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Fatty Liver Disease In Diabetes: Causes, Diagnosis And Management
- 1. WELCOME
- 2. Nonalcoholic Fatty Liver Disease In Diabetes Mellitus
- 3. A 52 years old female was found to have elevated liver enzyme [AST= 80U/L and ALT = 94 U/L] on routine blood check up. Viral hepatitis panel was negative. Ultrasonography of whole abdomen shows fatty infiltration of liver. Her medical history reveals that she is diabetic for 8 years and hypertensive for 5 years. The patient came to the hospital for further evaluation. She was overweight [BMI=29.5 kg/m2] and to have mild hepatomegaly with no sign of cirrhosis. After excluding other potential cause of patient’s liver enzymes elevation, NAFLD is considered the likely cause.
- 4. What is Fatty Liver Disease? The definition of nonalcoholic fatty liver disease (NAFLD) requires that (a) There is evidence of hepatic steatosis, either by imaging or by histology and (b) There are no causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication or hereditary disorders.
- 5. Usually seen in people who are overweight or obese Some fat in your liver is normal More than 5%-10% of the organ's weight, you may have fatty liver disease
- 6. What Are the Types of Nonalcoholic Fatty Liver disease? 1. Nonalcoholic fatty liver (NAFL) • the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. 2. Nonalcoholic steatohepatitis (NASH) • presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis.
- 8. What are the other causes of fatty liver disease?
- 9. Who's at Risk for Fatty Liver? Conditions with established association Conditions with emerging association Obesity Polycystic ovary syndrome Type 2 diabetes mellitus Hypothyroidism Dyslipidemia Obstructive Sleep apnea Metabolic syndrome Hypopituitarism Hypogonadism Pancreato-duodenal resection
- 10. A patient having fatty liver gave history that he used to drink occasionally Is it Alcoholic Fatty Liver disease or Nonalcoholic Fatty Liver disease??
- 11. MALE •>21 drinks per week FEMALE •>14 drinks per week Over a 2-year period prior to baseline liver histology
- 12. What is Diabetes mellitus? Diabetes mellitus is a clinical syndrome characterized by an increase in plasma blood glucose (hyperglycaemia). Diabetes has many causes, but is most commonly due to type 1 or type 2 diabetes.
- 19. # What is fatty liver disease? # What are the spectrums of fatty liver disease? # What is diabetes mellitus? # How diabetes causes fatty liver disease? ANSWERED ANSWERED ANSWERED ANSWERED
- 21. Global prevalence NAFLD 25.24% Lowest Africa Highest Middle east and southern America
- 23. ASIA 15-20% China, Japan, Korea = 12-24% Hong kong = 16% Taiwan = 12%
- 24. India General population • 9-32 % Type 2 DM •56.5% Female •60%
- 26. Prevalence of NASH among NAFLD patients in BANGLADESH Absent 10% Borderline 52.6% Present 42.4%
- 27. How can a diabetic patient with NAFLD presents?? • Feeling tired • Loss of weight or appetite • Weakness • Nausea • Confusion, poor judgment, or trouble concentrating. • Pain in the center or right upper part of abdomen.
- 28. Criteria of diagnosis of NAFLD Hepatic steatosis by imaging or histology No co- existing causes for CLD No competing etiologies for hepatic steatosis No significant alcohol consumption
- 29. How Is Fatty Liver Diagnosed? Routine Blood test Imaging Histopathology
- 30. Routine tests for diabetic patients having NAFLD The liver enzymes (AST, ALT) may higher than normal Fasting lipid profile shows dyslipidemia High blood sugar profile HbA1C is above normal level
- 31. Ultrasound Healthy liver in Ultrasound Fatty liver in Ultrasound
- 32. CT Scan and MRI of Fatty liver
- 33. MRS in Fatty liver
- 34. Liver biopsy Liver biopsy remains the best diagnostic tool for confirming NAFLD and evaluating necroinflammation/fibrosis, as well as the most sensitive and specific means of providing important prognostic information.
- 35. When should we do Liver biopsy ? • Patients with NAFLD who are at increased risk to have steatohepatitis and advanced fibrosis. • Patients with suspected NAFLD in whom competing etiologies for hepatic steatosis and co-existing chronic liver diseases cannot be excluded without a liver biopsy.
- 36. Limitations of Liver biopsy cost Procedure related morbidity and mortality sampling error
- 37. Emerging diagnostic tools • Imaging by transient elastography • Plasma biomarkers - plasma cytokeratin-18 fragments (marker of hepatocyte apoptosis)
- 38. If NAFLD discovered incidentally on imaging, should we evaluate in all cases? asymptomatic normal liver biochemistries No need to further evaluation lack any liver- related symptoms or signs normal liver biochemistries assess for metabolic risk factors and alternate causes for hepatic steatosis symptomatic abnormal liver biochemistries worked-up
- 39. Should we screen all the diabetic patients ?? NO uncertainties surrounding diagnostic tests lack of knowledge related to the long-term benefits Lack of treatment options
- 40. Should we screen the family members of a diabetic patient having NAFLD? CURRENTLY NOT RECOMMENDED
- 41. What Is the Long-Term Outlook for Fatty Liver? Fortunately, many cases of fatty liver don’t develop into liver disease. The liver can repair itself, if we take the necessary steps to treat high cholesterol, diabetes.
- 42. Who should be treated? All diabetic patient having NAFLD Lifestyle intervention treatments aimed at improving liver disease should be limited to those with NASH
- 44. Weight reduction Orlistate Improve liver enzyme But not histology Exercise alone May reduce steatosis Unknown about histology
- 45. Management of body weight and obesity Goal is sustained weight loss of 7-10% of body weight Weight loss of up to 1 kg/week is considered to be safe Rapid weight loss can result in worsening of the liver disease
- 46. Medical management • Metformin • Thiazolidinediones (TZDs) • Glucagon-like peptide-1 (GLP-1) analogs • Dipeptidyl peptidase-4 (DPP- 4) inhibitors Anti diabetic agents Others • Statins • Vitamin E • Ursodeoxycholic acid (UDCA) • Omega-3 fattyacids
- 47. Antidiabetic agents for NAFLD patients Metformin+ life style modification Not major improvement of aminotransferase and histology Not recommended as a specific treatment for NASH Pioglitazone Can be used to treat NASH
- 48. GLP-1 analogs Improved glucose tolerance and a small decrease in BMI Improved steatosis and NASH histology Antidiabetic agents for NAFLD patients DPP-4 inhibitors Improvement in HbA1c levels and a decrease BMI Decreases in alanine aminotransferase levels and improved liver histology
- 49. Statin use in patients with NAFLD and NASH • Statins can be used to treat dyslipidemia in patients with NAFLD and NASH. • Statins should not be used to specifically treat NASH.
- 50. Vitamin E (a-tocopherol) • improves liver histology • considered as a first-line pharmacotherapy Non- diabetic patients • Not recommended Diabetic patients
- 51. Ursodeoxycholic acid (UDCA) •Not recommended for the treatment of NAFLD or NASH Omega-3 fatty acids •Considered as the first line agents to treat hypertriglyceridemia in patients with NAFLD
- 52. Is blood glucose control helps in NAFLD improvement? Studies shows that decrease in hemoglobin A1c and the use of insulin were associated with an improvement in hepatic fibrosis.
- 53. What Else should be done? • Upper GI Endoscopy • HCC screening • Routinely repeating a liver biopsy is not recommended.
- 54. Prognosis of NAFLD NAFL Benign condition Improve naturally NASH Cirrhosis Liver cancerLiver failure
- 55. Type 2 diabetics, presence of NAFLD Increased total mortality, regardless of classic risk factors Have twice risk mortality compared with nondiabetics without NAFLD More common causes of death malignancy (33% of death) More liver related complications (19% of death)
- 56. Conclusion The identification of NAFLD should be sought as part of routine assessment of diabetic patients, because it is essential for the early diagnosis and proper implementation of lifestyle and pharmaceutical interventions. Diet, exercise, and weight loss provide significant clinical benefits and must be considered of first line for treating NAFLD/NASH. There is significant research effort in developing noninvasive monitoring of disease progression and effective treatment for the betterment of patients health.
Editor's Notes
- NAFLD is characterized by the accumulation of triglycerides, which are formed from the esterification of FFA and glycerol within the hepatocyte. FFAs arise in the liver from three distinct sources; lipolysis (the hydrolysis of FFA and glycerol from triglyceride) within adipose tissue, dietary sources, and de novolipogenesis (DNL). In contrast, FFA may be utilized either through β-oxidation, re-esterification to triglycerides and storage as lipid droplets, or packaged and exported as very low density lipoprotein (VLDL). Hence hepatic fat accumulation can occur as a result of increased fat synthesis, increased fat delivery, decreased fat export, and/or decreased fat oxidation.
- The traditional 2-hit hypothesis: steatosis represents the ‘first hit’, which then sensitises the liver to injury mediated by ‘second hits’, such as inflammatory cytokines, adipokines, oxidative stress and mitochondrial dysfunction, leading to steatohepatitis and fibrosis. The presence of high levels of oxidative stress reduces the ability of mature hepatocytes to proliferate, resulting in reduced endogenous liver repair.
- Modified 2-hit hypothesis: the accumulation of FFA alone has been suggested to be sufficient to induce liver damage, without recourse for a second hit. Indeed, rather than being harmful, triglyceride accumulation in the form of steatosis may actually be protective by preventing FFA-induced inflammation and oxidative stress.
- The 3-hit hypothesis: oxidative stress reduces the ability of mature hepatocytes to proliferate, resulting in the recruitment of other pathways of liver regeneration, such as HPCs. These cells have the capability of differentiating into both cholangiocytes and hepatocytes and contributing to liver repair. It has been suggested that an inability to mount such a ductular response, as is seen in patients transplanted for NASH who have denervated livers, may be responsible for a more progressive pattern of liver damage. Thus, impaired proliferation of hepatocyte progenitors represents the proposed ‘third hit’ in NAFLD pathogenesis.
- India is known as diabetic capital of world. In general population: 9-32 % have NAFLD. In T2 DM patients, 56.5% have NAFLD, and 60% are female. It is related to age proportionally. 25-50 year: 45.8% 61-70 year: 61.8%
- A retrospective study was done from JAN 2012 – 2013 among 59227 patients who visited hepatology dept of different hospital. Prevalence of NAFLD was 1.1- 7.6 % in the pt’s who were suffering from liver disease. another study was done in 2013 with 493 NAFLD patients, where NASE was absent: 10%, borderline: 52.6%, present: 42.4%. Another study was done in DMCH, where this fraction was 13 %.
- another study was done in 2013 with 493 NAFLD patients, where NASH was absent: 10%, borderline: 52.6%, present: 42.4%. It implicate that patients usually present at late, where NAFLD progress to its complication.
- Physical examination may reveal an enlarged liver. Otherwise, it may require the development of cirrhosis to elicit abnormalities on physical examination. These may initially include jaundice or a yellowish tinge to the skin and eyes, muscle wasting, hair thinning, spider angiomata, and splenomegaly etc.
- a–d Severe diffuse fatty liver disease. a Ultrasound image in a 58-year-old man known for intraductal papillary mucinous neoplasm (IPMN/IPMT) of the pancreas and alcoholic pancreatitis showing a hyperechoic liver compared with the right renal cortex. b CT, axial contrast-enhanced portal phase image shows a diffusely hypodense liver (42 HU) compared with the spleen (113 HU) (>25 HU difference). MRI, c axial T1-weighted in-phase and d out-of-phase images show an important signal drop of the liver on the opposed-phase image. MR images were obtained on a 1.5-T MRI system with TEs of 2.2 and 4.5 for in- and out-of-phase images respectively
- Three subjects with different intrahepatic lipid contents are compared. The subject in row (a) shows intrahepatic lipid content of about 20%; the subject in row (b) shows intrahepatic lipid content of about 10%; and the subject in row (c) shows intrahepatic lipid content in the normal range (about 1%). The figure shows IP (column I) and OP (column II) images of a T1-weighted gradient echo sequence. Column III shows the results of a fat-selective spectral-spatial imaging sequence, and column IV shows the results from single-volume 1H-MRS using a STEAM sequence.
- The presence of metabolic syndrome and the NAFLD Fibrosis Score may be used for identifying patients who are at risk for steatohepatitis and advanced fibrosis.
- There is an active search for more practical ways to study the large numbers of patients with NAFLD and T2DM. Efforts include the use of plasma biomarkers and imaging by transient elastography. A promising biomarker is the measurement of plasma cytokeratin-18 fragments (marker of hepatocyte apoptosis), which has been reported to be increased in patients with NASH compared to those with simple steatosis or normal livers and reduced with pioglitazone treatment in association with histological improvement. The use of transient elastography has recently shown a good correlation between liver ‘stiffness’ by this imaging technique and fibrosis stage.
- There isn’t a medication or surgery to treat fatty liver. Instead, recommendations are to reduce the risk factors. These recommendations include: >managing cholesterol >losing weight >controlling blood sugar
- Exercise alone in adults with NAFLD may reduce hepatic steatosis but its ability to improve other aspects of liver histology remains unknown.
- Vitamin E (a-tocopherol) administered at daily dose of 800 IU/day improves liver histology in non-diabetic adults with biopsy-proven NASH and therefore it should be considered as a first-line phar- macotherapy for this patient population. Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.
- Patients with NASH cirrhosis should be screened for gastroesophageal varices according to the AASLD/ACG practice guidelines. Patients with NASH cirrhosis should be considered for HCC screening according to the AASLD/ACG practice guidelines.