Portal hypertension in patients with nonalcoholic fatty liver disease:Current knowledge and challenges

Portal hypertension(PH)has traditionally been observed as a consequence of significant fibrosis and cirrhosis in advanced non-alcoholic fatty liver disease(NAFLD).However,recent studies have provided evidence that PH may develop in earlier stages of NAFLD,suggesting that there are additional pathogenetic mechanisms at work in addition to liver fibrosis.The early development of PH in NAFLD is associated with hepatocellular lipid accumulation and ballooning,leading to the compression of liver sinusoids.External compression and intraluminal obstacles cause mechanical forces such as strain,shear stress and elevated hydrostatic pressure that in turn activate mechanotransduction pathways,resulting in endothelial dysfunction and the development of fibrosis.The spatial distribution of histological and functional changes in the periportal and perisinusoidal areas of the liver lobule are considered responsible for the pre-sinusoidal component of PH in patients with NAFLD.Thus,current diagnostic methods such as hepatic venous pressure gradient(HVPG)measurement tend to underestimate portal pressure(PP)in NAFLD patients,who might decompensate below the HVPG threshold of 10 mmHg,which is traditionally considered the most relevant indicator of clinically significant portal hypertension(CSPH).This creates further challenges in finding a reliable diagnostic method to stratify the prognostic risk in this population of patients.In theory,the measurement of the portal pressure gradient guided by endoscopic ultrasound might overcome the limitations of HVPG measurement by avoiding the influence of the pre-sinusoidal component,but more investigations are needed to test its clinical utility for this indication.Liver and spleen stiffness measurement in combination with platelet count is currently the best-validated non-invasive approach for diagnosing CSPH and varices needing treatment.Lifestyle change remains the cornerstone of the treatment of PH in NAFLD,together with correcting the components of metabolic syndrome,using nonselective beta blockers,whereas emerging candidate drugs require more robust confirmation from clinical trials.

Pancreatic surgery and tertiary pancreatitis services warrant provision for support from a specialist diabetes team

Pancreatic surgery units undertake several complex operations,albeit with consi-derable morbidity and mortality,as is the case for the management of complicated acute pancreatitis or chronic pancreatitis.The centralisation of pancreatic surgery services,with the development of designated large-volume centres,has contribu-ted to significantly improved outcomes.In this editorial,we discuss the complex associations between diabetes mellitus(DM)and pancreatic/periampullary disease in the context of pancreatic surgery and overall management of complex pancreatitis,highlighting the consequential needs and the indispensable role of specialist diabetes teams in support of tertiary pancreatic services.Type 3c pan-creatogenic DM,refers to DM developing in the setting of exocrine pancreatic disease,and its identification and management can be challenging,while the glycaemic control of such patients may affect their course of treatment and outcome.Adequate preoperative diabetes assessment is warranted to aid identification of patients who are likely to need commencement or escalation of glucose lowering therapy in the postoperative period.The incidence of new onset diabetes after pancreatic resection is widely variable in the literature,and depends on the type and extent of pancreatic resection,as is the case with pancreatic parenchymal loss in the context of severe pancreatitis.Early involvement of a specialist diabetes team is essential to ensure a holistic management.In the current era,large volume pancreatic surgery services commonly abide by the principles of enhanced recovery after surgery,with inclusion of provisions for optimisation of the perioperative glycaemic control,to improve outcomes.While various guidelines are available to aid perioperative management of DM,auditing and quality improvement platforms have highlighted deficiencies in the perioperative management of diabetic patients and areas of required improvement.The need for perioperative support of diabetic patients by specialist diabetes teams is uniformly underlined,a fact that becomes clearly more prominent at all different stages in the setting of pancreatic surgery and the management of complex pancreatitis.Therefore,pancreatic surgery and tertiary pancreatitis services must be designed with a provision for support from specialist diabetes teams.With the ongoing accumulation of evidence,it would be reasonable to consider the design of specific guidelines for the glycaemic management of these patients.

Hepatolithiasis:Epidemiology,presentation,classification and management of a complex disease

The term hepatolithiasis describes the presence of biliary stones within the intrahepatic bile ducts,above the hilar confluence of the hepatic ducts.The disease is more prevalent in Asia,mainly owing to socioeconomic and dietary factors,as well as the prevalence of biliary parasites.In the last century,owing to migration,its global incidence has increased.The main pathophysiological mechanisms involve cholangitis,bile infection and biliary strictures,creating a self-sustaining cycle that perpetuates the disease,frequently characterised by recurrent episodes of bacterial infection referred to as syndrome of“recurrent pyogenic cholangitis”.Furthermore,long-standing hepatolithiasis is a known risk factor for development of intrahepatic cholangiocarcinoma.Various classifications have aimed at providing useful insight of clinically relevant aspects and guidance for treatment.The management of symptomatic patients and those with complications can be complex,and relies upon a multidisciplinary team of hepatologists,endoscopists,interventional radiologists and hepatobiliary surgeons,with the main goal being to offer relief from the clinical presentations and prevent the development of more serious complications.This comprehensive review provides insight on various aspects of hepatolithiasis,with a focus on epidemiology,new evidence on pathophysiology,most important clinical aspects,different classification systems and contemporary management.

Inflammation and fibrosis in chronic liver diseases including nonalcoholic fatty liver disease and hepatitis C

At present chronic liver disease(CLD),the third commonest cause of premature death in the United Kingdom is detected late,when interventions are ineffective,resulting in considerable morbidity and mortality.Injury to the liver,the largest solid organ in the body,leads to a cascade of inflammatory events.Chronic inflammation leads to the activation of hepatic stellate cells that undergo transdifferentiation to become myofibroblasts,the main extra-cellular matrix producing cells in the liver;over time increased extra-cellular matrix production results in the formation of liver fibrosis.Although fibrogenesis may be viewed as having evolved as a“wound healing”process that preserves tissue integrity,sustained chronic fibrosis can become pathogenic culminating in CLD,cirrhosis and its associated complications.As the reference standard for detecting liver fibrosis,liver biopsy,is invasive and has an associated morbidity,the diagnostic assessment of CLD by non-invasive testing is attractive.Accordingly,in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice.Due to differing disease prevalence and treatment efficacy,disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection.To facilitate this,a review of the pathogenesis of both conditions is also conducted.Finally,the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed,including the current use of antifibrotic therapy.

Alcohol and tobacco misuse: Reducing aerodigestive cancer risk

Significant concerns over the health,social and economic burdens of the two most common,and frequently co-misused drugs of abuse,alcohol and tobacco,has encouraged focused but separate health promotion and disease prevention policies.However,this separation of focus means that while individuals who present with alcohol-related problems are increasingly supported to attain and maintain abstinence from alcohol they are not routinely assisted to refrain from smoking.This is tragically inopportune as alcohol and tobacco have an established"synergistic"effect on aerodigestive cancer risk.Moreover,even when patients successfully tackle their alcohol problems they remain at increased risk for developing these cancers,especially if they continue to smoke.A case series is presented together with a discussion on how service provision for co-misuse could be improved to obviate aerodigestive cancer risk.Given the prevalence of alcohol and tobacco use in the United Kingdom,these observations may have far reaching implications for the individual,health provider(s)and wider society.

Non-invasive assessment of liver fibrosis in patients with alcoholic liver disease

Alcoholic liver disease(ALD) consists of a broad spectrum of disorders, ranging from simple steatosisto alcoholic steatohepatitis and cirrhosis. Fatty liver develops in more than 90% of heavy drinkers, however only 30%-35% of them develop more advanced forms of ALD. Therefore, even if the current "gold standard" for the assessment of the stage of alcohol-related liver injury is histology, liver biopsy is not reasonable in all patients who present with ALD. Currently, although several non-invasive fibrosis markers have been suggested as alternatives to liver biopsy in patients with ALD, none has been sufficiently validated. As described in other liver disease, the diagnostic accuracy of such tests in ALD is acceptable for the diagnosis of significant fibrosis or cirrhosis but not for lesser fibrosis stages. Existing data suggest that the use of noninvasive tests could be tailored to first tier screening of patients at risk, in order to diagnose early patients with progressive liver disease and offer targeted interventions for the prevention of decompensation. We review these tests and critically appraise the existing evidence.

Role of self-expanding metal stents in the management ofvariceal haemorrhage:Hype or hope?

Despite the advances of medical,endoscopic and radiological therapy over recent years the mortality rates of acute variceal haemorrhage are still 16%-20% and the medium term outcome has not improved in the last 25 years. Early transjugular intrahepatic portosystemic shunt has proved to be an effective therapy for selected groups of patients with a high risk of re-bleeding and moderate liver disease. However,there is an unmet need for a therapy that can be applied in patients with a high risk of re-bleeding and advanced liver disease either as definitive therapy or as a bridge to permanent therapy. Selfexpanding metal stents can be placed without the need for endoscopic or fluoroscopic control and,once in place,will provide effective haemostasis and allow a route for oral fluids and nutrition. They can remain in place whilst liver function recovers and secondary prophylaxis is initiated. We review the results of 6 case series including a total of 83 patients and the first randomised controlled trial of self-expanding metal stents vs balloon tamponade(BT) in the management of refractory variceal haemorrhage. We report that self-expanding metal stents provide effective haemostasis and perform better than BT in refractory bleeding,where they are associated with fewer complications. Whilst the most effective place for self-expanding metal stents in the management algorithm needs to be determined by further randomised controlled trials,currently they provide an effective alternative to BT in selected patients.

Review of incidence and outcomes of treatment of cholangiocarcinoma in patients with primary sclerosing cholangitis

Primary sclerosing cholangitis(PSC)is a premalignant condition and a welldocumented risk factor for cholangiocarcinoma(CCA)which is the most common malignancy in this setting and the leading cause of deaths in the recent years,with an increasing incidence.PSC-associated CCA has a geographical distribution that follows the incidence of PSC,with an observed ascending gradient from the Eastern to the Western and from the Southern to the Northern countries.It may arise at any location along the biliary tree but is most common in the perihilar area.Patients with PSC and intrahepatic or perihilar CCA are typically not suitable for liver resection,which is otherwise the treatment of choice with curative intent in patients with resectable tumours,providing a radical resection with clear margins can be achieved.This largely relates to the commonly advanced stage of liver disease at presentation,which allows consideration for liver resection only for a very limited number of suitable patients with PSC.On the other hand,remarkable progress has been reached in the last decades with the implementation of a protocol combining neoadjuvant chemoradiation and orthotopic liver transplantation(OLT)for the treatment of perihilar CCA,within specific criteria.Excellent results have been achieved particularly for PSC patients with this cancer,who seem to benefit the most from this treatment,having converted this into an accepted indication for transplantation and the standard of care in several experienced centres.Intrahepatic CCA as an indication for OLT remains controversial and has not been accepted given disappointing previous results.However,as recent studies have shown favourable outcomes in early intrahepatic CCA,it may be that under defined criteria,OLT may play a more prominent role in the future.Distal CCA in the context of PSC requires aggressive surgical treatment with curative intent,when feasible.This review provides insight about particular features of CCA in the setting of PSC,with a main focus on its incidence,considerations relating to its anatomical location and implications to treatment and outcomes,through the viewpoint of historical evolution of management,and future perspectives.

Exploitation of host clock gene machinery by hepatitis viruses B and C

Many aspects of cellular physiology display circadian(approximately 24-h)rhythms.Dysfunction of the circadian clock molecular circuitry is associated with human health derangements,including neurodegeneration,increased risk of cancer,cardiovascular diseases and the metabolic syndrome.Viruses triggering hepatitis depend tightly on the host cell synthesis machinery for their own replication,survival and spreading.Recent evidences support a link between the circadian clock circuitry and viruses’biological cycle within host cells.Currently,in vitro models for chronobiological studies of cells infected with viruses need to be implemented.The establishment of such in vitro models would be helpful to better understand the link between the clock gene machinery and viral replication/viral persistence in order to develop specifically targeted therapeutic regimens.Here we review the recent literature dealing with the interplay between hepatitis B and C viruses and clock genes.

Porcine model characterizing various parameters assessing the outcome after acetaminophen intoxication induced acute liver failure

AIM To investigate the changes of hemodynamic and laboratory parameters during the course of acute liver failure following acetaminophen overdose.METHODS Eight pigs underwent a midline laparotomy following jejunal catheter placement for further acetaminophen intoxication and positioning of a portal vein Doppler flow-probe. Acute liver failure was realized by intrajejunal acetaminophen administration in six animals, two animals were sham operated. All animals were invasively monitored and received standardized intensive care support throughout the study. Portal blood flow, hemodynamic and ventilation parameters were continuously recorded. Laboratory parameters were analysed every eight hours. Liver biopsies were sampled every 24 h following intoxication and upon autopsy.RESULTS Acute liver failure (ALF) occurred after 28 ± 5 h resulted in multiple organ failure and death despite maximal support after further 21 ± 1 h (study end). Portal blood flow (baseline 1100 ± 156 m L/min) increased to a maximum flow of 1873 ± 175 m L/min at manifestation of ALF, which was significantly elevated(P < 0.01). Immediately after peaking, portal flow declined rapidly to 283 ± 135 m L/min at study end. Thrombocyte values (baseline 307 × 103/μL± 34 × 103/μL) of intoxicated animals declined slowly to values of 145 × 103/μL± 46 × 103/μL when liver failure occurred. Subsequent appearance of severe thrombocytopenia in liver failure resulted in values of 11 × 103/μL± 3 × 103/μL preceding fatality within few hours which was significant(P > 0.01).CONCLUSION Declining portal blood flow and subsequent severe thrombocytopenia after acetaminophen intoxication precede fatality in a porcine acute liver failure model.

Fulminant Hepatitis: Definitions, Causes and Management

Fulminant hepatitis (FH) is a rare and devastating syndrome caused by a variety of hepatic insults. It characterized by severe metabolic derangements, neurologic complications and ultimately, multiorgan failure. Liver transplantation is the gold standard therapy for patients with irreversible FH. The major areas of current research in this field include the development of: hepatic support devices, strategies to accelerate hepatic regeneration and criteria for accurate prognostic classification of patients. This review aims to focus on the definitions, aetiologies and management strategies for FH.

Embrionary way to create a fatty liver in portal hypertension

Portal hypertension in the rat by triple partial portal vein ligation produces an array of splanchnic and systemic disorders, including hepatic steatosis. In the current review these alterations are considered components of a systemic inflammatory response that would develop through three overlapping phenotypes: The neurogenic, the immune and the endocrine. These three inflammatory phenotypes could resemble the functions expressed during embryonic development of mammals. In turn, the inflammatory phenotypes would be represented in the embryo by two functional axes, that is, a coelomic-amniotic axis and a trophoblastic yolk-sac or vitelline axis. In this sense, the inflammatory response developed after triple partial portal vein ligation in the rat would integrate both functional embryonic axes on the liver interstitial space of Disse. If so, this fact would favor the successive development of steatosis, steatohepatitis and fibrosis. Firstly, these recapitulated embryonic functions would produce the evolution of liver steatosis. In this way, this fat liver could represent a yolk-sac-like in portal hypertensive rats. After that, the systemic recapitulation of these embryonic functions in experimental prehepatic portal hypertension would consequently induce a gastrulationlike response in which a hepatic wound healing reaction or fibrosis occur. In conclusion, studying the mechanisms involved in embryonic development could provide key results for a better understanding of the nonalcoholic fatty liver disease etiopathogeny.

Development and validation of an artificial intelligence model for predicting post-transplant hepatocellular cancer recurrence

Dear Editor,In recent years,criteria based on the combinationof morphology and biology have been proposed forimproving the selection of hepatocellular cancer(HCC)patients waiting for liver transplantation(LT)[1,2].Since all the proposed models showed suboptimalresults in predicting the risk of postLT recurrence,aprediction model constructed using artificial intelligence(Al)could be an attractive way to surpass this limit[3,4].Therefore,the Time_Radiological-response_Alpha-fetoproteIN_Artificial-Intelligence(TRAIN-AI)modelwas developed,combining morphology and biology tumorvariables.

Clinical practice guidelines for acute-on-chronic liver failure: are we ready for reaching global consensus?

The concept of acute-on-chronic liver failure(ACLF)has gained increasing awareness during the last decade.It considers liver cirrhosis as a systemic disease where precipitating events lead to a sudden deterioration,decompensation and extrahepatic organ failures.Disease severity is determined by the number and types of organ failures and patients with ACLF have a distinct and worse prognosis than patients with acute decompensation but not fulfilling ACLF criteria(1-3).

Non-alcoholic fatty liver disease (NAFLD) and the quest for effective treatments

Non-alcoholic fatty liver disease(NAFLD)is the most common cause of chronic liver disease worldwide,affecting 24%of the population,and is impacting on global public health care with a considerable financial burden(1).NAFLD encompasses a wide disease spectrum ranging from simple steatosis to non-alcoholic steatohepatitis(NASH),fibrosis and cirrhosis.Patients with simple steatosis typically do not develop liver-related complications,whereas patients with NASH are at increased risk of hepatic and extra-hepatic mortality.Furthermore,NAFLD is associated with an increased risk of type 2 diabetes,cardiovascular disease and cancer(2).In addition,NASH is the second leading cause of cirrhosis in adult patients on the liver transplant waiting list in the United States(3,4).

Systematic review of novel ablative methods in locally advanced pancreatic cancer

Unresectable locally advanced pancreatic cancer with or without metastatic disease is associated with a very poor prognosis.Current standard therapy is limited to chemotherapy or chemoradiotherapy.Few regimens have been shown to have a substantial survival advantage and novel treatment strategies are urgently needed.Thermal and laser based ablative techniques are widely used in many solid organ malignancies.Initial studies in the pancreas were associated with significant morbidity and mortality,which limited widespread adoption.Modifications to the various applications,in particular combining the techniques with high quality imaging such as computed tomography and intraoperative or endoscopic ultrasound has enabled real time treatment monitoring and significant improvements in safety.We conducted a systematic review of the litera-ture up to October 2013.Initial studies suggest that ablative therapies may confer an additional survival benefit over best supportive care but randomised studies are required to validate these findings.

circadian clock circuitry in colorectal cancer

Colorectal cancer is the most prevalent among digestive system cancers.Carcinogenesis relies on disrupted control of cellular processes,such as metabolism,proliferation,DNA damage recognition and repair,and apoptosis.Cell,tissue,organ and body physiology is characterized by periodic fluctuations driven by biological clocks operating through the clock gene machinery.Dysfunction of molecular clockworks and cellular oscillators is involved in tumorigenesis,and altered expression of clock genes has been found in cancer patients.Epidemiological studies have shown that circadian disruption,that is,alteration of bodily temporal organization,is a cancer risk factor,and an increased incidence of colorectal neoplastic disease is reported in shift workers.In this review we describe the involvement of the circadian clock circuitry in colorectal carcinogenesis and the therapeutic strategies addressing temporal deregulation in colorectal cancer.

Multi-disciplinary clinic models for the management of non-alcoholic fatty liver disease

In recent years,there has been an increasing interest in the implementation of multi-disciplinary clinic(MDC)models in the medical field,in an effort to improve coordination of care due to the increasing complexity of medical practice.It is therefore unsurprising that there is such interest in non-alcoholic fatty liver disease(NAFLD),which is now the most prevalent liver disease worldwide.

In search of a roadmap towards improving care of patients with cirrhosis and ascites, could a platform trial design transform clinical research?

The authors of“Diagnosis,Evaluation,and Management of Ascites,Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome:2021 Practice Guidance by the American Association for the Study of Liver Diseases”are to be congratulated on their exhaustive assessment of the data published on patients with cirrhosis and ascites and their guidelines represent a pragmatic,evidence-based,common-sense approach(1).

Thoracic imaging outcomes in COVID-19 survivors

The coronavirus disease 2019(COVID-19)pandemic presents a significant global public health challenge.One in five individuals with COVID-19 presents with symptoms that last for weeks after hospital discharge,a condition termed“long COVID”.Thus,efficient follow-up of patients is needed to assess the resolution of lung pathologies and systemic involvement.Thoracic imaging is multimodal and involves using different forms of waves to produce images of the organs within the thorax.In general,it includes chest X-ray,computed tomography,lung ultrasound and magnetic resonance imaging techniques.Such modalities have been useful in the diagnosis and prognosis of COVID-19.These tools have also allowed for the follow-up and assessment of long COVID.This review provides insights on the effectiveness of thoracic imaging techniques in the follow-up of COVID-19 survivors who had long COVID.