DR. EMAM'S LECTURE FATTY LIVER

FATTY LIVER;The missed item in management of diabetic patient : 

FATTY LIVER;The missed item in management of diabetic patient Dr. Mohammed Emam Consultant, Gastroenterology, Riyadh National Hospital Professor of Gastroenterology Zagazic University, Egypt

CLINICAL SCENARIO : 

CLINICAL SCENARIO 52 year old women, known Diabetic since 10 years on oral hypoglycemic; Diamicron (80 mg twice a day plus metformin 850 mg twice daily), is noted to have slightly abnormal liver enzyme on 2 separate occasions obtained as a part of routine diabetic clinic care follow up. Most recently about 6 months after her first set of abnormal liver enzymes, ALT is 76u/L and AST 53 u/L. The patient denied any over the counter medication, any herbal supplementation and alcohol ingestion. Her medical history include; Hyperlipidemia (on lipitor 20 mg daily) and hypertension The patient is obese with body mass index of 32. Results for chronic hepatitis panel, autoimmune marker, serum Iron, Ferritin, are negative. Upper abdominal ultrasonography demonstrated an enlarged liver with bright echo patterance , consistent with Fatty Liver.

Q; : 

Q; Do you think that fatty liver is a problem in this patient that need management or just re-assurance of the patient? And why? How to differentiate between the pure fatty infiltration of the liver and steotohepatitis or even hepatic fibrosis? How to manage such cases?

NAFLD, Almost unheard of a decade ago, but now approaching epidemic level : 

NAFLD, Almost unheard of a decade ago, but now approaching epidemic level Bruce Bacon, 2008

THE PROBLEM : 

THE PROBLEM Non alcoholostic Fatty Liver (NAFLD), occurs frequently in clinical practice. It will likely to increase in future as the prevalence of obesity and diabetes continues to increase all over the world. This is worrisome because patient with NAFLD appear to have a higher all cause mortality in addition to liver related cause of death.

PREVALENCE : 

PREVALENCE The over all prevalence of NAFLD is between 20-35% in all population. Increase dramatically in obese to morbidity obese patient (Incidence may be more than 90% in some series)

COURSE : 

COURSE Most NAFLD follow a relatively benign natural history in relationship to the liver. The more aggressive form of NAFLD; non alcoholic steato hepatitis (NASH) occur in about 6-8% of general population. NASH increase to 35-40% in morbidity obese patients (especially those undergoing bariatric surgery) 10% of those will progress to cirrhosis during an approximate 14-year period.

COURSE : 

COURSE Once cirrhosis; end stage liver related complications occur in 38-45% of cases and about 20% will succumb to a liver related death 7 to 10 year period. HCC also has been linked to NASH cirrhosis (exact prevalence remain unknown) Many studies shown an increased risk of cardiovascular disease in presence of NAFLD The presence of NAFLD also increase the odds of developing diabetes by more than 4-fold.

Defining NAFLD : 

Defining NAFLD A liver biopsy showing moderate to gross macrovesicular fatty change with or without inflammation (lobular or portal), Mallory bodies, fibrosis, or cirrhosis. Negligible alcohol consumption (less than 40 g of ethanol per week) History obtained by three physicians independently. Random blood assays for ethanol should be negative. If performed, desialylated transferrin in serum should also be negative. Absence of serologic evidence of hepatitis B or hepatitis C.

NAFLD—Spectrum of Disease : 

NAFLD—Spectrum of Disease Steatosis Steatohepatitis (NASH) NASH with Fibrosis Cirrhosis NAFLD

NAFLD—Risk Factors : 

NAFLD—Risk Factors Obesity Diabetes Mellitus Hypertriglyceridemia

DIAGNOSIS : 

DIAGNOSIS Asymptomatic (most of cases) Come in attention secondary to mild to moderate increase liver enzyme or abnormal abdominal imaging ALT more predominate ALT rarely more than 3 folds

SYMPTOMS : 

SYMPTOMS Right hypochondriac pain & fullness Pain not associated with severity of disease The Novel Finding Increase dorsocervical lipohypertophy which in the only contributor to severity of histological finding.

Slide 14: 

Most of patient typically meet the criteria of metabolic syndrome (wait 740 inch mm), 35 in in women, triglyceride  150 mg,  HLD < 40 mg/dL in men and < 50mg/ dL in women, BLpr above 130/85, F.b. Sugar  100mg/dL The presence of metabolic syndrome has been linked to NASH as well as severe fibrosis in NAFLD patients

RADIOLOGY : 

RADIOLOGY echo contrast, Liver brightness, deep (posterior beam) attenuation, vascular blurring. Recent scoring system, based on liver brightness, attenuation and vascular blurring on U.S. examination showed 100%, specificity (in thin patient) The specificity and sensitivity is markedly  in obese patient (49.1 % to 75%) Sometimes show difficulty in differentiation between steatosis and fibrosis

Slide 16: 

CT Similar diagnostic yield as U.S. Much less accurate that U.S. in case of low – grade steatosis. Improved accuracy with using liver; spleen attenation ratios.

A. Demonstrates a heterogeneous-appearing echotexture “bright liver”B. Relatively hypodense liver compared to the spleen (liver-to-spleen ratio <1) : 

A. Demonstrates a heterogeneous-appearing echotexture “bright liver”B. Relatively hypodense liver compared to the spleen (liver-to-spleen ratio <1)

Slide 18: 

MR Good correlation with microscopic fat content MR spectroscopy, is a specialized radiologic study than can measure triglyceride content, non- invasively. Limitation for MR include, expense, inability to use in patient with implantable devices, claustrophobia, altered volume in patient with Iron overload.

Slide 19: 

Percutaneous Liver Biopsy Remain the standard for distinguishing NAFLD form NASH Adequate biopsy samples remain an issue and given the significant prevalence of NAFLD

Liver biopsy in NASH, Indications : 

Liver biopsy in NASH, Indications Peripheral stigmata of chronic liver disease Splenomegaly Cytopenia Abnormal iron studies Diabetes and/or significant obesity in an individual over the age of 45

IMAGING FOR NASH : 

IMAGING FOR NASH US, CT, and MR imaging clearly unable to accurately discriminate between NASH and isolated Fatty Liver. Novel technique are under development that is useful in diagnosis of NASH non invasively involve contrast ultrasound using Levovist (100% accuracy), early promise as a diagnostic tool.

IMAGING FOR NASH FIBROSIS : 

IMAGING FOR NASH FIBROSIS The use of imaging to identify those was advanced fibrosis is very promising Transient elastography is an ultrasound based technology that is used to measure liver stiffness Show very good correlation between liver biopsy fibrosis and liver stiffness Sensitivity and specificity 87% and 91% in patients with advanced fibrosis

DIFFERENTIATING ISOLATED FATTY LIVER FROM NASH : 

DIFFERENTIATING ISOLATED FATTY LIVER FROM NASH Non Invasive bio marker in NASH:

NAFLD—Pathogenesis : 

Insulin resistance  Fatty acids Steatosis Lipid peroxidation NASH NAFLD—Pathogenesis First Hit Second Hit Hepatic iron, leptin, anti-oxidant deficiencies, and intestinal bacteria

PATHOGENESIS : 

PATHOGENESIS

Slide 28: 

Ideally patient should combine the dietary and exercise recommendation in an effort to optimize life style modification. Cumulative weight loss of 8-10% baseline body weight is associated with histologic improvement of NASH

AREA OF UNCERTAINTY?! : 

AREA OF UNCERTAINTY?! Why African American do not habe the amount of fatty liver or the severity of NASH as their white or Hispanic? Despite having more DM, HTN, and Metabolic Syndrome. N.B. If the ethnicity can be elucidated a significant strides in treating this disease will be made.

Slide 30: 

The role of liver biopsy in diagnosis and unavailability of non- invasive test for diagnosis? Who will progress to severe disease? What the prevalence of HCC in NASH) Preliminary evidences suggests that it is less than that seen with CHCV? Even if the prevalence is much less, still remain a significant problem as a result of much higher prevalence of NASH compared to HCV?

Slide 31: 

The effective therapies remain the largest area of uncertainty: What is the ideal diet and exercise? Role of antioxidants, e.g., vitamin E and Betaine Role of metoformin Thiazolidinoendion (the insulin sensitizer, show promise but why they are not effective in every patient??? Role of other medication e.g.: Glucagon like peptides 1-receptors agonist Selective cannabinoid receptor antagonist AG Inhibitors Role of combination therapy e.g., pioglitazone and metoformine

Slide 32: 

Insulin resistance  Fatty acids Steatosis Lipid peroxidation NASH Cytoprotectants Insulin Sensitizers Antihyperlipidemics First Hit Second Hit Weight Loss Diet/Exercise Antioxidants How to Treat?

TREATMENT OF NASH : 

TREATMENT OF NASH Treatment regimen targeting insulin resistance; oxidative stress, diabetes, hyperlipedemia, obesity and hepatic fibrosis. Multiple treatment modalities are available including; diet, exercise, surgical interventions and finally pharmacological therapy.

WEIGHT LOSS : 

WEIGHT LOSS Patient with NAFLD –typically over weight, or obese, Insulin resistant with high energy intake Moderate weight loss of approximately 6-8% via moderate caloric restriction about (1400 l\kcl/daily) marked improvement of hepatic lipid content and improve AST &ALT. Extreme weight loss via starvation or Bariatric surgery worsening liver enzymes, liver histology and even fibrosis

MEDICINE THAT AUGMENT WEIGHT LOSS : 

MEDICINE THAT AUGMENT WEIGHT LOSS Orlistat Reversible inhibitor of gastric and pancreatic lipase Block approximately 30% of dietary triglyceride 6-9 months ttt 6-8% total weight loss plus improvement of hepatic steatosis both biochemically and histologically. Rimonabant Act by inhibition of cannobinoid receptor located both centrally and peripherally enhanced weight loss. Given in obese 20 mg daily/ moderate weight loss – plus improvement of ALT, hepatic steatosis Recently, association of this drug with depression limit use Glucagon like protein – 1 receptor agonist (Incretin analogs) or (Exendin-4): Proven therapeutic agent in treatment of NASH

EXERCISE : 

EXERCISE Regular exercise (walking – jogging daily) works synergistically with diet modification Improved ALT & AST F.B. glucose Hepatic steatosis Slow gradual weight loss through diet and exercise very beneficial in treatment of NASH The optimal exercise for NASH is not yet described

MACRONUTRIENTS IN NALFD : 

MACRONUTRIENTS IN NALFD

ALTERING FOOD CONTENT : 

ALTERING FOOD CONTENT Evidence suggested that: Nash patients have diets higher in simple carbohydrate, lower ratio of polysaturated fatty acid (PUFAS) to saturated fatty acids. There is a good concept that alternating the macronutrients content is more important than total calories. The Ideal diet for NASH has not been established

MODIFICATION OF DIETARY FAT : 

MODIFICATION OF DIETARY FAT Excess SFAs: should be avoided Monosaturated Fatty acids e.g., olive, peanuts butter nuts, avocados are generally beneficial because the  total cholesterol, triglycerides, LDL, main HDL also improve Insulin resistance. PUFAS ( polysaturated fatty acid) should replace SFAs - significant cardiovascular benefits N-3 PUFAs (alpha linoleicocid) (Fish oil) – significant improvement of NAFLD, triglyceride, blood glucose, LFT, hepatic steatosis

MODIFICATION OF DIETARY FAT : 

MODIFICATION OF DIETARY FAT Wallnuts as another source of PUFAS – improve lipid profile in diabetic patient Avoid – transfatty acid (dairy food) and hydrogenerated margarine -  inflammatory markers;  LDL: HDL ratio Avoid – sucrose and fructose in western diet Soft drink (Non diet) – contain high fructose -  lipogenesis,  triglycerides,  insulin resistance Avoid – rapidly absorbed carbohydrates -  steatosis Slowly absorbed carbohydrates much better.

GENERAL CONCEPT : 

GENERAL CONCEPT Food with low glycemic index, containing monosaturated fatty acid and N-3 PUFA, low SFAs and Limited fructose – seem to be acceptable general guideline

PHARMACOLOGIC THERAPIES IN THE TREATMENT OF NASH : 

PHARMACOLOGIC THERAPIES IN THE TREATMENT OF NASH

Slide 43: 

Metoformine Improve insulin resistance by  triglyceride production. Animal studies – improved serum (very promising in treatment of NASH) ALT & AST with metoformine hepatomegally  steatosis

Insulin Sensitizers : 

Insulin Sensitizers Marchesini et al. Lancet 2001 --20 patients, biopsy-proven NASH --14 metformin (500 tid) x 4 months; 6 controls --ALT & OGTT improved in metformin Nair et al. Gastroenterology (in press) --22 patients, biopsy-proven NASH --Received metformin 20 mg/kg/d x 12 months --Improvement in ALT & insulin sensitivity --No improvement in liver histology Metformin

Slide 45: 

Human studies (limited) – improved (dose 1500 mg/daily/4 month) insulin resistance Improve AST & ALT However, no significant improvement of necroinflammation and fibrosis Open label RCT study 110 NAFLD patient (in Italy) compared Metoformine to Vitamin E 800 IU/day – higher improvement in metoformine group with improved Necroinflammation, steatosis and fibrosis.

Slide 46: 

Also compared when, Metoformine with rosiglitazone showed similar result in both group with  hepatic fat Insulin – sensitizing medication show the most promise improvement of histopathology in NASH Combination therapy with metoformine TZD – more beneficial effect because the untoward weight gain with TZD mnotherapy

SURGICAL THERAPY FOR WEIGHT LOSS : 

SURGICAL THERAPY FOR WEIGHT LOSS Unitl an effective medical therapy is developed – surgical therapy will continue to remain alternative in selected patients. Newer surgical techniques e.g., adjustable gastric banding and Roux – en Y gastric bypass – better tolerated and improve the metabolic syndrome Markedly improve hepatic steatosis inflammation and fibrosis.

CONCLUSION : 

CONCLUSION The public health problems related to obesity continues to grow. The growing incidence of NAFLD and subsequently NASH, will reflected in subsequent increase in cirrhosis and HCC in future. The need for an accurate non-invasive test for diagnosis must be developed soon

Thank you… : 

Thank you…