Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care.

BACKGROUND: De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients. Cumulative immunosuppression has been shown to contribute to post-transplant malignancy (PTM) risk. There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs, independent of the net effect of immunosuppression. Calcineurin inhibitors such as tacrolimus may promote tumourigenesis, whereas mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, may limit tumour progression. Liver transplantation (LT) is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable, which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort. However, there is limited clinical data on this subject in both LT and other solid organ transplant recipients. AIM: To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation. METHODS: A literature search was conducted using MEDLINE and Embase databases using the key terms "solid organ transplantation", "tacrolimus", "mycophenolic acid", and "carcinogenicity", in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022. Related terms, synonyms and explosion of MeSH terms, Boolean operators and truncations were also utilised in the search. Reference lists of retrieved articles were also reviewed to identify any additional articles. Excluding duplicates, abstracts from 1230 records were screened by a single reviewer, whereby 31 records were reviewed in detail. Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria. RESULTS: A total of 6 studies were included in this review. All studies were large population registries or cohort studies, which varied in transplant era, type of organ transplanted and immunosuppression protocol used. Overall, there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation. Furthermore, no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients. CONCLUSION: The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies, and its application in solid organ transplantation, is yet to be confirmed in clinical studies. Thus, the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

Evaluating treatment response following locoregional therapy for hepatocellular carcinoma: A review of the available serological and radiological tools for assessment.

Hepatocellular carcinoma (HCC) is an aggressive primary malignancy of the liver and is the third most common cause of cancer-related global mortality. There has been a steady increase in treatment options for HCC in recent years, including innovations in both curative and non-curative therapies. These advances have brought new challenges and necessary improvements in strategies of disease monitoring, to allow early detection of HCC recurrence. Current serological and radiological strategies for post-treatment monitoring and prognostication and their limitations will be discussed and evaluated in this review.

Rate of early hospital readmission amongst cirrhotic patients is high in Australia: experience from a single liver transplant centre.

BACKGROUND AND AIMS: The 30-day hospital readmission rate in cirrhotic patients has been demonstrated to be up to 40% in international studies, but is not well studied in Australia. The aim of the current study was to report on the rate and cause of 30-day hospital readmission from a single liver transplant referral centre, including a cost analysis of readmissions. METHODS: This was a retrospective study of consecutive cirrhotic patients admitted to a liver transplant centre in Victoria, Australia, between 1 January 2019 and 31 December 2019. Cases were identified through International Classification of Diseases, Tenth Revision, 10 coding for cirrhosis and its complications. Baseline demographic data, liver-related complications and unrelated extra-hepatic comorbidities, laboratory values and prognostic scores were collected from the electronic medical record. RESULTS: One hundred seventy-nine (63% men; median age at index admission, 59 years) patients who were admitted 427 times during the study period were included in the final analysis. The 30-day hospital readmission rate was 46%, with the majority of readmissions attributable to fluid overload (29%), miscellaneous reasons (27%) and infection (20%). One fifth of readmissions were considered preventable. History of variceal haemorrhage was found to be an independent predictor of 30-day hospital readmission. The annual cost of readmission is over AU$2.7 million and the median cost of hospital readmission was about AU$9000. CONCLUSIONS: The 30-day hospital readmission rate of 46% is higher than previously reported and almost half of cases were caused by either fluid overload or infection.

Herb-Induced Liver Injury: A Report on Two Australian Cases.

Two 40-year-old males were admitted to our tertiary hepatology unit with acute hepatitis after presentation with generalized abdominal pain, nausea, and jaundice. There was no history of paracetamol overdose, and common viral and autoimmune causes were excluded through serology. Imaging and liver biopsy were performed with both investigations demonstrating non-specific features of hepatic inflammation. A history of herbal supplement use was elucidated in each patient, which was deemed to be the cause of liver injury in both men. Each patient recovered within two months of presentation following the withdrawal of the offending agent and supportive care.

Hepatocellular carcinoma surveillance and quantile regression for determinants of underutilisation in at-risk Australian patients.

BACKGROUND: While clinical guidelines recommend hepatocellular carcinoma (HCC) surveillance for at-risk individuals, reported surveillance rates in the United States and Europe remain disappointingly low. AIM: To quantify HCC surveillance in an Australian cohort, and assess for factors associated with surveillance underutilisation. METHODS: All patients undergoing HCC surveillance liver ultrasounds between January 1, 2018 to June 30, 2018 at a tertiary hospital in Melbourne, Australia, were followed until July 31, 2020, or when surveillance was no longer required. The primary outcome was the percentage of time up-to-date with HCC surveillance (PTUDS). Quantile regression was performed to determine the impact of factors associated with HCC surveillance underutilisation. RESULTS: Among 775 at-risk patients followed up for a median of 27.5 months, the median PTUDS was 84.2% (IQR: 66.3%-96.3%). 85.0% of patients were followed up by specialist gastroenterologists. Amongst those receiving specialist care, quantile regression demonstrated differential associations at various quantile levels of PTUDS for several factors. Older age at the 25th quantile (estimate 0.002 per percent, P = 0.03), and cirrhotic status at the 75th quantile (estimate 0.021, P = 0.017), were significantly associated with greater percentage of time up-to-date. African ethnicity (estimate -0.089, P = 0.048) and a culturally and linguistically diverse (CALD) background (estimate -0.063, P = 0.01) were significantly associated with lower PTUDS at the 50th quantile, and again for CALD at the 75th quantile (estimate -0.026, P = 0.045). CONCLUSION: While median PTUDS in this Australian cohort study was 84.2%, awareness of the impact of specific factors across PTUDS quantiles can aid targeted interventions towards improved HCC surveillance.

Hemodynamic Effects of the Non-Peptidic Angiotensin-(1-7) Agonist AVE0991 in Liver Cirrhosis.

BACKGROUND & AIMS: Although in cirrhosis with portal hypertension levels of the vasoconstrictor angiotensin II are increased, this is accompanied by increased production of angiotensin (Ang)-(1-7), the endogenous ligand of the Mas receptor (MasR), which blunts hepatic fibrosis and decreases hepatic vascular resistance. Therefore, we investigated the effects of the non-peptidic Ang-(1-7) agonist, AVE0991, in experimental cirrhosis. METHODS: Cirrhosis was induced by bile duct ligation (BDL) or carbon tetrachloride (CCl4) intoxication. The coloured microsphere technique assessed portal and systemic hemodynamic effects of AVE0991 in vivo. Hepatic expression of eNOS, p-eNOS, iNOS, JAK2, ROCK and p-Moesin were analyzed by western blots. Activities of ACE and ACE2 were investigated fluorometrically. Moreover, fibrosis was assessed in BDL rats receiving AVE0991. RESULTS: In vivo, AVE0991 decreased portal pressure (PP) in both rat models of cirrhosis. Importantly, systemic effects were not observed. The hepatic effects of AVE0991 were based on upregulation of vasodilating pathways involving p-eNOS and iNOS, as well as by downregulation of the vasoconstrictive pathways (ROCK, p-Moesin). Short-term treatment with AVE0991 decreased the activity of ACE2, long-term treatment did not affect hepatic fibrosis in BDL rats. CONCLUSIONS: The non-peptidic agonist of Ang-(1-7), AVE0991, decreases portal pressure without influencing systemic pressure. Thus, although it does not inhibit fibrosis, AVE0991 may represent a promising new therapeutic strategy for lowering portal pressure.

Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis.

BACKGROUND & AIMS: Splanchnic vascular hypocontractility with subsequent increased portal venous inflow leads to portal hypertension. Although the renin-angiotensin system contributes to fibrogenesis and increased hepatic resistance in patients with cirrhosis, little is known about its effects in the splanchnic vasculature, particularly those of the alternate system in which angiotensin (Ang) II is cleaved by the Ang-converting enzyme-2 (ACE2) to Ang-(1-7), which activates the G-protein-coupled Mas receptor (MasR). We investigated whether this system contributes to splanchnic vasodilatation and portal hypertension in cirrhosis. METHODS: We measured levels of renin-angiotensin system messenger RNA and proteins in splanchnic vessels from patients and rats with cirrhosis. Production of Ang-(1-7) and splanchnic vascular reactivity to Ang-(1-7) was measured in perfused mesenteric vascular beds from rats after bile-duct ligation. Ang-(1-7) and MasR were blocked in rats with cirrhosis to examine splanchnic vascular hemodynamics and portal pressure response. RESULTS: Levels of ACE2 and MasR were increased in splanchnic vessels from cirrhotic patients and rats compared with healthy controls. We also observed an ACE2-dependent increase in Ang-(1-7) production. Ang-(1-7) mediated splanchnic vascular hypocontractility in ex vivo splanchnic vessels from rats with cirrhosis (but not control rats) via MasR stimulation. Identical effects were observed in the splanchnic circulation in vivo. MasR blockade reduced portal pressure, indicating that activation of this receptor in splanchnic vasculature promotes portal inflow to contribute to development of portal hypertension. In addition, the splanchnic effects of MasR required nitric oxide. Interestingly, Ang-(1-7) also decreased hepatic resistance. CONCLUSIONS: In the splanchnic vessels of patients and rats with cirrhosis, increased levels of ACE2 appear to increase production of Ang-(1-7), which leads to activation of MasR and splanchnic vasodilatation in rats. This mechanism could cause vascular hypocontractility in patients with cirrhosis, and might be a therapeutic target for portal hypertension.

Therapeutic potential of targeting the renin angiotensin system in portal hypertension.

Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis. Drug therapy to reduce portal pressure involves targeting two vascular beds. The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin II, endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells. The second approach is to reduce mesenteric and portal blood flow. Non-selective ß-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis. However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients. Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding. This review briefly outlines current therapeutic approaches to the management of portal hypertension, and the evidence supporting the role of the renin angiotensin system (RAS) and the use of RAS blockers in this condition. It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.

Hepatopulmonary syndrome: update on recent advances in pathophysiology, investigation, and treatment.

Hepatopulmonary syndrome (HPS) is an important cause of dyspnea and hypoxia in the setting of liver disease, occurring in 10-30% of patients with cirrhosis. It is due to vasodilation and angiogenesis in the pulmonary vascular bed, which leads to ventilation-perfusion mismatching, diffusion limitation to oxygen exchange, and arteriovenous shunting. There is evidence, primarily from animal studies, that vasodilation is mediated by a number of endogenous vasoactive molecules, including endothelin-1 and nitric oxide (NO). In experimental HPS, liver injury stimulates release of endothelin-1 and results in increased expression of ET(B) receptors on pulmonary endothelial cells, leading to upregulation of endothelial NO synthase (eNOS) and subsequent increased production of NO, which causes vasodilation. In addition, increased phagocytosis of bacterial endotoxin in the lung not only promotes stimulation of inducible NO synthase, which increases NO production, but also contributes to intrapulmonary accumulation of monocytes, which may stimulate angiogenesis via vascular endothelial growth factor pathway. Despite these insights into the pathogenesis of experimental HPS, there is no established medical therapy, and liver transplantation remains the main treatment for symptomatic HPS, although selected patients may benefit from other surgical or radiological interventions. In this review, we focus on recent advances in our understanding of the pathophysiology of HPS, and discuss current approaches to the investigation and treatment of this condition.

Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options.

The RAS (renin-angiotensin system) is now recognized as an important regulator of liver fibrosis and portal pressure. Liver injury stimulates the hepatic expression of components of the RAS, such as ACE (angiotensin-converting enzyme) and the AT(1) receptor [AngII (angiotensin II) type 1 receptor], which play an active role in promoting inflammation and deposition of extracellular matrix. In addition, the more recently recognized structural homologue of ACE, ACE2, is also up-regulated. ACE2 catalyses the conversion of AngII into Ang-(1-7) [angiotensin-(1-7)], and there is accumulating evidence that this 'alternative axis' of the RAS has anti-fibrotic, vasodilatory and anti-proliferative effects, thus counterbalancing the effects of AngII in the liver. The RAS is also emerging as an important contributor to the pathophysiology of portal hypertension in cirrhosis. Although the intrahepatic circulation in cirrhosis is hypercontractile in response to AngII, resulting in increased hepatic resistance, the splanchnic vasculature is hyporesponsive, promoting the development of the hyperdynamic circulation that characterizes portal hypertension. Both liver fibrosis and portal hypertension represent important therapeutic challenges for the clinician, and there is accumulating evidence that RAS blockade may be beneficial in these circumstances. The present review outlines new aspects of the RAS and explores its role in the pathogenesis and treatment of liver fibrosis and portal hypertension.

Angiotensin-(1-7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat.

Ang-(1-7) (angiotensin-1-7), a peptide product of the recently described ACE (angiotensin-converting enzyme) homologue ACE2, opposes the harmful actions of AngII (angiotensin II) in cardiovascular tissues, but its role in liver disease is unknown. The aim of the present study was to assess plasma levels of Ang-(1-7) in human liver disease and determine its effects in experimental liver fibrosis. Angiotensin peptide levels were measured in cirrhotic and non-cirrhotic patients with hepatitis C. The effects of Ang-(1-7) on experimental fibrosis were determined using the rat BDL (bile-duct ligation) model. Liver histology, hydroxyproline quantification and expression of fibrosis-related genes were assessed. Expression of RAS (renin-angiotensin system) components and the effects of Ang-(1-7) were examined in rat HSCs (hepatic stellate cells). In human patients with cirrhosis, both plasma Ang-(1-7) and AngII concentrations were markedly elevated (P<0.001). Non-cirrhotic patients with hepatitis C had elevated Ang-(1-7) levels compared with controls (P<0.05), but AngII concentrations were not increased. In BDL rats, Ang-(1-7) improved fibrosis stage and collagen Picrosirius Red staining, and reduced hydroxyproline content, together with decreased gene expression of collagen 1A1, alpha-SMA (smooth muscle actin), VEGF (vascular endothelial growth factor), CTGF (connective tissue growth factor), ACE and mas [the Ang-(1-7) receptor]. Cultured HSCs expressed AT1Rs (AngII type 1 receptors) and mas receptors and, when treated with Ang-(1-7) or the mas receptor agonist AVE 0991, produced less alpha-SMA and hydroxyproline, an effect reversed by the mas receptor antagonist A779. In conclusion, Ang-(1-7) is up-regulated in human liver disease and has antifibrotic actions in a rat model of cirrhosis. The ACE2/Ang-(1-7)/mas receptor axis represents a potential target for antifibrotic therapy in humans.