Publications

Antiplatelet agents reduce liver fibrosis by inhibiting platelet activation and platelet-derived growth factor production. Previous cross-sectional epidemiological studies suggest that the use of aspirin is related to reduced liver fibrosis. The Aspirin-Myocardial Infarction Study (AMIS) aims to examine this relationship in a multicenter, randomized, double-blind and placebo-controlled trial. The existing clinical trial of aspirin was conducted to study the benefit of one gram aspirin daily among 4 524 individuals who had experienced at least one documented myocardial infarction. The aspartate aminotransferase (AST)-to-Platelet Ratio Index (APRI) was calculated at baseline and annually from the platelet count and AST levels. Participants in the AMIS trial had a mean baseline APRI of 0.34±0.36, and only 1% individuals had APRI scores higher than 1.0, a common cutoff for cirrhosis. The daily use of aspirin was associated with an increase, rather than a reduction of APRI, by 0.007 per year (95% CI 0.002-0.015, P=0.12). The use of aspirin did not significantly affect platelet counts. In a sensitivity analysis of individuals with probable significant fibrosis at baseline (APRI≥0.7), the aspirin group had a sustained reduction in APRI over time, although this change was not significant compared to that in the placebo group. In the AMIS trial, the daily use of high-dose aspirin did not significantly affect APRI, a surrogate index of liver fibrosis. This study highlights the need for de novo clinical trials to investigate the potential benefit of antiplatelet agents on liver fibrosis.

GOALS: We set out to determine whether variation from this 3-year follow-up interval was associated with the finding of subsequent high-risk adenoma (HRA).

BACKGROUND: HRAs include the following: (1) an adenoma measuring ≥10 mm, (2) ≥3 adenomas found during a single procedure, and (3) an adenoma with high-grade dysplasia or villous architecture. The current Multi-Society Task Force guideline for timing of surveillance colonoscopy after removal of a HRA is 3 years.

STUDY: In 2016, we analyzed 495 patients who had a HRA removed during a 2008 colonoscopy. We compared the frequency of finding another HRA at follow-up intervals. We used the current guidelines as our referent group and performed logistical regression to identify whether any patient characteristics, procedural factors, or type of HRA predicted the development of HRAs on follow-up colonoscopy.

RESULTS: Individuals who followed-up at a median of 4.5 years did not have more HRA on follow-up compared with those who followed-up at 3 years (25.2% vs. 21.0%, P=0.062). These groups had similar baseline characteristics. Older individuals, male gender, having a history of polyps, and piecemeal resection of an HRA predicted future HRAs. The removal of ≥3 adenomas in 2008 as well as a combination of multiple, large, and advanced polyps showed a higher risk of future HRAs.

CONCLUSIONS: The 2012 Multi-Society Task Force recommendation of 3-year follow-up after removal of HRAs may not apply to all patients. We showed that a combination of patient demographics, procedural factors, and pathology best determines the surveillance colonoscopy interval.

A pathophysiologic risk score consisting of insulin resistance and genetic risk predicts incident liver outcomes in NAFLD. Such scores may represent a viable strategy for risk stratification in NAFLD.

PURPOSE OF REVIEW: The liver is the central hub of lipoprotein metabolism. A complex relationship exists between dyslipidemia and chronic liver diseases (CLDs). Recent advances in the genetics of nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) exemplify the pivotal role of lipoprotein metabolism in the pathogenesis of CLD. We review these relationships in four quintessential forms of CLD: NAFLD, ALD, cholestatic liver disease and cirrhosis, with a focus on recent discoveries.

RECENT FINDINGS: An I148 M variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3) and an E167K variant in transmembrane 6 superfamily 2 (TM6SF2) are major genetic risk factors for the development and progression of NAFLD. These genetic variants also increase the risk of ALD. Both PNPLA3 and TM6SF2 are involved in the hepatic assembly of very low-density lipoprotein. The discovery of these two genetic variants highlights the risk of CLD when environmental factors are combined with functional modifications in the lipoprotein metabolism pathway.

SUMMARY: The relationship between CLD and lipoprotein metabolism is reciprocal. On the one hand, the progression of CLD impairs lipoprotein metabolism; on the other hand, modifications in lipoprotein metabolism can substantially increase the risk of CLD. These relationships are at play among the most common forms of CLD affecting a significant proportion of the population.

Nonalcoholic fatty liver disease (NAFLD), a common diagnosis in the United States and other developed countries, has been increasing in prevalence. The American Association for the Study of Liver Diseases recently published updated practice guidelines for diagnosing and managing NAFLD, including the following recommendations: Routine screening for NAFLD in high-risk groups is not advised because of uncertainties surrounding test and treatment options, along with a lack of knowledge about cost-effectiveness and long-term benefits. Noninvasive studies, including biomarkers from laboratory tests and liver stiffness measured through elastography, are clinically useful tools for identifying advanced fibrosis in patients with NAFLD. Liver biopsy should be considered in patients with NAFLD who are at increased risk for nonalcoholic steatohepatitis (NASH) or advanced fibrosis. Weight loss of at least 3% to 5% generally reduces NASH, but greater weight loss (7% to 10%) is needed to improve most histopathologic features, including fibrosis. Pharmacologic therapies (such as pioglitazone and vitamin E) should be considered only in patients with biopsy-proven NASH. Patients with NAFLD should not consume heavy amounts of alcohol, although insufficient data exist to provide advice about other levels of alcohol use. Here, 2 clinicians with expertise in this area debate whether to screen for NAFLD in primary care, how to monitor patients with NAFLD, and what interventions should be used to manage this condition.

BACKGROUND & AIMS: The I148M variant (rs738409) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is by far the most important genetic determinant of non-alcoholic fatty liver disease (NAFLD). However, in the context of NAFLD, the transcriptional regulation of PNPLA3 in human liver cells is not known. In this study, we aimed to define the relationship between PNPLA3 transcription and disease characteristics of human NAFLD.

METHODS: The abundance of PNPLA3 and collagen 1α (COL1α) transcripts was quantified in situ at single-cell resolution using RNAscope® in 87 patients with NAFLD. We examined the association of PNPLA3 and COL1α transcript levels with NAFLD disease severity, defined by histology.

RESULTS: While the majority of PNPLA3 transcripts were found in hepatocytes, approximately 7% of PNPLA3-positive cells co-express COL1α, representing activated myofibroblasts. There is no association between the rs738409 genotype and the level of PNPLA3 transcript. The overall PNPLA3 transcript abundance is lower in zone 1 hepatocytes, patients with higher body mass index, and those with advanced liver fibrosis. The negative association between the PNPLA3 transcript levels and liver fibrosis is largely driven by COL1α-positive cells. A significant proportion of PNPLA3 mRNA is seen in the nucleus. The cytoplasmic-to-nuclear PNPLA3 mRNA ratio is inversely associated with NAFLD disease activity.

CONCLUSIONS: PNPLA3 transcript abundance and nuclear-to-cytoplasmic translocation are negatively associated with hepatic steatosis and NAFLD disease activity, while its abundance in activated myofibroblasts is inversely associated with the stage of liver fibrosis.

LAY SUMMARY: A genetic variant in patatin-like phospholipase domain-containing protein 3 (or PNPLA3) is the most important genetic determinant of non-alcoholic fatty liver disease (NAFLD). However, it is not known how transcriptional regulation of the PNPLA3 gene contributes to the disease characteristics of human NAFLD. Herein, we show that the mRNA levels of PNPLA3, particularly in the cytoplasm, are negatively associated with the severity of NAFLD in humans.

Purinergic signaling is important in the activation and differentiation of macrophages, which play divergent roles in the pathophysiology of liver fibrosis. The ectonucleotidase CD39 is known to modulate the immunoregulatory phenotype of macrophages, but whether this specifically impacts cholestatic liver injury is unknown. Here, we investigated the role of macrophage-expressed CD39 on the development of biliary injury and fibrosis in a mouse model of sclerosing cholangitis. Myeloid-specific CD39-deficient mice (LysMCreCd39fl/fl) were generated. Global CD39 null (Cd39-/-), wild-type (WT), LysMCreCd39fl/fl, and Cd39fl/fl control mice were exposed to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to induce biliary fibrosis. Hepatic hydroxyproline levels, liver histology, immunohistochemistry, mRNA expression levels, and serum biochemistry were then assessed. Following 3 weeks of DDC-feeding, Cd39-/- mice exhibited more severe fibrosis, when compared to WT mice as reflected by morphology and increased liver collagen content. Myeloid-specific CD39 deletion in LysMCreCd39fl/fl mice recapitulated the phenotype of global Cd39-/-, after exposure to DDC, and resulted in similar worsening of liver fibrosis when compared to Cd39fl/fl control animals. Further, DDC-treated LysMCreCd39fl/fl mice exhibited elevated serum levels of transaminases and total bilirubin, as well as increased hepatic expression of the profibrogenic genes Tgf-β1, Tnf-α, and α-Sma. However, no clear differences were observed in the expression of macrophage-elaborated specific cytokines between LysMCreCd39fl/fl and Cd39fl/fl animals subjected to biliary injury. Our results in the DDC-induced biliary type liver fibrosis model suggest that loss of CD39 expression on myeloid cells largely accounts for the exacerbated sclerosing cholangitis in global CD39 knockouts. These findings indicate that macrophage expressed CD39 protects from biliary liver injury and fibrosis and support a potential therapeutic target for human hepatobiliary diseases.

Primary biliary cholangitis (PBC) is an autoimmune liver disease associated with altered lipoprotein metabolism, mainly cholesterol. Hypercholesterolaemia, a major modifiable risk factor for cardiovascular disease in the general population, occurs in 75%-95% of individuals with PBC. The impact of hypercholesterolaemia on cardiovascular risk in PBC, however, is controversial. Previous data have shown that hypercholesterolaemia in PBC is not always associated with an increase in cardiovascular events. However, patients with PBC with cardiovascular risk factors may still warrant cholesterol-lowering therapy. Treatment of hypercholesterolaemia in PBC poses unique challenges among primary care providers due to concerns of hepatotoxicity associated with cholesterol-lowering medications. This review summarises the current understanding of the pathophysiology of hypercholesterolaemia in PBC and its pertinent cardiovascular risk. We will also discuss indications for treatment and the efficacy and safety of available agents for hypercholesterolaemia in PBC.