Browsing by Subject "non-alcoholic fatty liver disease"

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  • Lahelma, Mari; Luukkonen, Panu K.; Qadri, Sami; Ahlholm, Noora; Lallukka-Brück, Susanna; Porthan, Kimmo; Juuti, Anne; Sammalkorpi, Henna; Penttilä, Anne K.; Arola, Johanna; Orho-Melander, Marju; Yki-Järvinen, Hannele (2021)
    Only some individuals with obesity develop liver fibrosis due to non-alcoholic fatty liver disease (NAFLD-fibrosis). We determined whether detailed assessment of lifestyle factors in addition to physical, biochemical and genetic factors helps in identification of these patients. A total of 100 patients with obesity (mean BMI 40.0 +/- 0.6 kg/m(2)) referred for bariatric surgery at the Helsinki University Hospital underwent a liver biopsy to evaluate liver histology. Physical activity was determined by accelerometer recordings and by the Modifiable Activity Questionnaire, diet by the FINRISK Food Frequency Questionnaire, and other lifestyle factors, such as sleep patterns and smoking, by face-to-face interviews. Physical and biochemical parameters and genetic risk score (GRS based on variants in PNPLA3, TM6SF2, MBOAT7 and HSD17B13) were measured. Of all participants 49% had NAFLD-fibrosis. Independent predictors of NAFLD-fibrosis were low moderate-to-vigorous physical activity, high red meat intake, low carbohydrate intake, smoking, HbA(1c), triglycerides and GRS. A model including these factors (areas under the receiver operating characteristics curve (AUROC) 0.90 (95% CI 0.84-0.96)) identified NAFLD-fibrosis significantly more accurately than a model including all but lifestyle factors (AUROC 0.82 (95% CI 0.73-0.91)) or models including lifestyle, physical and biochemical, or genetic factors alone. Assessment of lifestyle parameters in addition to physical, biochemical and genetic factors helps to identify obese patients with NAFLD-fibrosis.
  • Huuskonen, Antti (Helsingin yliopisto, 2021)
    Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic in the Western world. It covers a spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. Only a small fraction of patients with NAFLD develop advanced liver disease. We wished to determine whether NAFLD is familial based on review of literature and set up a study to examine index patients and their first degree relatives. The participants underwent a detailed survey of family history and clinical examination. We used transient elastography (TE) as well as magnetic resonance elastography (MRE) to non-invasively measure liver fibrosis. So far we have studied three families in which the index patient had liver cirrhosis due to NAFLD or the index had undergone a liver transplantation due to NAFLD cirrhosis. The review of the literature suggests NAFLD is familial and only 10-30% of its genetic causes have been identified. Our goal is to continue study NAFLD families and to identify new genes underlying NAFLD cirrhosis.
  • Porkka, Laura (Helsingfors universitet, 2016)
    Ei-alkoholiperäinen rasvamaksa (NAFLD) on noin neljäsosalla länsimaisesta väestöstä. Se on yhteydessä metaboliseen oireyhtymään, sydän- ja verisuonisairauksiin sekä tyypin 2 diabetekseen. Tämän tutkimuksen tavoite oli selvittää, mitkä tekijät korreloivat maksan rasvapitoisuuteen ja vaikuttavat sen muutoksiin seuranta-aikana. Erityisen kiinnostuneita oltiin liikunnan vaikutuksesta maksan rasvaan. Seurasimme keskimäärin 12 vuoden ajan 89 henkilöä, joiden maksan rasvapitoisuus määritettiin magneettiresonanssispektroskopialla (1H-MRS). Tutkimuksessa vahvistettiin maksan rasvapitoisuuden korreloivan merkitsevästi metabolisen oireyhtymän tekijöihin, maksaentsyymeihin sekä vapaa-ajan liikuntaan käytettyyn energiamäärään. Myös lähtötilanteen maksa-arvot ja metabolisen oireyhtymän komponentit, verenpainetta lukuun ottamatta, korreloivat merkitsevästi maksan rasvapitoisuuteen 12 vuotta myöhemmin. Monimuuttuja-analyysissä maksan rasvaa parhaiten ennakoivat ALAT-taso, ikä ja triglyseridit. Maksan rasvan muutokseen seuranta-aikana korreloivat muun muassa triglyseridien, vyötärönympäryksen, paastoinsuliinin, HbA1c:n, systolisen verenpaineen ja maksaentsyymien muutokset. Vaikka liikunta ei ollut merkitsevästi yhteydessä maksan rasvan muutokseen, sen vaikutus oli selvä. Liikuntamäärältään alimpaan kolmannekseen kuuluvien maksan rasvapitoisuuden mediaani oli yli yhdeksän prosenttiyksikköä korkeampi kuin ylimmällä kolmanneksella ja täysin passiivisista henkilöistä 70 %:lla oli NAFLD.
  • Männistö, Ville T.; Salomaa, Veikko; Färkkilä, Martti; Jula, Antti; Mannisto, Satu; Erlund, Iris; Sundvall, Jouko; Lundqvist, Annamari; Perola, Markus; Åberg, Fredrik (2021)
    Background & Aims Non-alcoholic fatty liver disease (NAFLD) increases morbidity and mortality. However, patients in biopsy-based cohorts are highly selected and the absolute risks of liver- and non-liver outcomes in NAFLD in population remains undefined. We analysed both liver-related and non-liver-related outcomes in Finnish population cohorts of NAFLD. Methods We included 10 993 individuals (6707 men, mean age 53.3 +/- 12.6 years) with NAFLD (fatty liver index >= 60) from the Finnish population-based FINRISK and Health 2000 studies. Liver fibrosis was assessed by the dAAR score, and genetic risk by a recent polygenic risk score (PRS-5). Incident liver-related outcomes, cardiovascular disease (CVD), cancer and chronic kidney disease (CKD) were identified through linkage with national registries. Results Mean follow-up was 12.1 years (1128 069 person-years). The crude incidence rate of liver-related outcomes in NAFLD was 0.97/1000 person-years. The cumulative incidence increased with age, being respectively 2.4% and 1.5% at 20 years in men and women aged 60 years at baseline, while the relative risks for CVD and cancer were 9-16 times higher. The risk of CKD exceeded that of liver outcomes at a baseline age around 50 years. 20-year cumulative incidence of liver-related outcomes was 4.3% in the high, and 1.5% in the low PRS-5 group. The dAAR score associated with liver outcomes, but not with extra-hepatic outcomes. Conclusion The absolute risk of liver-related outcomes in NAFLD is low, with much higher risk of CVD and cancer, emphasizing the need for more individualized and holistic risk-stratification in NAFLD.
  • Cuthbertson, Daniel J.; Brown, Emily; Koskinen, Juha; Magnussen, Costan G.; Hutri-Kähönen, Nina; Sabin, Matthew; Tossavainen, Päivi; Jokinen, Eero; Laitinen, Tomi; Viikari, Jorma; Raitakari, Olli T.; Juonala, Markus (2019)
    Background & Aims We aimed to determine how childhood body mass index and metabolic health, along with the change in body mass index between childhood and adulthood, determine the risk of adult non-alcoholic fatty liver disease. Methods Data from 2020 participants aged 3-18 years at baseline, followed up 31 years later, were examined to assess the utility of four childhood metabolic phenotypes (Metabolic Groups I: normal body mass index, no metabolic disturbances; II: normal body mass index, one or more metabolic disturbances; III: overweight/obese, no metabolic disturbances; IV: overweight/obese, one or more metabolic disturbances) and four life-course adiposity phenotypes (Adiposity Group 1: normal child and adult body mass index; 2, high child, normal adult body mass index; 3, normal child body mass index, high adult body mass index; 4, high child and adult body mass index) in predicting adult non-alcoholic fatty liver disease. Results The risk for adult non-alcoholic fatty liver disease was similar across all four groups after adjustment for age, sex, lifestyle factors and adult body mass index. Risk of adult non-alcoholic fatty liver disease was not increased among individuals overweight/obese in childhood but non-obese in adulthood. In contrast, overweight or obese adults, irrespective of their youth body mass index status, had similar to eight-fold to 10-fold increased risk (P <0.001). Conclusions Childhood overweight/obesity, not metabolic health, is associated with increased risk for adult non-alcoholic fatty liver disease. However, the increased risk associated with childhood overweight/obesity can be largely removed by obtaining a normal body mass index by adulthood.
  • Setti, Mounir Ould; Voutilainen, Ari; Tajik, Behnam; Niskanen, Leo; Tuomainen, Tomi-Pekka (2021)
    Background and objectives Fatty liver disease (FLD) and hypertension are separately associated with cardiovascular (CV) mortality. The two conditions are related in multiple ways. This work aimed to study the joint effect and interaction of FLD and hypertension in respect to overall and CV mortality. Methods The population-based cohort, Kuopio Ischaemic Disease Risk Factor Study, followed 1569 middle-aged non-diabetic Finnish men for 34 years. Considering adjustment for age, body mass index, smoking and alcohol consumption, separate and combined effects of FLD and hypertension and their interaction at the multiplicative and additive scales regarding all-cause and CV death were assessed using Cox proportional hazards models. Results FLD and hypertension coexisted in 8.54% of the men (n = 134). FLD and hypertension associated, independently and combined, with an increased hazard of all-cause and CV deaths. Non-CV mortality associated with FLD, but not with hypertension. We found a negative interaction between FLD and hypertension regarding the hazard of all-cause (relative excess risk due to interaction (RERI), -0.97; 95% confidence interval (CI), -1.65 to -0.28) and CV mortality (RERI, -1.74; 95% CI, -2.98 to -0.5). The interaction was also found on a multiplicative scale. Conclusions We found evidence of a negative interaction between FLD and hypertension in respect to CV mortality. We thus recommend adjusting for FLD or hypertension when studying the effect of the other condition on mortality or CV diseases in middle-aged men.
  • Lallukka, Susanna; Luukkonen, Panu K.; Zhou, You; Isokuortti, Elina; Leivonen , Marja; Juuti, Anne; Hakkarainen, Antti; Orho-Melander, Marju; Lundbom, Nina; Olkkonen, Vesa M.; Lassila, Riitta; Yki-Järvinen, Hannele (2017)
    Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity [insulin-resistant ('IR') versus insulin-sensitive ('IS')] and PNPLA3 genotype (PNPLA3(148MM/MI) vs PNPLA3(148II)). Liver fat content (H-1-MRS) was similarly increased in 'IR' (13 +/- 1%) and PNPLA3(148MM/MI) (12 +/- 2%) as compared to 'IS' (6 +/- 1%, p
  • Balkhed, Wile; Åberg, Fredrik O.; Nasr, Patrik; Ekstedt, Mattias; Kechagias, Stergios (2022)
    Background and Aims The presence of advanced hepatic fibrosis is the prime marker for the prediction of liver-related complications in non-alcoholic fatty liver disease (NAFLD). Blood-based non-invasive tests (NITs) have been developed to evaluate fibrosis and identify patients at risk. Current guidelines propose monitoring the progression of NAFLD using repeated NITs at 2-3-year intervals. The aim of this study was to evaluate the association of changes in NITs measured at two time points with the progression of NAFLD. Methods We retrospectively included NAFLD patients with NIT measurements in whom the baseline hepatic fibrosis stage had been assessed by biopsy or transient elastography (TE). Subjects underwent follow-up visits at least 1 year from baseline to evaluate the progression of NAFLD. NAFLD progression was defined as the development of end-stage liver disease or fibrosis progression according to repeat biopsy or TE. The following NITs were calculated at baseline and follow-up: Fibrosis-4 (FIB-4), NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet ratio index (APRI) and dynamic aspartate-to-alanine aminotransferase ratio (dAAR). Results One hundred and thirty-five patients were included with a mean follow-up of 12.6 +/- 8.5 years. During follow-up, 41 patients (30%) were diagnosed with progressive NAFLD. Change in NIT scores during follow-up was significantly associated with disease progression for all NITs tested except for NFS. However, the diagnostic precision was suboptimal with area under the receiver operating characteristics 0.56-0.64 and positive predictive values of 0.28-0.36 at sensitivity fixed at 90%. Conclusions Change of FIB-4, NFS, APRI, and dAAR scores is only weakly associated with disease progression in NAFLD. Our findings do not support repeated measurements of these NITs for monitoring the course of NAFLD.
  • Lahelma, Mari; Qadri, Sami; Ahlholm, Noora; Porthan, Kimmo; Ruuth, Maija; Juuti, Anne; Orešič, Matej; Hyötyläinen, Tuulia; Öörni, Katariina; Yki-Järvinen, Hannele (2022)
    Background and aims: The susceptibility of low-density lipoprotein (LDL) to aggregation predicts atherosclerotic cardiovascular disease. However, causes of interindividual variation in LDL lipid composition and aggregation susceptibility remain unclear. We examined whether the lipid composition and aggregation susceptibility of LDL reflect the lipid composition of the human liver. Methods: Liver biopsies and blood samples for isolation of LDL particles were obtained from 40 obese subjects (BMI 45.9 ± 6.1 kg/m2, age 43 ± 8 years). LDL was isolated using sequential ultracentrifugation and lipidomic analyses of liver and LDL samples were determined using ultra-high performance liquid chromatography–mass spectrometry. LDL aggregation susceptibility ex vivo was analyzed by inducing aggregation by human recombinant secretory sphingomyelinase and following aggregate formation. Results: The composition (acyl carbon number and double bond count) of hepatic triglycerides, phosphatidylcholines, and sphingomyelins (SMs) was closely associated with that of LDL particles. Hepatic dihydroceramides and ceramides were positively correlated with concentrations of the corresponding SM species in LDL as well with LDL aggregation. These relationships remained statistically significant after adjustment for age, sex, and body mass index. Conclusions: Lipid composition of LDL reflects that of the human liver in obese patients. Changes in hepatic sphingolipid metabolism may contribute to interindividual variation of LDL lipid composition and susceptibility to aggregation.
  • Luukkonen, Panu K.; Qadri, Sami; Lehtimäki, Tiina E.; Juuti, Anne; Sammalkorpi, Henna; Penttilä, Anne K.; Hakkarainen, Antti; Orho-Melander, Marju; Arola, Johanna; Yki-Järvinen, Hannele (2021)
    Context: The I148M (rs738409-G) variant in PNPLA3 increases liver fat content but may be protective against cardiovascular disease. Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat. Objective: To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients. Design: Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in 2 cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR. Setting: Tertiary referral center. Patients: A total of 298 obese patients who underwent a liver biopsy during bariatric surgery (bariatric cohort: age 49 +/- 9 years, body mass index [BMI] 43.2 +/- 6.8 kg/m(2)), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (nonbariatric cohort: age 45 +/- 14 years, BMI 29.7 +/- 5.7 kg/m(2)). Main Outcome Measures: Nuclear magnetic resonance profiling of plasma lipids, lipoprotein particle subclasses and their composition. Results: In both cohorts, individuals carrying the PNPLA3-I148M variant had significantly higher liver fat content than noncarriers. In insulin-resistant and homozygous carriers, PNPLA3-I148M exerted a distinct antihyperlipidemic effect with decreased very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles and their constituents, and increased high-density lipoprotein particles and their constituents, compared with noncarriers. VLDL particles were smaller and LDL particles larger in PNPLA3-I148M carriers. These changes were geometrically opposite to those due to IR. PNPLA3-I148M did not have a measurable effect in patients with lower IR, and its effect was smaller albeit still significant in the less obese than in the obese cohort. Conclusions: PNPLA3-I148M confers an antiatherogenic plasma lipid profile particularly in insulin-resistant individuals.
  • Qadri, Sami; Lallukka-Brück, Susanna; Luukkonen, Panu K.; Zhou, You; Gastaldelli, Amalia; Orho-Melander, Marju; Sammalkorpi, Henna; Juuti, Anne; Penttilä, Anne K.; Perttilä, Julia; Hakkarainen, Antti; Lehtimäki, Tiina E.; Oresic, Matej; Hyötyläinen , Tuulia; Hodson, Leanne; Olkkonen, Vesa M.; Yki-Järvinen, Hannele (2020)
    Background & Aims The I148M variant in PNPLA3 is the major genetic risk factor for non-alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA-TGs) in PNPLA3-I148M carriers. Gene expression data indicate that PNPLA3 is liver-specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3-I148M modifies AT metabolism in human NAFLD. Methods Profiling of the AT lipidome and fasting serum non-esterified fatty acid (NEFA) composition was conducted in 125 volunteers (PNPLA3(148MM/MI), n = 63; PNPLA3(148II), n = 62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3(148MM), n = 25) or lacking the variant (PNPLA3(148II), n = 25). Whole-body insulin sensitivity of lipolysis was determined using [H-2(5)]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers. Results PUFA-TGs were significantly increased in AT in carriers versus non-carriers of PNPLA3-I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33-fold higher in the liver than in AT (P <.0001). In contrast, PNPLA3 protein levels per tissue protein were three-fold higher in AT than the liver (P <.0001) and nine-fold higher when related to whole-body AT and liver tissue masses (P <.0001). Conclusions Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3-I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3-I148M carriers.
  • Qadri, Sami; Yki-Järvinen, Hannele (2022)
    Park, MacLean, et al. conduct an exome-wide association study of liver fat content in the Penn Medicine BioBank. By leveraging machine learning-assisted analysis of clinical CT scans to quantify steatosis, they uncover previously undescribed liver fat-associated genetic variants.
  • Hintikka, Jukka; Lensu, Sanna; Makinen, Elina; Karvinen, Sira; Honkanen, Marjaana; Linden, Jere; Garrels, Tim; Pekkala, Satu; Lahti, Leo (2021)
    We have shown that prebiotic xylo-oligosaccharides (XOS) increased beneficial gut microbiota (GM) and prevented high fat diet-induced hepatic steatosis, but the mechanisms associated with these effects are not clear. We studied whether XOS affects adipose tissue inflammation and insulin signaling, and whether the GM and fecal metabolome explain associated patterns. XOS was supplemented or not with high (HFD) or low (LFD) fat diet for 12 weeks in male Wistar rats (n = 10/group). Previously analyzed GM and fecal metabolites were biclustered to reduce data dimensionality and identify interpretable groups of co-occurring genera and metabolites. Based on our findings, biclustering provides a useful algorithmic method for capturing such joint signatures. On the HFD, XOS-supplemented rats showed lower number of adipose tissue crown-like structures, increased phosphorylation of AKT in liver and adipose tissue as well as lower expression of hepatic miRNAs. XOS-supplemented rats had more fecal glycine and less hypoxanthine, isovalerate, branched chain amino acids and aromatic amino acids. Several bacterial genera were associated with the metabolic signatures. In conclusion, the beneficial effects of XOS on hepatic steatosis involved decreased adipose tissue inflammation and likely improved insulin signaling, which were further associated with fecal metabolites and GM.