COMMENTED ARTICLES

Commentary

The aim of the study was to assess ultrasound attenuation coefficient in adult liver and spleen. The authors calculated attenuation coefficient liver to spleen ratio in 36 adult volunteers. There were 12 normal livers and 24 steatotic livers in this study.

Liver attenuation coefficient increased, and spleen attenuation coefficient did not change following the development of hepatic steatosis. It appears that the feasibility of attenuation coefficient liver to spleen ratio in determining hepatic steatosis needs further investigation.

Commentary

Metabolomic studies suggest plasma levels of bile acids are elevated amongst subjects with NAFLD compared to healthy controls. However, it remains unclear whether or not specific bile acids are associated with the clinically relevant transition from NAFLD to NASH, or enhanced progression of hepatic fibrosis, or genetic determinants of NAFLD/NASH. Among 102 subjects undergoing diagnostic liver biopsy, the authors examined the associations of a broad panel of bile acids with distinct histopathological features of NAFLD, the presence of NASH, and their associations with genetic variants linked to NAFLD and NASH.

The authors conclude that circulating bile acid levels are associated with histopathological and genetic determinants of the transition from simple hepatic steatosis into NASH.

Commentary

Inflammasome activation followed by maturation has been observed in both preclinical models and NASH patients suggesting the crucial importance of inflammasome activation in NAFLD progression.

In this article, D. Das et al. (CSIR-Indian Institute of Chemical Biology, Kolkata, India) describe an ex vivo method for investigating the role of inflammasome activation in macrophages and its impact on hepatocytes. It provides a comprehensive protocol for investigating hepatocellular inflammasome activation.

Commentary

The conventional detection of necrosis in vivo is not currently available, whereas the detection method for apoptosis has been relatively well-established.

S. Tsurusaki et al. (Research Institute, National Center for Global Health and Medicine, Tokyo, Japan) recently reported a method for the in vivo detection of necrotic cells in liver disease models. They also provide standard methods for the evaluation of lipid accumulation and fibrosis. They also show that ferroptosis, a type of apoptosis dependent on iron and characterised by the accumulation of lipid peroxides, could be involved in the pathogenesis of NASH.

Commentary

3D organoid culture has become a powerful tool and model for various human diseases, including NASH. The hepatic progenitor cells can be induced to form hepatic organoids, passaged or cryopreserved for future use, and can be manipulated to study the disease progression of NASH-related fibrosis.

Here, J. Yan et al. (Medical College of Virginia, Virginia Commonwealth University, Central Virginia Veterans Health System, USA) describe a protocol to establish mouse liver ductal organoids.

Commentary

In an activated form, human hepatic stellate cells are the drivers of fibrosis following chronic liver injury. In NASH specifically, activated human hepatic stellate cells are drivers of induction and progression of fibrogenesis. Isolation and purification of hepatic stellate cells from donor liver samples provides an avenue to study human hepatic stellate cells and their fibrotic capabilities.

In this article, S. Lele et al. (School of Medicine, Virginia Commonwealth University, USA) described protocols for isolation of human and rodent human hepatic stellate cells.

Commentary

Deciphering the molecular mechanisms underlying the pathogenesis of NASH requires loss- or gain-of-function experimental approaches. Adenovirus is a fast, effective, and versatile tool that allows transient knockdown, knockout, or overexpression of genes of interest in primary hepatocytes in vitro and in mouse liver in vivo.

Y. Liu et al. (Huazhong University of Science and Technology, China, and Harvard Medical School, USA) describe a protocol to generate adenovirus for basic medical research, and discuss critical steps during virus propagation and purification.

Commentary

NASH is characterized by multiple underlying genetic mutations, with no approved cure to date. Gene therapies that target those genetic mutations may play a major role in treating this disease, once delivered specifically to the hepatocytes.

K. Ebeid et al. present the synthesis and the characterization of a gene delivery system capable of targeting hepatocytes by exploiting the overexpression of asialoglycoprotein receptors on their cell surface. For the authors, this formulation appears as “a promising tool to treat any type of genetic abnormality that arises in hepatocytes, and specifically NASH.”

Commentary

The current clinical practice is urged to incorporate biopsy-free scoring systems that demonstrate adequate performance metrics for the accurate detection of patients with MAFLD and underlying conditions or those with contraindications of biopsy.

This article presents a thorough review of biopsy-free scoring systems proposed for the diagnosis of MAFLD. It compares the severity of the disease by contrasting the corresponding serum markers, clinical associations, and performance metrics of these biopsy-free scoring systems.

Commentary

Bile acids synthesis and metabolism have been impaired in NASH patients because of liver injury, inflammation or obstruction of bile ducts. Changes in bile acids composition might contribute to NASH pathogenesis.

B. Kong et al. (Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA) “focus on the method for analysing individual bile acids profile in mouse biofluids and tissues by high-performance liquid chromatography coupled with ion trap mass spectrometry (HPLC-MS).”

Commentary

Development and severity of NAFLD have been linked to obesity and white adipose tissue dysfunction plays a key role in this relation. Ó. Osorio-Conles et al. (Instituto de Salud Carlos III, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain) compared the main features of subcutaneous and visceral white adipose tissue dysfunction in 48 obese women without and with NAFLD undergoing bariatric surgery and matched for age, BMI and T2D status.

Their data “support the existence of distinctive NAFLD signatures in white adipose tissue from women with severe obesity”.

Commentary

The so far well-received new name and redefinition of fatty liver disease have generated debates. The most common argument is that there is no consensus on any name change. A craft group was created to identify and refine methods of consensus building in hepatology.

Y. Fouad, et al. (Minia University, Egypt) “believe that the time has come for redirecting stakeholder focus and energy on capitalising on the momentum generated by the debate to improve the lives of people at its centre, our patients.”

Commentary

I. Y. CHoi et al. (Total Healthcare Centre, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea) investigated the association between heart rate variability and incident NAFLD in a cohort of 154,286 Korean adults.

For the authors, autonomic imbalance assessed by heart rate variability may help to identify individuals at a high risk of Hepatic steatosis and its progression and warrant further studies.

Commentary

The impact of changes in sleep duration and sleep quality over time on the risk of NAFLD is not known. In a cohort study included 86,530 Korean adults, YJ Um et al. (Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea) investigated whether changes in sleep duration and quality are associated with the risk of developing incident NAFLD.

For the authors, a decrease in sleep duration or poor sleep quality over time is associated with an increased risk of incident NAFLD.

Commentary

In this review, C. Engelmann C and F. Tacke (Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Germany) critically discuss the currently existing evidence for the involvement of cellular senescence in NAFLD in order to identify areas requiring further exploration.

In summary, “there are substantial data suggesting that senescence plays an important role in NAFLD development and disease progression.” Several markers of senescence are linked with fat accumulation, inflammation and fibrogenesis.

Commentary

This retrospective study aimed to evaluate a possible connection between NAFLD, colonic diverticulosis, and metabolic syndrome.

For the authors, “components of metabolic dysregulation were prominent in patients diagnosed with colonic diverticulosis and concomitant hepatic steatosis”, and HTA, T2DM, and hypothyroidism were more frequently observed in this group.

Commentary

Recently, there has been interest in the apparent co-incidence of NAFLD in patients with IBS mainly driven by improved understanding of their shared risk factors and pathophysiology.

H. Purssell et al. (Manchester University NHS Foundation Trust, UK) summarise the shared risk factors and describe “how these shared risk factors and etiological factors may have practical clinical implications for these highly prevalent conditions.”

As a conclusion, the authors precise: “patients with known IBS who have abnormal liver function tests or significant risk factors for NAFLD should be investigated appropriately for this possibility. Similarly, IBS should be considered in patients with NAFLD and symptoms of abdominal pain associated with defecation, an altered bowel habit and bloating.”

Commentary

J. Romano et al. (Medical University of South Carolina, Charleston, USA) evaluated whether these non-invasive markers and/or any other clinical parameters may be used to identify patients with liver cirrhosis who are likely to have large esophageal varices, and therefore would benefit most from screening esophagogastroduodenoscopy.

Commentary

Liver homeostasis is strongly influenced by the circadian clock. Disruption of the clock has been heavily implicated in the pathogenesis of NAFLD and NASH. There has been little consideration of the application of chronopharmacology in NASH, a strategy whereby the timing of drug delivery is informed by biological rhythms in order to maximise efficacy and tolerability.

The authors describe the potential for chronopharmacology in NASH and encourage greater consideration of the timing of drug administration in the design of future clinical trials.

Commentary

The aim of this study was to investigate whether a nutritional intervention motivating increased vegetable consumption would be an effective treatment and diet therapy for patients with non-alcoholic fatty liver disease.

During the 6-month intervention period, 15 participants received a small amount of vegetables twice a month as a nutritional education tool aimed at increasing vegetable consumption. They also received nutritional counselling.

The results suggest that a nutritional approach effectively increase vegetable consumption in at least some patients with NAFLD, consequently improving their condition.

Commentary

NAFLD is increasingly recognised in obese and overweight children. In this cross-sectional study, S. Thiagarajan et al. (Indira Gandhi Medical College and Research Institute, India) aimed to assess the prevalence of NAFLD in this population and to identify the associated anthropometric and metabolic risk factors. NAFLD was diagnosed in 51.3% of overweight and obese children. NAFLD is common in overweight and obese southern Indian children, and High LDL cholesterol level is a risk factor for NAFLD in these children.

In conclusion, “screening of obese and overweight children for early diagnosis of NAFLD is essential to prevent and monitor further progression of the disease.”

Commentary

Oncostatin M is a pleiotropic cytokine of the interleukin (IL)-6 family that contributes to the progression of chronic liver disease.

G. Di Maira et al. (University of Firenze, Italy) aimed to investigate the role of oncostatin M in the development and progression of hepatocellular carcinoma in NAFLD/NASH.

In a murine model of NAFLD/NASH-related hepatocarcinogenesis, and in analysis of liver specimens from human NASH-related HCCs with vascular invasion, oncostatin M up-regulation appears to be a specific feature of HCC arising on a NAFLD/NASH background, and it correlates with clinical parameters and disease outcome. For the authors, these data highlight a novel pro-carcinogenic contribution for oncostatin M in NAFLD/NASH.

Commentary

R. Pais et al. (Hôpital Pitié-Salpêtrière, Paris, France) describe the histological outcome in patients with advanced NASH and its relationship with weight loss and metabolic improvement after bariatric surgery.

For the authors, “while bariatric surgery successfully reverses active steatohepatitis, advanced fibrosis can persist for many years and is associated with lesser weight-loss and metabolic improvement. Weight-loss alone may not be sufficient to reverse advanced fibrosis.”

Commentary

This review by C. H. Lee et al. (University of Hong Kong, Hong Kong) aims to provide a summary of the latest evidence that support NAFLD as an emerging diabetic complication of increasing importance, and to present the current recommendations, focusing on the assessment and therapeutic strategies, on the management of NAFLD among T2D patients.

Commentary

MicroRNA levels in blood may change in liver disease including NAFLD. K. Johnson et al. (Newcastle University, UK) carried out microRNA sequencing in a group of 183 patients with NAFLD. One particular microRNA miR-193a-5p consistently increased.
Measuring this microRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy.

Commentary

MAFLD might be considered as a multisystem disease that affects not only the liver but involves wider implications, relating to several organs and systems, the brain included.

The present study by S. Nucera et al. (University Magna Graecia of Catanzaro, Italy) aims to investigate changes associated with MAFLD-induced alteration of thalamic metabolism in vivo.

The experimental results suggest that thalamic energy metabolism is affected by MAFLD progression. This metabolic imbalance “might cause structural damage to brain cells and dysfunctions of neurotransmitter release.”

Commentary

Hepatocellular carcinoma is the most common type of liver cancer, increasingly arising in patients with NAFLD or MAFLD. S. Myers et al. (University of Geneva, Switzerland) assessed all patients with hepatocellular carcinoma between 1990 and 2014 in the canton of Geneva and found an increase in all hepatocellular carcinoma cases, particularly in women. They also found that hepatocellular carcinoma caused by NAFLD or MAFLD significantly increased over the years, particularly in women, possibly driving the increase in overall hepatocellular carcinoma cases.

Commentary

To investigate incidence and predictors of NAFLD and NASH by employing noninvasive testing in liver transplant recipients (i.e. controlled attenuation parameter and cytokeratin 18), A. Alhinai et al. (McGill University, Montreal, Canada) prospectively recruited 40 consecutive adult patients who received liver transplant at the McGill University Health Centre between 2015-2018.

During a median follow-up of 16.8 mo, 63% and 48% of patients developed NAFLD and NASH, respectively. As highlighted by the authors, “close follow-up and nutritional counselling should be planned in overweight patients.”

Commentary

Colorectal adenoma is linked to metabolic dysfunction. S. Fukunaga et al. (Kurume University School of Medicine, Japan) aimed to investigate the impact of MAFLD on the prevalence of colorectal adenoma by comparing it to NAFLD in health check-up examinees in a multicenter retrospective study.

According to this study, MAFLD, particularly non-obese MAFLD, is the most important factor associated with the presence of colorectal adenoma rather than NAFLD. Colonoscopy examination should be considered in patients with MAFLD, especially those who are non-obese.

Commentary

According to this article by D. Pfister et al. (German Cancer Research Center, Germany), the response to immunotherapy is better in patients with virus-induced HCC than in patients with non-viral HCC (that is, NASH). This might be due to the amount or quality of viral antigens or to a different liver micro-environment, possibly one that does not impair immune surveillance.

“These results might also have implications for patients with obesity and NALFD or NASH who have cancer at other organ sites”.

Commentary

In this retrospective cohort study of 1158 patients with biopsy-proven fibrotic NASH without cirrhosis, bariatric surgery was significantly associated with a lower risk of major adverse liver outcomes and major adverse cardiovascular events.

For the authors, in this study, “among patients with nonalcoholic steatohepatitis and obesity, bariatric surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident major adverse liver outcomes and major adverse cardiovascular events.

Commentary

Macrophage-mediated inflammation is critical in the pathogenesis of NASH. T-cell immunoglobulin domain and mucin domain-4 (TIM-4) is selectively expressed on antigen-presenting cells and modulates various immune responses. However, the role of TIM-4 expressed by Kupffer cells in liver fibrosis remains unclear. In this article, S. Daemen et al. (Washington University School of Medicine, St. Louis, MI, USA) describe that, with high-fat, high-sucrose-diet feeding, mature TIM4pos Kupffer cells decrease in number, while Tim4neg macrophages, which are monocyte-derived, accumulate.

Taken together, their data reveal dynamic changes in liver macrophage subsets during the pathogenesis of NASH and link these shifts to pathologic tissue remodeling.