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NASH
- 1. نيرفعد اللد الذنيند آمناواد من وُمد توالذنيند أتوتاواد ال ْلِل د َ ( د َ َمْ د َ ْلِ َّ َّ ْلِ د َ د َ وُ ْلِ َمْك َمْ د َ َّ ْلِ د َ وُ وُ َمْع َمْمد وُ درج اتد تواللد بم اد تع د َلاوند خبرير( د َ د َ د َ ٍ د َ َّ ْلِ د َ د َ َمْموُ د َ د َ ْلِ (ٌ وُ )المجادلة: من الةية11( صدق ال العظيم د
- 2. NASH BY Prof.Dr.BAHAA HASANIN HEAD of PAEDIATrICS HEPAToLoGY DEPArTMENT BENHA fACULTY of MEDEDCINE
- 3. The دaim دof دthis دlecture دis دto دstudy دthe د role دof دdietary دhabits د دnutrient دintake د in دNASH د دChronic دliver دdisease.
- 4. Definition • NASH دis دaccumulation دof دlipid دin دthe دliver دprimarily دin د the دform دof دtriglycerol دin دindividual دwho دdon't دconsume د significant دamount دof دalcohol د 02دgm دethanol د /دday د • دNAFLD دis دrecognized دas دthe دmost دcommon دcause دof د chronic دliver دdisease دworld دwide. د د • NAFLD دrefer دto دwide دspectrum دof دclinicopathologic دliver د disease دranging دfrom دrelatively دbenign دform (دfatty دliver) د to دmore دsevere دform دknown دas دNASH. • دNASH دis دa دprogressive دform دof دliver دinjury دthat دcarry د risk دfor دprogressive دfibrosis, دcirrhosis, دhepatocellular د carcinoma دand دliver دfailure. دIt دmay دbe 1دry دcause دof دup د to د %51دof دcryptogenic دcarcinoma. دIt دrepresents دthe د hepatic دmanifestation دof دmetabolic دsyndrome د
- 5. History of NASH In د ,0891دLudwig دet al. described a series of patients who دlacked دa دhistory دof ‘دsignificant’ دalcohol دintake د but دin دwhom دthe دliver دhistology دresembled دthat دof د alcoholic دliver دdisease. دThey دwere دthe دfirst د دto دuse د the دterm ‘دnonalcoholic دsteatohepatitis’ دfor دthis د condition, دthe دprincipal دfeatures دof دwhich دwere د hepatic دsteatosis (دfatty دchange), دinflammation دand د exclusion دof دalcohol دas دan دaetiological دfactor. دFurther دsmall دcase دseries دwere دpublished دduring د the دnext د 51دyears
- 6. • 1950 د دCirrhosis دnoted دin دdiabetics • 1970 د دJejuno-ileal دbypass دliver دdisease دresembles د alcoholic دhepatitis • 1979/80 د دLudwig دet al. Coined term NASH for steatohepatitis in non-drinkers د 8~دpapers/year ,دSmall د series • 1990 دPowell دet al. دNASH دis دbenign .د • 1994 دBacon دet al. 1994 دExpanded دscope دof دNASH .د • 1996 د دCYP2E1 دinduced دin دrodent دdietary دmodel د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د د دandEndotoxin د induces دinflammation دin دsteatotic دliver • 1998 د دCYP2E1 دinduced دin دhuman دNASH,First دNIH د conference دon دNASH, دPivotal دimportance دof دinsulin د resistance
- 7. • • • • • • • 1999 د دSeveral دanimal دmodels First دclinical دtrials 2002 د 06~د دpapers/year AASLD دsingle دtopic دconference First دEuropean دand دJapanese دsingle دtopic دconferences NASH دestablished دas دpart دof دinsulin دresistance دsyndrome 2004 دRelease دof دfirst دbook دon دNAFLD/NASH
- 8. Reasons why NAFLD/ NASH is important. • Possible دrole دof دNASH/hepatic دsteatosis دin د hepatocarcinogenesis • Most دcommon دcause دof دabnormal دliver دtests دin د community د %8–2دof دpopulation دhave دNAFLD – NASH دnow دrivals دalcoholic دliver دdisease دand دchronic د hepatitis دC دas دreason دfor دreferral دto دgastroenterologist دor د liver دclinic • NASH دis دa دpotential دcause دof دcirrhosis, دwhich دmay د be ‘دcryptogenic’, دand دlead دto دend-stage دliver د disease • High دprevalence دof دfatty دliver دdisorders دin د urbanized دcommunities دwith دaffluent ‘(دWestern’) د economies دthroughout دthe دworld
- 9. cont. • Liver دfailure دis دmost دcommon دcause دof دdeath دin د patients دwith دcirrhosis دresulting دfrom دNASH • Standardized دmortality دof دliver دdisease دin دtype د 2د diabetes دgreatly دexceeds دvascular دdisease • NASH دrecurs دafter دliver دtransplantation • Hepatic دsteatosis دas دa دcause دof دprimary دgraft دnonfunction دafter دliver دtransplantation • Role دof دmetabolic دdeterminants دof دNASH دin د pathogenesis دof دother دliver دdiseases, دparticularly • hepatitis دC دand دalcoholic دcirrhosis
- 10. Causes of fatty liver in children are divided into • Hepatic دcauses. د • Non-hepatic دcauses. د • I- Hepatic causes: – Over دweight دand دobesity دrelated. د – Metabolic دliver دdisease (دWilson دdisease, دglactosaemia, د hereditary دfructose دintolerance دand دglycogen دstorage د disease). د – Syndromes (دschwachman-diamond دsyndromes, دalastram د syndrome دlipodystrophy دsyndrome دand دturner دsyndrome). د – Chronic دhepatitis دC. د – Autoimmune دhepatitis. د د • II- Non-hepatic causes.
- 11. • • • • • • • • • • • A) Nutritional: Protein دcaloric دmalnutrition. د Total دparentral دnutrition. د Starvation. د Intestinal دbypass دsurgery. د Rapid دweight دloss. د Celiac دdisease B) Drugs: Glucocorticoid. د Hypervitaminosis دA. د Toxins (دmashrooms- دAminatta دphalloid). د
- 13. Risk Factors for NASH • Type د 2دDiabetes د د • Hypertriglyceridemia • Obesity د
- 14. The pathogenesis of NAFLD NASH • The دpathogenesis دof دNAFLD د دNASH د remain دpoorly دdefined. دCurrent دconcept د suggest دthe دdevelopment دof دNASH دis دa د Two دhit دprocess د * First hit. • Involve accumulation of Fat in hepatocytes. * Second hit. • Oxidative دstress دis دthought دto دbe دa دkey دrole د in دthe د 2دnd دhit د
- 19. Diagnosis of NASH * Clinical diagnosis: • Clinical experience with pediatric NASH is limited, while there are no characteristic symptoms. • Children may complain of abdominal pain although they are often asymptomatic • Hepatomegaly can often detected on examination, however this physical finding may be missed in clinical practice. • Acanthosis nigricans, a black pigmentation found in skin fold and axilla associated with hyperinsulinaemia • Malaise or tiredness, history of drug ingestion may be elicited at time of presentation.
- 20. Pointers to NAFLD/ NASH in clinical practice • Unexplained elevation of ALT and GGT, typically minor, in a person with metabolic risk factors • ‘Rubbery’ hepatomegaly • Recent weight gain and expanding waistline • Lifestyle or medication changes favouring weight gain • Family history of type 2 diabetes, NAFLD, vascular disorders or hyperlipidaemia
- 21. cont. • Raised serum ferritin not attributable to iron storage disorder or alcohol • Abnormalities of hepatic imagingadiffuse echogenicity on ultrasonogram (‘bright liver’), radiolucency on CT • Patient with chronic HCV infection and diabetes and/or obesity, ‘rubbery’ hepatomegaly or steatosis with HCV genotype 1 infections • Patient with chronic HBV infection, raised ALT but nondetectable HBV DNA in presence of metabolic risk factors • ALT, alanine aminotransferase; CT, computerized tomography; GGT, gamma-glutamyl transpeptidase; HBV DNA, hepatitis B
- 22. • Imaging studies. – – – – – U/S. CT. MRI MRS Fibroscan (Transient elastography). • Non invasive biomarkers: – – – – – Liver enzyme. NASH fibro SURE. New generation of biomarker as FT, ST and NT. Breath test. Auto immune marker.
- 24. C.T of fatty liver
- 25. MRI
- 26. Liver enzymes: • Serum ALT was found to be reliable as screening tool for fatty liver. – Aminotramsferase: the ratio of AST/ALT is usually 1 – in NASH often 2 – Alkaline phosphatase: increase or may be normal. • GGT can be mildely elevated
- 27. NASH FibroSURE • NASH fibrosure is non invasive assessment of liver status for patient with NAFLD. • Quantitative results of to biochemical including. • α 2Macroglobulin. • Haptoglobulin. • Apolipoprotein A. • Bilirubin.
- 28. cont. • • • • • • • γ glutamyl transpeptides (GGT). Alanine aminotransferase (ALT). Asparatate aminotransferase (AST) Totoal cholesterol. Triglyceride. Fasting glucose. NASH fibro SURE should only be used for patient with suspected NAFLD, it is not recommended for patient with other liver disease.
- 29. Steatosis marker • Steatosis marker: has been studied in a variability of patient types including hepatitis C, alcoholic liver disease and NAFLD. Provide quantitative marker for hepatic steatosis grade • steatosis score 0.5 had sensitivity of 71% and specificity of 72% for identification of significant steatosis
- 30. • Biomarker to predict steatosis (Steatotest) fibrosis (fibrotest) among patient – NAFD, the diagnostic accuracy of all biomarker used to identify liver fibrosis seldom exceed 75-80%. These serum markers not available in all lab., may be expensive can't substitute liver biopsy
- 31. Breath test • Both microsomal and mitochondrial function are disturbed in NASH, • MBT for liver microsomal function • KBT for liver mitochondrial function. Liver breath test predirect higher state of NASH
- 32. Autoimmune Ab: (Auto immune marker). • In a pediatric study, seven of 14 children with NAFLD were found to be +ve for ANA or SMA in six and GPC in one, 4 of 6 children were be +ve for Ab.
- 33. Several NASH-specific biomarkers • Several NASH-specific biomarkers have recently been developed. The CK-18, a biomarker of apoptosis, was developed and tested in patients with NAFLD. Another non-invasive biomarker (NASH Diagnostics) is a simple panel that includes Cleaved CK-18, a product of the subtraction of Cleaved CK-18 level from intact CK-18, serum adiponectin
- 34. Liver Biopsy Liver biopsy is considered to be the gold standard for diagnosis of NASH
- 37. Category Pathology Clinicopathological correlation Type 1 Simple steatosis Known to be nonprogressive type2 Steatosis plus lobular inflammation Probably benign (not regarded as NASH Type3, Steatosis, lobular inflammation and ballooning degeneration NASH without fibrosis may progress to cirrhosis Type 4 Steatosis, ballooning degeneration and Mallory bodies, NASH with fibrosis may progress to cirrhosis and liver failure
- 38. —Natural history of nonalcoholic fatty liver disease. Small proportion of patients with fatty liver develop nonalcoholic steatohepatitis. Less than 10% of nonalcoholic steatohepatitis patients develop cirrhosis. Current research is aimed at detecting early stages of fibrosis that are potentially reversible. aProbable percentage of patients with hepatic steatosis progressing to nonalcoholic steatohepatitis. bDisease progression (%) of all nonalcoholic steatohepatitis patients.
- 40. Differential diagnosis of NASH In contrast to adults, with whom the major differential diagnosis is with alcoholic liver disease. In children the main considerations are metabolic or inflammatory disease that cause fatty liver in children. • Relatively common:– – – – – – Cystic fibrosis. Wilson disease. Hereditary fructose intolerance. Galactosaemia. Glycogen storage disease. Familial hyperlipidaemia.
- 41. Differential diagnosis of NASH • Less common: – – – – – – – – – Lipid storage disease. Cholesterol ester storage disease. Sialidosis. Hereditary tryrosinaemia type 1. A beta or hypo beta lipoprotienaemia. Tangier disease. argininaemia. Weber ehristian disease. Porphyria cutanea tarda .
- 42. Diseases Associated with NASH Established condition Emerging condition Obesity Obstructive steep apnea Type 2-diabetes/glucose intolerance Hypothyroidism Dyslipidaemia Polycystic ovary Metabolic Hypopitutrism.
- 43. Treatment of NASH in children The current best treatment of any form of NAFLD in children is life style modification in contrast to adult NAFLD. This is not centered around weight reduction programs, but directed towards increased physical activity promotion of healthy balanced diet to support normal growth and development. The success of this approach is variable and additional drug intervention might be needed.
- 44. Therapeutic option available for patient with NAFLD • • • • • • • • • • • Change in habit: diet physical exercise. Drugs that improve insulin sensitivity. Antioxidant. Lipid lowering agent. Usodeoxycolid acid. Antibiotics: lactobacillus prevent gut derived endotoxaemia. Anti TNF antibodies, TNF- receptor antagonist. Nutritional supplementation: Carnitine, choline. Therapeutic phelobotomies. Liver transplantation The main goal therapy for NAFLD should be to prevent progression of NAFLD to cirrhosis, un fortunately although a variety of treatment modalities have been proposed, none has proven efficacy in changing this end point
- 45. Role of nutrition in treatment of NASH • Nutritional recommendation for NASH focus on the underlying disease (Metabolic syndrome other secondary causes) • Diet composition: Dietary composition has an important consideration. There is some evidence that carbohydrate loading may be problematic, thus the food with high amount of corn syrup, product of high sugar content, high starch food may be particularly dangerous. It may not be just the total calorie intake that lead to NASH, but the types of calorie.
- 46. • Polyunsaturated fatty acid especially formulation rich in omega-3 are widely accepted in medical community for their beneficial affect on hyperlipidaemia • Recent studies ameliorate hepatic steatosis in human animal models of NASH by reducing hepatic fat content. One year course of omega-3 fatty acid (3gm/day) will produce improvement in NASH histological injury
- 47. Fiber in diet - • Children require help with appetite control. Food make individual feel full without delivering high amount of calories, in this regard fruits vegetables come to forfront of good selection. The most satisfying component of vegetable is dietary fiber in particular soluble fiber. • The most interesting of all soluble fiber is delivered from oats. Oat contain unique type of fiber hydrocolloid or oat-beta glycan it is proposed as fat substitute in foods
- 48. Cont. • This soluble fiber has an ability to smooth out blood sugar concentration following meals. This is called second meal effect of low glycaemic index food. • So soluble fiber is valuable in ↓ weight, ↓ IR control blood sugar • High fiber diet may tend to ↓ cholesterol
- 49. • Diet will therefore need to be tailored to individual needs. The inclusion of n-3 fatty acid, high MUFA foods, fruits, vegetables, low GI, high fiber foods reduced intake of saturated fat, simple carbohydrate sweetened drink may be universally recommended to NAFLD patient
- 50. Drug therapy of NASH • Although diet and exercise is the mainstay of treatment, medication might be warranted if an appropriate diet and regular physical activity don't improve biochemical markers and liver morphology
- 51. • Most attention of pediatric NAFLD is given to either vitamin E as antioxidant or to anti diabetic drugs, Metformin as an agent that counter IR • Antioxidant: the use of antioxidants for the treatment of NAFLD to protect cellular structures against damage from oxygen free radicals and from reactive products of lipid peroxidation
- 52. Antioxidant against oxidative stress • Metadoxine • Natural antioxidants (vitamin E, ubiquinone) • Synthetic antioxidants (including dihydroquinoline-type – only used experimentally) • Ursodeoxycholic acid • Lecithin • Selenium • Betaine • Silymarin
- 53. vitamin E • Oral vitamin E 400-1200 IU daily improves hepatic enzymes in patients with NAFLD • It might improve NASH by modulating cytokines and inhibiting the expression of intrahepatic TGF-ß, which is involved in fibrogenesis.
- 55. Lipid Lowering Drugs • As hypertriglyceridaemia and low HDL cholesterol levels are a manifestation of insulin resistance and common among subjects with NAFLD, several investigators have used lipid lowering drugs to treat NAFLD The use of statin drugs is currently contraindicated in the presence of active liver disease or persistent unexplained increases of aminotransaminases
- 56. Drug that protect hepatocyte • Several drugs believed to be hepatoprotective have been used in patient with NASH .these include UDCA, betain, vitamin E, lecithin, βcarotin ,and selenium and taurine
- 57. Nutritional supplementation • Dietary supplement of antioxidant as vitamin E ,selenium and restriction of iron intake may be beneficial for prevention of advanced disease, further regulation of bacterial flora in the gut using probiotic is promising for prevention and treatment of NASH.
- 58. Milk Thistle • Silymarin this is the active ingredient in the • • • • • milk thistle herb. It has a history of improving liver health. Many studies have shown that milk thistle might: Increase the speed of liver cell regeneration Restrain liver fibrosis Protect the liver from injury Decrease cholesterol absorption It is believed that it increase production of anti oxidant enzyme that help liver breakdown toxin,
- 59. Selenium • Selenium is a powerful anti oxidant that works synergistically to asses protection against further damage in liver injury. Selenium is a mineral that functions as a component of glutathione peroxidase, an essential antioxidant system. It is involved in metabolism of vitamin E. • Recommended daily intake in childhood (110 years): 40-50µg. • Selenium dietary source: Organ meat,fish,mashroom and selfish are generally selenium-rich.
- 60. Zinc • Many studies reported that zinc protected induced liver injury,not only reduction of oxidative stress in hepatocyte ,but also by prevention of intestinal permeability Recommended intake in children: 10mg • Zinc dietary source: zinc is found abundantly in shelfish,red meat,legumes and nuts
- 61. Prognosis and Prevention • Prognosis of NASH :Prognosis is dependant not only on the severity of the disease and number of risk factors, but also on the degree of histological damage. The presence of NASH Vs NAFLD and the stage of fibrosis provide a gradient for prognosis
- 62. Can NAFLD /NASH be prevented or reversed? • Because liver failure doesn't occur in NAFLD/ NASH unless cirrhosis has developed, reducing or reversing fibrotic progression must be of ultimate objective of treatment. • There is now compelling evidence that type 2 diabetes can be prevented or at least delayed in onset by life style intervention. NASH, a consequence of IR should also be prevented by change in diet physical activity
- 63. Summary • Summary: • Nonalcoholic fatty liver disease (NAFLD), a condition associated with obesity and diabetes, is increasingly being recognized in the western population. • Simple fatty liver is the most common form of NAFLD and seems to be a benign condition. In contrast, nonalcoholic steatohepatitis may progress to advanced fibrosis and cirrhosis.
- 64. • The diagnosis is often made after incidentally finding elevated liver enzyme levels or by clinical suspicion in patients with obesity or diabetes. Laboratory results or imaging examinations may confirm the diagnosis. However, at present, only a liver biopsy can differentiate simple steatosis from NASH. • There is no clear consensus on the effectiveness of the pharmacologic treatment of NAFLD. Several therapies, including insulin-sensitizing, antioxidant agents, and hepatoprotective medications, have been studied. Lifestyle modifications, particularly weight loss, have been shown to be particularly beneficial.
- 65. Conclusions • NAFLD affects a substantial portion of the general population and is associated with the metabolic syndrome, which includes obesity, insulin resistance, hyperlipidemia, and hypertension. Patients with NAFLD not only suffer from the metabolic sequlae of insulin resistance but have increased overall mortality.
- 66. • Although simple fatty liver seems to be a benign condition, some patients may progress to NASH and ultimately to cirrhosis. Because of the consequences of the disease, we emphasize the importance of the detection of NAFLD in high-risk groups, including obese patients, as well as those with evidence of insulin resistance or other components of the metabolic syndrome
- 67. • Screening and surveillance methods should be applied more uniformly from center to center, and reliable non invasive techniques are needed for the diagnosis of NAFLD and the detection of progressive liver disease. The diagnosis of NAFLD should prompt management of the metabolic risk factors.
- 68. • . Weight loss regimens are believed to be helpful, and numerous drugs have been investigated in small studies. Large, randomized, clinical trials are necessary to determine the real benefit of these agents. Finally, studies on the pathogenesis of NAFLD may not only improve our understanding of the mechanisms involved in NAFLD progression, but may lead to potentially novel therapeutic strategies to treat this condition.
- 69. Recommendation • We should screen all children at risk for development of NASH (obese diabetic children) by U/S laboratory investigation. • We should encourage our children to avoid unhealthy food which lead to obesity. • Encourage mother for exclusive breast feeding at 1st 6 month of life which proved to prevent obesity at childhood period adolescence.
- 71. Thank you