixa intensidade resultaram em melhora dos biomarcadores relacionados à enfermidade. Nos pacientes com fatores de risco para SM a intervenção dietética, psicológica e na atividade física, também resultou em redução significativa da massa gorda, perfil lipidico e PCR. É importante salientar o papel multidisciplinar das intervenções, demonstrando a importância do atendimento integral à saúde do adolescente.Objective: To evaluate the impact of interventions related to lifestyle change in the management of metabolic syndrome and NAFL in adolescents. Methodology: Systematic review of the literature covering randomized clinical trials in individuals aged 12 to 18 years with diagnosis of metabolic syndrome and / or NAFL, with a minimum intervention period of three months. The studies were identified by means of a search in the Pubmed, Embase and Cochrane Library randomized clinical trials database. The search was performed using the terms 'Teenager', 'Non-Alcoholic Fatty Liver', 'Metabolic Syndrome', 'Diet', 'Physical Activity', 'Lifestyle' and its related terms. The studies published in English, Spanish, Portuguese, Italian, French, German and Swedish were considered. Results: A total of 1,676 articles were found during the search and, after adequate evaluation, five articles were considered relevant to the objective of this systematic review. Dietary interventions have been shown to be effective in weight reduction, BMI, lipid profile and intrahepatic fat. Interventions in physical activity, in the form of aerobic training associated with resistance training, were effective in reducing the prevalence of NAFL, as well as the training of high and low intensity resulted in improvement of biomarkers related to the disease. In patients with risk factors for MS, dietary, psychological and physical activity intervention also resulted in significant reduction of fat mass, lipid profile and CRP. It is important to highlight the multidisciplinary role of interventions, demonstrating the importance of integral care to adolescent health

A Practical Approach to Diagnosing Non-Alcoholic Fatty Liver Disease

Dijagnoza bolesti nealkoholne masne jetre (engl. non-alcoholic fatty liver disease, NAFLD) počinje već na temelju kliničkih obilježja bolesnika. Tipičan rizični profil predstavlja bolesnik s prekomjernom tjelesnom težinom, pogotovo ako su tome pridruženi šećerna bolest tipa 2, arterijska hipertenzija i/ili hiperlipidemija, uz uvjet isključene rizične konzumacije alkohola. Postojanje masne jetre najčešće se utvrđuje ultrazvukom na kojem je jetra svjetlija (ehogenija) u odnosu na korteks bubrega. Ultrazvukom se ne može prepoznati blaže oblike steatoze kada je < 20 – 30 % hepatocita masno transformirano. Elastografskim metodama može se kvantificirati stupanj steatoze i stadij fibroze. Stadij fibroze je najznačajniji prognostički čimbenik, dok je značaj upalne aktivnosti dvojben, a stupanj steatoze ne utječe bitno na ishod bolesti jetre. Za neinvazivnu procjenu steatoze i fibroze koriste se i biokemijski testovi, od najjednostavnijih dobivenih iz rutinskih laboratorijskih nalaza do složenih koji uključuju cirkulirajuće makromolekule i komponente izvanstaničnoga matriksa. Neinvazivne metode su pouzdane za isključivanje ciroze, no imaju relativno skromnu pozitivnu prediktivnu vrijednost, jer često precjenjuju stadij fibroze i ne daju informaciju o aktivnosti upale. Objektivniju dijagnozu ovih histoloških komponenti i time pouzdanu prognostičku informaciju pruža biopsija jetre. Obradu bolesnika s NAFLD-om treba započeti na primarnoj razini zdravstvene zaštite jednostavnim biokemijskim testom (npr. FIB-4) kojim se isključuje značajna fibroza. U slučaju povišenih vrijednosti potreban je potvrdni test (najbolje elastografija). Ako taj nalaz isključi značajnu fibrozu, bolesnik ostaje u skrbi obiteljskoga liječnika, a u slučaju teške fibroze/ciroze bolesnik se nastavlja liječiti kod specijaliste. Na ovaj način za 80 % se smanjuje upućivanje bolesnika specijalisti, te za pet puta poboljšava otkrivanje značajne fibroze/ciroze.Diagnosing non-alcoholic fatty liver disease (NAFLD) begins with analysing patient’s clinical features. The typical risk profile includes an overweight patient with comorbidities such as type 2 diabetes mellitus, arterial hypertension and/or hyperlipidaemia, excluding harmful alcohol consumption. Ultrasonography is the most widely used diagnostic tool for detecting fatty liver, which has higher echogenicity, i.e. is lighter in colour, compared to renal cortex. However, ultrasound cannot detect mild steatosis where < 20 – 30% of hepatocytes have been infiltrated by fat. Elastographic methods are used for grading steatosis and staging fibrosis. Liver fibrosis stage is the most significant prognostic indicator. On the other hand, the relevance of inflammatory activity is questionable and the degree of steatosis has no significant impact on the outcome of the disease. Steatosis and fibrosis can be evaluated using non-invasive biochemical tests, ranging from simple routine laboratory tests to more complex tests that include circulating macromolecules and components of extracellular matrix. Non-invasive methods provide reliable results for the exclusion of cirrhosis; however, their positive predictive value is relatively modest, as they often over-estimate the fibrosis stage and provide no information on inflammatory activity. Liver biopsy provides a more objective diagnosis of the histological features and, as a result, a more reliable prognosis. The workup of NAFLD patients should start at the primary healthcare level, with simple biochemical tests such as FIB-4, which excludes significant fibrosis. Elevated results need to be additionally confirmed by another test, most preferably elastography. If this test excludes significant fibrosis, the patient remains under the care of a primary care physician, and if it detects severe fibrosis/cirrhosis, the patient is referred to specialist treatment. This pathway has resulted in an 80 % decrease in referrals to a specialist and a 5-fold improvement in the detection of significant fibrosis/cirrhosis

Einfluss der antithrombozytären Therapie auf den klinischen Verlauf der Steatosis hepatis

Die NAFLD stellt die häufigste chronische Lebererkrankung in Industrienationen dar (Loomba and Sanyal, 2013). Neben diätetischen Therapiemaßnahmen sind medikamentöse Therapieoptionen dringend erforderlich. Die Arbeit beschäftigt sich hierbei mit dem möglichen Einfluss einer antithrombozytären Therapie auf den klinischen Verlauf der Steatosis hepatis

Single-cell transcriptomics of hepatic stellate cells uncover crucial pathways and key regulators involved in non-alcoholic steatohepatitis

Background: Fibrosis is an important pathological process in the development of non-alcoholic steatohepatitis (NASH), and the activation of hepatic stellate cell (HSC) is a central event in liver fibrosis. However, the transcriptomic change of activated HSCs (aHSCs) and resting HSCs (rHSCs) in NASH patients has not been assessed. This study aimed to identify transcriptomic signature of HSCs during the development of NASH and the underlying key functional pathways. Methods: NASH-associated transcriptomic change of HSCs was defined by single-cell RNA-sequencing (scRNA-seq) analysis, and those top upregulated genes were identified as NASH-associated transcriptomic signatures. Those functional pathways involved in the NASH-associated transcriptomic change of aHSCs were explored by weighted gene co-expression network analysis (WGCNA) and functional enrichment analyses. Key regulators were explored by upstream regulator analysis and transcription factor enrichment analysis. Results: scRNA-seq analysis identified numerous differentially expressed genes in both rHSCs and aHSCs between NASH patients and healthy controls. Both scRNA-seq analysis and in-vivo experiments showed the existence of rHSCs (mainly expressing a-SMA) in the normal liver and the increased aHSCs (mainly expressing collagen 1) in the fibrosis liver tissues. NASH-associated transcriptomic signature of rHSC (NASHrHSCsignature) and NASH-associated transcriptomic signature of aHSC (NASHaHSCsignature) were identified. WGCNA revealed the main pathways correlated with the transcriptomic change of aHSCs. Several key upstream regulators and transcription factors for determining the functional change of aHSCs in NASH were identified. Conclusion: This study developed a useful transcriptomic signature with the potential in assessing fibrosis severity in the development of NASH. This study also identified the main pathways in the activation of HSCs during the development of NASH