Primary Liver Injury and Delayed Resolution of Liver Stiffness after Alcohol Detoxification in Heavy Drinkers with the PNPLA3 Variant I148M

Rausch, Vanessa; Peccerella, T.; Lackner, C.; Yagmur, Eray; Seitz, Helmut‐Karl; Longerich, Thomas; Mueller, Stefan O.

doi:10.1016/s0168-8278(16)00250-6

Cited by 8 publications

(11 citation statements)

References 43 publications

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“…Whether the sum of export, elimination, import and synthesis of hepatic fat has mechanic consequences remains to be elucidated. Preliminary data in patients with ALD suggest that steatosis is not correlated with LS which fulfills the general perception that fat tissue is soft[32]. It has also been occasionally observed that LS decreases while steatosis drastically increases (as measured by non-invasive CAP) during improvement of acute hepatitis of various etiology[22].…”

Section: Important Consequences Of Sphmentioning

confidence: 84%

“…Vice versa, LS improves after elimination of liver pathology e.g ., after clearance of HCV[28], water elimination by diuretics in patients with heart failure and liver congestion[25] or alcohol withdrawal[29] (Figure 3); and (4) LS is an independent predictor of liver-related mortality[30,31]. Genetic risk factors of liver disease such as some PNPLA3 variants are also known to cause LS elevation e.g ., in the presence of alcohol consumption[32]. …”

Section: Observations Leading To Sph: the Role Of Matrix And Pressurementioning

confidence: 99%

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Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis

Mueller¹

2016

WJG

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Independent of their etiology, all chronic liver diseases ultimately lead to liver cirrhosis, which is a major health problem worldwide. The underlying molecular mechanisms are still poorly understood and no efficient treatment strategies are available. This paper introduces the sinusoidal pressure hypothesis (SPH), which identifies an elevated sinusoidal pressure (SP) as cause of fibrosis. SPH has been mainly derived from recent studies on liver stiffness. So far, pressure changes have been exclusively seen as a consequence of cirrhosis. According to the SPH, however, an elevated SP is the major upstream event that initiates fibrosis via biomechanic signaling by stretching of perisinusoidal cells such as hepatic stellate cells or fibroblasts (SPH part I: initiation). Fibrosis progression is determined by the degree and time of elevated SP. The SPH predicts that the degree of extracellular matrix eventually matches SP with critical thresholds > 12 mmHg and > 4 wk. Elevated arterial flow and final arterialization of the cirrhotic liver represents the self-perpetuating key event exposing the low-pressure-organ to pathologically high pressures (SPH part II: perpetuation). It also defines the “point of no return” where fibrosis progression becomes irreversible. The SPH is able to explain the macroscopic changes of cirrhotic livers and the uniform fibrotic response to various etiologies. It also opens up new views on the role of fat and disease mechanisms in other organs. The novel concept will hopefully stimulate the search for new treatment strategies.

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Section: Important Consequences Of Sphmentioning

confidence: 84%

Section: Observations Leading To Sph: the Role Of Matrix And Pressurementioning

confidence: 99%

Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis

Mueller¹

2016

WJG

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“…Furthermore, due to the transplant setting, patients with ongoing alcohol consumption were excluded from this study, which might limit the generalisability of its findings. Following alcohol withdrawal, Rausch and colleagues observed a delayed regression of liver stiffness measured by transient elastography in PNPLA3 G allele carriers. Moreover, an analysis based on data of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial revealed an association between PNPLA3 genotype and severe alcoholic hepatitis development as well as medium‐term mortality.…”

Section: Discussionmentioning

confidence: 99%

Impact of patatin‐like phospholipase domain containing 3 rs738409 G/G genotype on hepatic decompensation and mortality in patients with portal hypertension

Mandorfer

Scheiner

Stättermayer

et al. 2018

Aliment Pharmacol Ther

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SummaryBackgroundThe rs738409 C>G p.I148M variant in the patatin‐like phospholipase domain containing 3 (PNPLA3)‐gene promotes triglyceride accumulation in hepatocytes and hepatic stellate cell activation and has previously been linked to hepatic steatosis/liver fibrosis.AimTo investigate its impact on hepatic decompensation and (liver‐related) mortality in patients who had already developed portal hypertension. Moreover, we assessed its link with hepatic steatosis as evaluated by controlled attenuation parameter.MethodsWe performed a retrospective analysis in prospectively characterised patients with viral hepatitis/fatty liver disease‐induced portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) diagnosed at the Medical University of Vienna who underwent HVPG measurement (until 2013; n = 372; longitudinal study) or simultaneous HVPG and controlled attenuation parameter measurement (2014‐2017; n = 153; cross‐sectional study).ResultsWhile survival was similar between PNPLA3‐C/C and ‐C/G patients, we observed substantially increased mortality in PNPLA3‐G/G patients. PNPLA3‐G/G had no impact on mortality in the subgroup of patients with viral hepatitis; however, we observed a strong independent association between PNPLA3‐G/G and hepatic decompensation (adjusted subdistribution hazard ratio [aSHR]: 2.1, 95% confidence interval [95% CI]: 1.1‐4; P = 0.024) as well as mortality (overall: aSHR: 2.2, 95% CI: 1.22‐3.98; P = 0.009; liver‐related: aSHR: 2.2, 95% CI: 1.08‐4.46; P = 0.029) in patients with fatty liver disease. Interestingly, even in the subgroup of patients who had already progressed to clinically significant portal hypertension (HVPG ≥ 10 mm Hg), PNPLA3‐G/G substantially increased mortality (aSHR: 2.33, 95% CI: 1.27‐4.29; P = 0.006). PNPLA3‐genotype had no influence on controlled attenuation parameter or the prevalence of values ≥248 dB/m.Conclusion PNPLA3‐G/G‐genotype seems to double the risks of hepatic decompensation and (liver‐related) mortality in patients with portal hypertension due to fatty liver disease. Further studies are warranted to investigate potential underlying pathophysiological mechanisms unrelated to hepatic steatosis.

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“…Both ALD and NAFLD not only share a similar histology, but they also show common risk factors, such as female sex, obesity, and diabetes, as well as genetic and mechanistic similarities . For instance, for both diseases, polymorphisms in the gene encoding for patatin‐like phospholipase 3/adiponutrin have been recently identified as an important genetic risk factor, whereas cytochrome P450 2E1–associated liver damage has been established as an important progression factor …”

mentioning

confidence: 99%

“…(4) For instance, for both diseases, polymorphisms in the gene encoding for patatin-like phospholipase 3/adiponutrin have been recently identified as an important genetic risk factor, whereas cytochrome P450 2E1-associated liver damage has been established as an important progression factor. (5)(6)(7) One of the major unresolved clinical issues is the development of early and noninvasive prognostic markers of alcoholic steatohepatitis (ASH)/nonalcoholic steatohepatitis (NASH). Increasing evidence suggests an important role for hepatocyte apoptosis in the progression of ALD and NAFLD, (8,9) although several other forms of cell death have been described, including necrosis, necroptosis, autophagic cell death, and others.…”

mentioning

confidence: 99%