Liver, what do you know?

• Food

– Liver

– Foie gras

• Alcohol use

Liver anatomy

• 1,5 kg

• Supplied by blood from

– Hepatic artery

– Portal system (gut, pancreas, spleen)

• Liver sinusoids => central vene

• Bile duct

Liver function

• Detoxification of various metabolites

– Reduction, oxidation, conjugation, excretion

– Drugs, alcohol

• Protein synthesis

• Production of biochemicals necessary for digestion

• Bile

• Numerous functions in the human body

• Glycogen storage

• Decompensation of red blood cells

• Hormone production

Liver function

• Detoxification of various metabolites

– Reduction, oxidation, conjugation, excretion

– Drugs, alcohol

• Protein synthesis

• Production of biochemicals necessary for digestion

• Bile

• Numerous functions in the human body

• Glycogen storage

• Decompensation of red blood cells

• Hormone production

Liver disease

• Alcohol

• Steatosis (NASH/NAFLD)

• Chronic Hepatitis (B/C)

• Auto-immune hepatitis

• Primairy Biliair Cholangitis (PBC)

• Primairy Sclerosing Cholangitis (PSC)

• Metabolic diseases

• Hemochromatose

• M. Wilson

• Alfa-1-antitrypsine deficiëncy

• Drugs

• Infections

• Cryptogenic

Liver fibrosis -> cirrhosis

Complications livercirrhosis

• Portal hypertension

– Oesofageal varices

– Splenomegaly en hypersplenism

– Ascites en Spontaneous Bacterial peritonitis (SBP)

– Hepatorenal Syndrome

– Hepatic encefalopathy

• Liver failure

– Clotting problems

– Hypoalbuminaemia

• Hepatocellulair carcinoma

End stage

NAFLD / NASH

• 2016 worldwide more obesity than malnutrition

– 500.000.000

• 2016 more deaths related to obesity than malnutrition

• 15% world population obese

• 40% world population overweight

• NAFLD 17-46% of adults in western population

• Steatosis No1 indication for liver transplantation (US)

USA

Steatosis No1 indication for

liver transplantation

NAFLD / NASH

• WHO: 2016 worldwide more obesity than malnutrition

– 500.000.000

• 2016 more deaths related to obesity than malnutrition

• 15% world population obese (BMI >30)

• 40% world population overweight (25< BMI<30)

• NAFLD 17-46% of adults in western population

– NAFL & NASH

• NASH 3 -5% prevalence

Dimension of the problem

General population

NAFLD

20-40%

NASH 2-5%

Obesity

NAFLD

NASH 15-55%

DM type 2

NAFLD

NASH 20-80%

DM: >380 million

>550 in 2030

1 billion

NAFLD / NASH

• Characterised by

– Excessive hepatic fat accumulation

– Associated with insulin resistance

• Definition:

– Steatosis in 5% of hepatocytes (histology or proton magnetic

resonance spectroscopy 1H-MRS or MRI)

• Exclusion:

– Alcohol daily >30g(♂) and >20g (♀)

Risk factors

• Obesity

• Hypertension

• Dyslipidemia

• Type 2 diabetes

• Metabolic syndrome

Pathophysiology

NAFLD / NASH

Pathogenesis

• High-calorie diet

• Excess (saturated) fats

• Refined carbohydrates

• Sugar-sweetened beverages

• High fructose intake

• Western diet

• Genetic factors?

Weight gain

Obesity

NAFLD

Identification

• Identify risk factors of NAFLD

• Imaging

– US, (MRI)

• Markers of inflammation

– ALAT

• Markers of fibrosis

– NFS, FIB-4, ELF, Fibrotest

• Transient elastography - liverbiopsy

Diagnostic flow chart

Treatment

• Liver transplantation ($600.000)

Treatment

• Bariatric surgery

– ($ 6.000 - 30.000)

Treatment

Diet and lifestyle changes

• Small amounts of weight loss!

– reduce liver fat and improve hepatic IR

• 7% histological improvement

• Progressive increase in exercise

Treatment

• Insulin sensitizers

– Metformine

– Pioglitazone

– Rosiglitazone

– Incretin mimetics

• Antioxidants, cytoprotective and lipid lowering agents

– Vit E (800IU/day)

– UDCA

– Obeticholic acid

– N-3 polyunsaturated fatty acids (PUFA)

• Iron depletion

Treatment

Experimental therapies

• Anti-inflammatory

• Antifibrotic agents

• Insulin sensitizing

• Fatty acid/ bile acid conjugates

• Choline (Vitacholine)

Future perspective

• Fighting steatosis

• Lifestyle changes

• Drugs

• Supplements

Choline, an essential nutrient for humans• Required to make essential membrane phospholipids. • Precursor for biosynthesis of neurotransmitter acetylcholine • Source of labile methyl groups. • Choline NOT considered a vitamin (body synthesizes small amounts) still considered an

essential nutrient in humans because choline MUST be consumed to maintain health.• Design:

– Healthy male volunteers fed choline-free diet with 500 mg/day choline X1wk.– Randomized into 2 groups, with choline (control) & without (deficient) for 3wk. – Final wk – all received choline.

• Results:– choline-deficient group, plasma choline and phosphatidylcholine concentrations 30%; plasma and RBC

phosphatidylcholine 15%; no such changes occurred in the control group.– In choline-deficient group, serum alanine aminotransferase activity

• Observations support conclusion and choline is an essential nutrient for humans when excess methionine and folate are not available in the diet.

Zeisel S.H., et al; FASEB J. 1991 Apr;5(7):2093-8.

1. Phosphorylated down cytidine diphosphate-choline (CDP-choline) pathway to produce phosphatidylcholine (PC) for cell membranes and circulating lipoproteins.

or2. Oxidized to betaine, as a source of methyl groups for the synthesis of methionine &

S-adenosyl-methionine (SAM), principal methylating agent in mammalian cells. and

3. Generate PC via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, & catalyzes SAM-dependent sequential trimethylation of phosphatidylethanolamine.

Yan, J., et al; Am J Clin Nutr December 2013 vol. 98 no. 6 1459-1467

Choline Metabolic Pathways

Betaine (Trimethylglycine)

Choline

Glycine

MethionineHomocysteine

Methyl glycine

S-Adenyl Methionine

Methyl tetrahydrofolate

Folate

DNARNAProteinLipid

Choline Oxidation Pathway

What Pregnancy can teach us about Choline

• Large amounts of PC needed for cellular division, tissue expansion, and lipoprotein synthesis.

• 12-wk feeding study examining impact of pregnancy on biomarkers of choline metabolism– 26 healthy, third-trimester, singleton pregnant women– 21 non-pregnant women – 2 choline intake levels (380mg from diet) and

• 100mg & 550mg (Balchem Vitacholine).

– All participants also took a multivitamin• 600ug folate, 2.6ug B12, 1.9mg B6• 200mg DHA (Neuromins, Natures Way).

Yan, J., et al; Am J Clin Nutr December 2013 vol. 98 no. 6 1459-1467

PC-DHA

480mg

linoleic (18:2n−6) oleic (18:1n−9)

Yan J, et al; Am J Clin Nutr December 2013 vol. 98 no. 6 1459-1467

DHA (22:6n−3) ARA (20:4n−6)

PC-DHA

VLDL

DHA

PC-DHA

cytidine diphosphate

930mg

PEMTYan J, et al; Am J Clin Nutr December 2013 vol. 98 no. 6 1459-1467

40% Genetic Polymorphism in PEMT gene – unresponsive to estrogen

Betaine

CholineGlycine

MethionineHomocysteine

Methyl glycine

S-Adenyl MethionineSAM

Methyl tetra hydrofolate

Folate

Methyl Cobalamin

Vitamin B12

DNARNAProteinLipid

XX

B12 Deficiency & Choline Steal

Tetra hydrofolate

X

X

CH3- B12 B12X39% US pop subclinical

deficiency

Corbin KD & Zeisel SH. Curr Opin Gastroenterol. 2012 Mar; 28(2): 159–165.

http://www.histology.leeds.ac.uk/cell/plasma_membrane.php

Maintaining the Balance

34

Membrane Integrity

Phosphatidylcholine Packaging of Triglyceride rich VLDL

VLDL

Choline

Gene Silencing & ActivationProtein SynthesisLipid Synthesis

Methylation

Cystein

Imbalance = Choline Steal

35

Leaky Membrane

Triglyceride Trapping Fatty Liver Cirrhosis Liver Cancer

VLDL

Liver Enzymes

Stealing Choline from membranes

Liver Enzymes

Insulin ResistanceMetabolic Syndrome

Deficiency in USA

0.5%

39%

MethylationSurvival Mode

Robs Peter (liver) to Pay Paul (methylation)

Gene Silencing & ActivationProtein Synthesis

Lipid Synthesis

Muscle Enzymes

Muscle Enzymes

Gene

• Choline intake exceeding current recommendations may be needed to support both PC production via CDP-choline pathway and choline-mediated one-carbon metabolism.

• The competing demands for choline by the phosphorylation or oxidative pathways and the critical importance of this compound in a variety of key metabolic functions make the necessity for ensuring at least recommended intakes of choline, and preferably more.

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