Metabolic Syndrome and NAFLD Dr. Mohamed A. Alsenbesy Assistant Professor & Head of Internal Medicine Department Qena Faculty of Medicine South Valley University (SVU), Egypt Qena University Hospital

What is Metabolic Syndrome (MetS)?? A cluster of cardiovascular risk factors associated with obesity and insulin resistance. is dramatically increasing in Western and developing countries. Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of MetS.

Mtabolic Syndrome WHO (1998) AACE (2003) NCEP ATP III (2005)   WHO (1998) AACE (2003) NCEP ATP III (2005) IDF (2005) IDF (2009) Criteria IGT, IFG, T2D, or reduced insulin sensitivity plus any two of the following IGT or IFG plus any of the following Any three of the following Increased WC plus any two of the following Three out of five of the following Obesity Men:WHR> 0.90;Wome n:WHR>0.8 5 and/or BMI >30 kg/m 2 BMI ≥25 kg/m 2 WC ≥102 cm in men or ≥88 cm in women Population- specific increased WC cutoffs Population- and country-specific WC cutoffs Glucose IGT, IFG,or T2D IGT or lFG ≥100 mg/dl(inclu ding T2D) ≥100 mg/dL Triglycerides (TG) TG ≥150 mg/dl TG ≥150 mg/dl or on therapy lowering TG TG ≥150 mg/dl HDL- cholesterol( HDL-C) HDL-C<40 mg/dl in men or HDL-C<50 mg/dl in women HDL-C <40 mg/dl in men or HDL-C <50 mg/dl in women on therapy increasing HDL-C HDL-C <40 mg/dl in men or HDL-C<50 mg/dl in women on therapy increasing HDL-C HDL-C <40 mg/dl in men or HDL-C <50 mg/dl in women Blood pressure ≥140/90 mmHg ≥130/85 mmHg ≥130/85 mmHg or on antihyperte nsive therapy ≥130/85 mmHg or on antihypertensive therapy

Diagnosis of Metabolic Syndrome ↑Waist circumference. ≥89 ♀ - ≥102 cm♂ ↑Triglycerides. >150 mg/dL) ↓(HDL) cholesterol <40 ♂ - <50 mg/dL ♀ ↑ Blood pressure ≥130/85 mm Hg ↑Fasting blood sugar ≥100 mg/dL IDF 2015

Insulin effects on lipid Metabolism ↓ adipose tissue lipolysis. ↑ de novo lipogenesis (liver & adipose tissue). ↑ Hepatic VLDL Export Insulin has a fat sparing effect

Insulin Resistance ↓ Utilisation of Glucose& ↑ Gluconeogenesis. ↑ Adipose tissue Lypolysis (failure to supress). Preserved metabolic pathway for de novo hepatic Lipogenesis (selective Insulin resistance)

HOMA Model for IR

NAFLD (NAFLD) is a clinico-pathological syndrome that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) with varying amounts of fibrosis, and cirrhosis (Rinella,et.al JAMA 2015)

NAFLD To define (NAFLD) : (A) Evidence of hepatic steatosis, either by imaging or by histology . (B) No secondary causes of hepatic fat accumulation e.g significant alcohol consumption, use of steatogenic medications or hereditary disorders (AASLD Guidelines, 2012)

Steatosis ALD: > 21 drinks/week for ♂ - 14 for ♀ Amiodarone Medications: Amiodarone Methotrexate Tamoxifen Corticosteroids Diltiazem Valproic acid

Common Causes of Secondary Hepatic Steatosis Macrovesicular steatosis - Excessive alcohol consumption - Hepatitis C (genotype 3) - Wilson’s disease - Lipodystrophy - Starvation - Parenteral nutrition - Abetalipoproteinemia - Medications (e.g., amiodarone, methotrexate, tamoxifen, corticosteroids)

Microvesicular steatosis - Reye’s syndrome - Medications (valproate, anti-retroviral medicines) - Acute fatty liver of pregnancy - HELLP syndrome - Inborn errors of metabolism (e.g., LCAT deficiency, cholesterol ester storage disease, Wolman disease)

Fatty liver Normal liver Liver is divided histologically into lobules. The center of the lobule is the central vein. At the periphery of the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor. Zone 2 is located in between.

NAFLD: Emerging association Polycystic ovary syndrome Obstructive sleep apnea Hypopituitarism Hypogonadism Pancreatic-duodenal resection

NAFLD NAFLD is the most common liver disorder in Western countries,affecting 17–46% (AASLD Guidelines, 2012) 4th most common reason for liver transplant Up to 20-40% adults 6 million children

Prevalence of NAFLD worldwide 20-30% in Europe according to 2 large multicenter population studies. Asia: increased from 13% to 30% in Japan and reported in lower BMI Africa: 90% in one study in Nigeria and maybe common in Egypt but this requires further studies. (clinical Dilemmas in NAFLD, 2016)

DM & CVD Mortality

NAFLD is a risk for CVS Eevents!!??? NAFLD is associated with an increased risk of fatal and non-fatal CVD events. (Giovanni, J of Hepatol., 2016)

Insulin Resistance (IR) and NASH Mechanism of inflammation is uncertain, but IR plays a role. IR is proinflammatory with raised Cytokines & acute phase proteins. IL6, TNF-α and IL-1β, CRP ↑ 3-hydroxbuterate and Acetoacetate in NASH more than simple steatosis.

NASH NASH related HCC is the 2nd leading cause of HCC –related transplantation (clinical Dilemmas in NAFLD, 2016)

Clinical Exceptions Adults with conventionally treated hypopituitarism , who are deficient in growth hormones, are insulin resistant and have metabolic syndrome - NAFLD????? Genetic insulin receptor mutation

Diagnosis and Treatment ????????????????????? US is less sensitve but mostly used. Immaging and biopsy Non invasive : Fibroscan (Transient Elastography) - NAFLD Fibrosis Score and cytokeratin-18

Fibroscan 502, Echosens – France Qena University Hospital

Future Treatments Modulating the gut microbiome. Adiponectin agonists. GLP-1 analogues. CC Chmokine receptor 2 & 5 antagonists. Imm124-E

Inttragastric Balloon for Treatment of Obesity Hghggh Inttragastric Balloon for Treatment of Obesity Qena University Hospital

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