Trends in hepatocellular carcinoma due to non-alcoholic fatty liver disease

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is associated with hepatocellular carcinoma (HCC), the most frequent malignant liver tumor. The increasing prevalence of obesity and diabetes is influencing the epidemiology of HCC with the most dramatic increases in NAFLD-related HCC seen in Western countries. Although cirrhosis is the major risk factor for HCC in NAFLD, there is increasing recognition that NAFLD-HCC occurs in the absence of cirrhosis.

Areas covered: The epidemiology of NAFLD related HCC and its impact on changing the incidence of HCC globally. We overview risk factors for NAFLD-HCC in the presence and absence of cirrhosis and examine trends in liver transplantation (LT) related to NAFLD-HCC.

Expert commentary: The incidence of NAFLD-related cirrhosis will continue to rise globally in parallel with risk factors of obesity and diabetes. Consequently, NAFLD-related HCC will become an increasingly important cause of liver-related morbidity and mortality and a common indication for LT worldwide. Further identification of risk factors for NAFLD-HCC and effective treatments for NAFLD are required to reduce this future burden of disease.     

Pediatric NAFLD: an overview and recent developments in diagnostics and treatment

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adults in industrialized countries. Besides liver-related morbidity, NAFLD is also associated with an increased risk of cardiovascular disease, type 2 diabetes and mortality at adult age. However, despite the high prevalence and serious complications, diagnosing and staging of disease remains complicated due to a lack of accurate screening tools and non-invasive methods to detect fibrosis.

Areas covered: Recent insights in epidemiology, pathogenesis, diagnostic evaluation and treatment options in pediatric NAFLD are being reviewed, with a particular focus on new developments in diagnostic tools.

Expert opinion: Due to their long life span, children with NAFLD are particularly at risk of complications in their lifetime. Therefore, an effective screening strategy for children to identify those with NAFLD at risk of complications is urgently needed. This is further underscored by new pharmacological therapies that are expected to become available in the next 5 years. Momentarily no accurate non-invasive method for diagnosing pediatric NAFLD is available. New promising biomarkers and imaging tools could hopefully provide better screening tools and could contribute to the development of a successful management plan to identify children with NAFLD.     

The association between nonalcoholic fatty liver disease and risk of colorectal adenoma and cancer incident and recurrence: a meta-analysis of observational studies

Background & aim: Lifestyle modification plays a key role in nonalcoholic fatty liver disease (NAFLD) and colorectal adenoma and/or cancer (CRA/CRC) development. However, the association between NAFLD and the risk of CRA/CRC has not been carefully evaluated.

Methods: In this meta-analysis, we assessed 21 eligible studies including 124,206 participants to determine the association between NAFLD and the risk of incident and recurrent CRA/CRC.

Results: NAFLD presence was associated with an increased risk of any incident CRA (aOR: 1.30, 95% CI: 1.19–1.43) and advanced incident CRA/CRC (aOR: 1.57, 95% CI: 1.21–2.04). The severity of NAFLD affected this correlation: compared to mild and/or moderate NAFLD, severe NAFLD was associated with an increased risk of incident CRA/CRC (aOR: 2.19, 95% CI: 1.33–3.60). Although pooled cOR revealed that NAFLD was associated with an increased risk of recurrent CRA/CRC (cOR = 1.73; 95% CI: 1.12–2.68), after adjustment for confounding factors, NAFLD had less correlation with the risk of recurrent CRA/CRC (aOR: 1.81, 95% CI: 0.70–4.65).

Conclusions: The presence and severity of NAFLD are associated with an increased risk of incident CRA/CRC. However, there is insufficient evidence to indicate that NAFLD is associated with an increased risk of recurrent CRA/CRC.     

Non-invasive assessment of liver fibrosis and prognosis: an update on serum and elastography markers

Introduction: Non-invasive assessment of fibrosis is increasingly utilized in clinical practice to diagnose hepatic fibrosis. Non-invasive assessment of liver fibrosis relies on biologic and/or physical properties to assess tissue fibrosis. Serum markers estimate fibrosis by incorporating markers reflecting hepatic function (indirect markers) and/or markers measuring extracellular matrix degradation/fibrogenesis (direct markers). Radiology based techniques relay the mechanical properties and stiffness of a tissue, with increased stiffness associated with more advanced fibrosis.

Areas covered: In this comprehensive review, the recent literature discussing serum markers and elastography-based techniques will be covered. These modalities are also explored in the setting of various liver diseases.

Expert opinion: The etiology of liver disease and clinical context should be taken into consideration when non-invasive markers are incorporated in clinical practice. Non-invasive assessment of fibrosis has been most extensively utilized in hepatitis C, followed by hepatitis B and nonalcoholic fatty liver disease, but its role remains less developed in other etiologies of liver disease such as alcohol-associated liver disease and autoimmune liver disease. The role of non-invasive markers in predicting progression or regression of fibrosis, development of liver-related events and survival needs to be further explored.     

Predictive value of the red blood cell distribution width-to-platelet ratio for hepatic fibrosis

Aims: The red blood cell distribution width-to-platelet ratio (RPR) has been reported to be an indicator of hepatic fibrosis in patients with chronic hepatitis B (HBV), nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C (HCV). However, no research has explored the RPR in all patients with hepatic fibrosis. There is a recognized need to establish whether the RPR could assess hepatic fibrosis and reflect the severity of fibrosis, regardless of the patient’s etiology.

Methods: Quantitative data from 1282 patients who underwent liver biopsy between January 2010 and December 2014 at the Second Affiliated Hospital of Zhejiang University School of Medicine were included. The etiologies included HBV or HCV infection, NAFLD, schistosomiasis, granulomatous liver disease, and vascular abnormalities. Five noninvasive models were calculated for all patients based on laboratory parameters. The degrees of fibrosis severity were evaluated based on the Metavir scoring scale.

Results: The RPR demonstrated the best accuracy of predicting hepatic fibrosis among the selected five models (0.75, p?<?.001) regardless of etiology. In addition, the RPR values increased with advanced hepatic fibrosis progression. Furthermore, combining the RPR with the white blood cell (WBC) count improved the accuracy of grading hepatic fibrosis as reflected by the likelihood ratio (LR + 9.03, LR ? 0.49).

Conclusion: The RPR is a useful indicator for hepatic fibrosis, regardless of etiology, and can reflect the severity of fibrosis. This study supports further clinical development of the RPR both in a stepwise manner or in combination with inflammatory parameters to improve the accuracy of scoring hepatic fibrosis.     

Gut microbiota: novel therapeutic target for nonalcoholic fatty liver disease

Introduction: Nonalcoholic fatty liver disease (NAFLD) is one of the most common and increasing liver diseases worldwide with a prevalence of 20–33%. NAFLD may progress to fibrosis, compensated cirrhosis, advanced cirrhosis, or hepatocellular carcinoma. Despite the increasing prevalence of NAFLD, definitive medical treatment has not been established, with the exception of lifestyle modification with exercise. Because of the direct connection via portal vein between the intestines and the liver (gut–gut microbiota–liver axis), gut microbiota and associated dysbiosis have been known as regulators in the pathophysiology of NAFLD.

Area covered: New therapeutic approaches for modulation of gut microbiota have been proposed and the effectiveness of new therapies including probiotics, prebiotics, synbiotics, bile acid regulation, absorbent, and fecal microbiota transplantation have been demonstrated in recent several studies. This review focuses on the available evidences for new therapies modulating gut microbiota in the management and the prevention of NAFLD.

Expert commentary: Gut–gut microbiota–liver axis may play an important role in the etiology of many liver diseases, including NAFLD. It is logical to seek the manipulation of this axis, and further studies are required to understand the underlying precise mechanisms of microbiota-modulation on NAFLD.     

Nonalcoholic steatohepatitis before and after liver transplant: keeping up with the times

Introduction: In the last years, nonalcoholic steatohepatitis (NASH) has become a leading indication for liver transplant (LT). After transplant, both recurrent and de novo nonalcoholic fatty liver disease (NAFLD) can be commonly diagnosed. However, dedicated surveillance programs for patients with pre- or post-transplant NAFLD are not available.

Areas covered: Patients waiting for LT for NASH show specific peculiarities and would deserve targeted stratification of mortality risk. Obesity, hyperlipidemia, and diabetes mellitus can be often found after transplant. These conditions, together with immunosuppressive regimen, make LT recipients a high-risk population for both recurrent and de novo NAFLD. Development of fatty liver disease after LT has a relevant impact on both morbidity and mortality.

Expert commentary: A targeted stratification of neoplastic and cardiovascular risk for patients with NASH waiting for LT would be mandatory. In both pre- and post-transplant period, NAFLD should be considered not only a liver disease but also a cardiovascular risk factor. Patients within Transplant Program, especially those with known metabolic risk factors, should be followed with personalized diagnostic and life-style interventions before and after LT.     

Hepatitis C virus (HCV) related liver fibrosis in people who inject drugs (PWID) at the Stockholm Needle Exchange – evaluated with liver elasticity

Background and aims: Sharing of unsterile injection equipment among people who inject drugs (PWID) is the major transmission-route for hepatitis C (HCV). HCV is highly prevalent in PWID in the Stockholm needle exchange programme (NEP). The frequency of advanced liver fibrosis among the participants is, however, unknown.

Methods: From December 2016 to April 2018, all participants with chronic hepatitis C infection (CHC) were offered liver fibrosis evaluation at the Stockholm NEP, including liver stiffness measurement (LSM), a medical history and expanded blood tests to evaluate APRI and FIB-4 scores.

Results: A total of 2037 individuals were enrolled of whom 964 (47.3%) had CHC. LSM was performed in 203 (21.1%) of eligible participants of whom 85% had mild fibrosis (LSM ≤9.4?kPa) and 15% advanced fibrosis (LSM ≥9.5?kPa). APRI >1 and FIB-4?>?3.25 only identified 30% of participants with advanced fibrosis. However, all 31(100%) participants with advanced fibrosis were detected when APRI >1 was combined with an age of ≥40 years and an injection drug use (IDU) duration of ≥15 years.

Conclusions: We found that the diagnostic work-up for advanced fibrosis can be simplified with this combination of easily available factors. This allows identification of PWID in need of immediate HCV treatment to prevent further disease progression. Furthermore, LSM can be avoided among PWID with mild fibrosis, identified by age <40 years combined with IDU duration of <15 years and APRI score <1. This strategy enhances the HCV care cascade where LSM is not easily available, and will thus facilitate HCV treatment initiation.     

Noninvasive monitoring of hepatic steatosis: controlled attenuation parameter and magnetic resonance imaging-proton density fat fraction in patients with nonalcoholic fatty liver disease

Introduction: With an increase in the worldwide prevalence of obesity, the incidence of non-alcoholic fatty liver disease (NAFLD) has been on the rise, such that it has been recently considered to be a major public health concern. Traditional interventions, such as lifestyle modifications, regular exercise, and healthy diet, have been significant in improving NAFLD with reduction of liver fat.

Areas covered: Although liver biopsy is still the gold standard for diagnosis of NAFLD, there is a need for non-invasive, quantitative assessments of hepatic steatosis, especially in clinical trials of anti-steatotic medications or in the follow-up of patients undergoing lifestyle modifications. Liver biopsy has various shortcomings, such as invasive nature, risk of complications and possibility of sampling error. Therefore, it is impractical to use liver biopsy routinely in patients with NAFLD, clearly indicating the need for non-invasive and accurate diagnostic methods. Recently, controlled attenuation parameter (CAP) and magnetic resonance imaging–proton density fat fraction (MRI–PDFF) have been employed in various studies to monitor the dynamic changes of hepatic steatosis in response to treatment in patients with NAFLD.

Expert commentary: Although further validations are required, CAP and MRI–PDFF could be used as potential diagnostic and monitoring tools in clinical setting.     

Characteristics and risk factors for recurrence of nonalcoholic steatohepatitis following liver transplantation

Objectives: Nonalcoholic steatohepatitis (NASH), which is a common and increasing indication for liver transplantation (LT), is known to recur after LT. Since the recurrence of NASH can lead to graft failure, the identification of predictive factors is needed and preventive strategies should be implemented.

Methods: We retrospectively examined 95 patients who had undergone LT for NASH or alcoholic liver disease (ALD) as a primary indication. We evaluated peritransplant characteristics and histological findings 1-year post LT among liver transplant patients due to NASH or ALD.

Results: Pre-LT body mass index (BMI) was higher and pre-LT diabetes was more prevalent in NASH patients than in ALD patients (p?<?.01). The difference of BMI persisted at 3 months and 1 year after LT. There were no differences between the groups regarding histopathological findings including the degree of steatosis and fibrosis in 1-year biopsy. In multivariate analysis, recipient age and 1-year BMI were independent risk factors for post-LT fatty liver disease development. Regarding predictive factors of NASH recurrence, the prevalence of pre-LT insulin-dependent diabetes was significantly higher in patients who developed NASH recurrence than those who did not. The increase of HbA1c at 1-year post-LT checkup was higher in patients who developed recurrence than those who did not, although the difference did not reach statistical significance.

Conclusions: The results of this study suggest that insulin-dependent diabetes has detrimental effects on NASH recurrence following LT. Optimal glycemic control should be recommended, but studies are needed to prove its preventive effect on NASH recurrence.     

Amyloid in parenchymal organs in gelsolin (AGel) amyloidosis

Objectives: Previous clinical studies have shown frequent cardiac symptoms in patients with hereditary gelsolin (AGel) amyloidosis, possibly related to amyloid deposition in the heart and other internal organs. Previous studies on internal organ amyloid deposition in AGel amyloidosis have been based on small patient series.

Methods: Paraffin-embedded tissue sections from 25 autopsied individuals (age at death 44.4–88.6?years) with AGel amyloidosis were stained with HE, Congo red and Herovici stains and immunohistochemistry against the low molecular weight gelsolin fraction was performed. The amount of amyloid was estimated semi-quantitatively.

Results: AGel-based amyloid deposits were found in the myocardium and cardiac blood vessels in every patient. The deposits were mainly small and co-localized with regions with excess fibrosis in the myocardium. The lungs were positive for amyloid in 79%, renal parenchyma in 54% and renal blood vessels in 71% of the cases. The amount of myocardial, renal and hepatic amyloid correlated with age at death of the patients.

Conclusions: We show the constant presence of AGel amyloid in the hearts of patients with AGel amyloidosis. Although the deposits were mainly small, the co-localization of amyloid with fibrosis may amplify the effect of pure amyloid deposition, possibly leading to clinical signs and symptoms.     

Urban–rural environmental exposure during childhood and subsequent risk of inflammatory bowel disease: a meta-analysis

Background: The relationship between living conditions in urban and rural areas during childhood and subsequent inflammatory bowel disease (IBD) remains controversial.

Aim: To explore the association between environmental exposures early in life and the subsequent risk of IBD.

Methods: Literature searches were conducted in the following databases: PubMed, EMBASE, and Conference Proceedings Citation Index. Studies were analyzed separately using rate ratios (RRs) or odds ratios (ORs) with 95% confidence intervals.

Results: The search strategy identified 15 studies. Of these, 9 studies explored the association between urban exposure during childhood and ulcerative colitis (UC), and 12 and 4 studies explored this relationship with Crohn’s disease (CD) and IBD, respectively. A meta-analysis showed that the pooled ORs estimated for the case–control studies of UC, CD, and IBD were 1.16 (0.83, 1.61), 1.45 (1.45, 1.85), and 1.34 (1.11, 1.62), respectively. The pooled RR estimated for the cohort studies of CD and IBD was 1.48 (1.17, 1.87). The stratified analysis and meta-regression showed significant relationships between CD and living conditions in case–control studies published during 2010–2017 and in non-European countries (P < 0.05).

Conclusions: Living conditions during childhood are positively associated with the subsequent development of IBD. Urban living environment is more common among those with CD than UC.     

Dual biological therapy with anti-TNF,vedolizumab or ustekinumab in inflammatory bowel disease: a systematic review with pool analysis

Background: Inflammatory bowel diseases patients eligible for biological therapy represent a group with considerable disease burden and biologics only achieve 40% clinical remission rates in responders after 1 year of therapy.

Aims: To collect all the published data about patients treated with dual biological therapy with an Anti-TNF, vedolizumab or ustekinumab, for a period of at least 3 months and to pool the data about the effectiveness and safety.

Methods: A MEDLINE, and Web of Science search of all studies published in English until 1 January 2019 was conducted.

Results: We included 7 studies with a total of 18 patients. Fifteen patients were treated with a combination of an anti-TNF and vedolizumab, 3 patients were treated with vedolizumab and ustekinumab. Fifty-six percent of patients were affected by Crohn’s disease and 50% of patients were treated with an immunosuppressant drug or steroid too. A clinical improvement was obtained in 100% of patients, and an endoscopic improvement in 93% of patients. No serious adverse events were reported.

Conclusions: The use of dual biological therapy is an attractive therapeutic option and may be an opportunity to better tailor and personalize the therapies for patients. Further studies, as randomized control trials, to provide comparative efficacy and safety endpoints of combination therapies, and to clarify potential advantages of combined biological therapies, are needed.     

Risk of Social Isolation among Older Patients: What Factors Affect the Availability of Family,Friends, and Neighbors upon Hospitalization?

Objectives: To examine the prevalence of social isolation among older patients admitted to a hospital, and the effects of sociodemographic and health-related factors on the availability of their family, friends, and neighbor networks.

Methods: Analyses are based on interviews with a sample of 2,449 older patients admitted to an urban academic medical center in the United States. A nine-item version of Lubben’s Social Network Scale was developed and used to assess the availability of different social networks.

Results: About 47% of the sample was at risk of social isolation. The oldest old and non-White older adults showed greater risk. The availability of family networks was associated with age, sex, marital status, and prior hospitalization; friend networks with age, race, education, prior hospitalization, and functional limitations; neighbor networks with race, education, marital status, and functional limitations.

Conclusions: The risk of social isolation and the availability of social support for hospitalized older adults varies by both patient and network characteristics. Health professionals should attend to this risk and the factors associated with such risk.

Clinical Implications: By assessing the availability of various types and frequency of support among older patients, health professionals can better identify those who may need additional support after discharge. Such information should be used in discharge planning to help prevent unnecessary complications and potential readmission.     

Efficacy and safety of curcumin in primary sclerosing cholangitis: an open label pilot study

Goals: To assess if curcumin improves markers of cholestasis among subjects with primary sclerosing cholangitis (PSC).

Background: PSC is a chronic cholestatic liver disorder for which there is no established medical therapy. Preclinical data suggest curcumin may have a beneficial effect in PSC.

Study: Subjects with PSC and a serum alkaline phosphatase (SAP) greater than 1.5 times the upper limit of normal (ULN) received curcumin 750?mg orally twice daily for 12 weeks in an open-label pilot study. The primary composite endpoint was proportion of subjects who had a reduction of SAP to less than 1.5 times ULN or a 40% reduction in SAP between baseline and week 12. Secondary endpoints included changes in serum aspartate aminotransferase, total bilirubin, Mayo PSC risk score and self-reported health questionnaires.

Results: Two-hundred and fifty-eight patients with PSC were screened and 15 subjects were enrolled and all completed 12 weeks of therapy. The most common reason for subject exclusion was SAP less than 1.5 times the ULN (n?=?98). Curcumin did not result in a significant median (interquartile range) change in SAP times the ULN [3.43 (2.10–4.32) to 2.46 (1.89–4.41), p?=?.36], and only 20% (3/15) subjects achieved the primary endpoint. Similarly, there was no significant change in the secondary endpoints. There were no serious adverse events reported.

Conclusion: While curcumin was well tolerated, it was not associated with significant improvements in cholestasis or symptoms. Moreover, this study also illustrates that a low SAP is common among those with PSC.

Abbreviations

PSC: Primary sclerosing cholangitis; IBD: inflammatory bowel disease; CCA: cholangiocarcinoma; SAP: serum alkaline phosphatase; ULN: upper limit of normal; UDCA: ursodeoxycholic acid; CRP: c-reactive protein; AST: aspartate aminotransferase; ALT: alanine aminotransferase; INR: international normalized ratio; FIS: fatigue impact scale; AE: adverse events; PREsTo: PSC risk estimate tool; IQR: interquartile range; ELF: enhanced liver fibrosis     

Pneumococcal vaccination in celiac disease

Introduction: Celiac disease (CD) is an immune-mediated disorder associated with gluten exposure in genetically predisposed subjects.

Areas covered: Infectious disease is one of the causes of morbidity and mortality in CD patients. Invasive streptococcus pneumoniae (pneumococcus) is a particularly dangerous morbid condition in both the general population and celiac patients. Pneumococcal vaccination is the most effective means for its prevention.

Expert opinion: In CD, evaluation of spleen function should be useful to select patients who may benefit from vaccination to reduce the risk of pneumococcal disease. Different strategies could be employed: physicians could search for signs of hyposplenism on peripheral blood smear or abdominal ultrasound. However, the best strategy to identify which patients will benefit from pneumococcal vaccination has not yet been defined.     

Autobiographical Narration as a Tool for the Empowerment of Older Adults’ Subjective and Psychological Wellbeing in Nursing Homes

Objectives: Conceiving narration as a resource to promote older people’s wellbeing, the present work aimed to implement a narrative-based intervention to empower the subjective and psychological wellbeing of older adults living in nursing homes.

Methods: Twenty-one nursing-home residents took part in a narrative training experience consisting of three weekly interview sessions. During each interview, a psychologist helped the participants to construct an autobiographical narrative about their present life in the nursing home based on a Deconstruction-Reconstruction technique. Subjective and psychological wellbeing variables were assessed before and after the intervention.

Results: Subjective but not psychological wellbeing increased over the course of the intervention. The participants reported to appreciate the intervention.

Conclusions: Although preliminary, the results suggest that brief narrative training based on narrative therapy can positively affect nursing-home residents’ subjective wellbeing.

Clinical Implications: Brief narrative interventions implementing deconstruction-reconstruction techniques are feasible for long-term care residents.     

Recent advances in the management of perianal fistulizing Crohn’s disease: lessons for the clinic

Introduction: Managing fistulizing perianal disease is among the most challenging aspects of treating patients with Crohn’s disease. Perianal fistulas are indicative of poor long-term prognosis. They are commonly associated with significant morbidities and can have detrimental effects on quality of life. While durable fistula closure is ideal, it is uncommon.

In optimal circumstances, reported long-term fistula healing rates are only slightly higher than 50% and recurrence is common. Achieving these results requires a combined medical and surgical approach, highlighting the importance of a highly skilled and collaborative multidisciplinary team.

In recent years, advances in imaging, biologic therapies and surgical techniques have lent to growing enthusiasm amongst treatment teams, however the most advantageous approach is yet to be determined.

Areas covered: Here we review current management approaches, incorporating recent guidelines and novel therapies. Additionally, we discuss recently published and ongoing studies that will likely impact practice in the coming years.

Expert opinion: Investing in concerted collaborative multi-institutional efforts will be necessary to better define optimal timing and dosing of medical therapy, as well as to identify ideal timing and approach of surgical interventions. Standardizing outcome measures can facilitate these efforts. Clearly, experienced multidisciplinary teams will be paramount in this process.     

Evaluation of fatigue in inflammatory bowel disease - a useful tool in daily practice

Background: Fatigue is a common symptom reported in inflammatory bowel disease (IBD) patients. It can be severe and modify the self-perception of disease.

Objective: To evaluate the contribution of clinical and demographic factors to the level of fatigue in IBD patients.

Methods: Patients consecutively observed in an outpatient IBD clinic during a 9-month period were studied. Demographic and clinical data were collected. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). A FACIT-F score <30 was considered as severe fatigue.

Results: One hundred and five patients were evaluated. Of them, 57.1% had Crohn´s Disease (CD) and 42.9% had Ulcerative Colitis. Also 85.0% and 77.8% were in clinical remission, respectively. The mean FACIT-F score was 39.63?±?9.67. Severe fatigue was observed in 17.1% of patients. Female gender and active CD were significantly associated with a severe level of fatigue (p?=?.05 and p?=?.04). There was no significant correlation between the level of fatigue (severe vs. non-severe) and type of IBD, hemoglobin, C-reactive protein, ferritin levels or previous surgeries. Patients under biological therapy had a significantly higher level of fatigue and a higher rate of previous hospitalizations (p?=?.02).

Conclusions: Fatigue level is a simple and useful tool to evaluate the disease’s impact in patients’ life, and it should, therefore, be included in clinical practice. Biological therapy was associated to higher levels of fatigue. Future studies should evaluate the impact of therapy on the level of fatigue.