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Non Alcoholic Fatty Liver Disease (NAFLD)

Definition:

A condition where liver is accumulated with fat and usually associated with metabolic conditions. Risk factors for NAFLD included obesity, diabetes and dyslipidemia. During the last decade NAFLD has reached epidemic proportions even in pediatric population.

Categories:

NAFLD is sub categorixed into non alcoholic fatty liver (NAFL) and non alcoholic steatohepatosis (NASH). NAFL has just fat accumulation whereas NASH has fat as well as inflammation of the liver tissues.

Prevalence of NAFLD:

Prevalence varies widely and it depends on age, sex and race of the population. Studies show that men are at highest risk for NAFLD, 31% in men Vs 16% in women. Compared to non-Hispanic whites, Hispanics have higher prevalence of NAFLD.

Who are at High Risk:

People with the following conditions are at high risk to develop NAFLD:

Obesity, type 2 diabetes mellitus, dyslipidemia, Hypothyroidism, Obstructive Sleep apnea, Hypopituitarism, Hypogonadism, Pancreato-duodenal resection.

When to Obtain a Liver Biopsy in Patients with NAFLD?

Liver biopsy will be needed when the diagnosis of liver disease is uncertain and other causes need to be ruled out.

Is there a screening test?!

Due to the increased morbidity and mortality, a screening test if present will be helpful. But, in most cases liver function will be normal and cannot be a good sensitive test. USG of liver will give more helpful information about the liver but it is expensive making screening test less affordable. So, high risk patients are offered USG of liver.

Management of NAFLD:

Initial step - Making the diagnosis:

1. Diagnosis of NAFLD requires that (a) there is hepatic steatosis by imaging or histology, (b) there is no significant alcohol consumption, (c) there are no other causes for hepatic steatosis, and (d) there are no co-existing causes for chronic liver disease.

2. Exclude other causes of hepatic steatosis like significant alcohol consumption, hepatitis C, medications, parenteral nutrition, Wilson’s disease, and severe malnutrition, other chronic liver disease including hemochromatosis, autoimmune liver disease and chronic viral hepatitis.

3. Liver biopsy is the gold standard for characterizing liver histology in patients with NAFLD. Due to procedural risk, cost, it should be performed in those who would benefit the most from diagnostic, therapeutic guidance, and prognostic perspectives.

Treatment:

Treatment of NAFLD includes treating liver disease as well as the associated metabolic co-morbidities such asobesity, hyperlipidemia, insulin resistance and T2DM. As patients with NAFLD without steatohepatitis have excellent prognosis from a liver standpoint, treatments aimed at improving liver disease should be limited to those with NASH. Lifestyle modification will reduce aminotransferases and improve hepatic steatosis when measured by ultrasound. Exercise programs consisted of 2 to 3 sessions a week of 30 – 60 minutes over a period of 6 to 12 weeks and showed liver fat content diminished without a significant change in body weight.

Effect of exercise and diet on NAFLD:

Studies have shown that weight loss generally reduces hepatic steatosis evidenced by USG/imaging studies. It can be done by low caloric diet alone or with increased physical activity. Loss of at least 3–5% of body weight appears to improve steatosis, but a greater weight loss (up to 10%) may be needed to improve necroinflammation. Exercise alone in adults with NAFLD may reduce hepatic steatosis.

Role of metformin in NASH:

Role of metformin is unclear NAFLD. Few studies have shown that metformin might help NASH and decrease aminotranferase levels. However, a open label study found that Metformin has no significant effect on liver histology and is not recommended as a specific treatment for liver disease in adults with NASH.

Pioglitazone and NASH:

Pioglitazone can be used to treat steatohepatitis in patients with biopsy-proven NASH. But, the caveat in the study which showed the benfit is that majority of the patients who took pioglitazone for NASH were non- diabetic and that long term safety and efficacy of this drug in patients with NASH is not established.

Oxidative stress and Vitamin E:

Vitamin E changes the liver histology in non-diabetic adults with biopsy-proven NASH and therefore it should be considered as a first-line pharmacotherapy for this patient population. However, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.

Other treatment considerations for NASH:

Statins can be used to treat dyslipidemia in patients with NAFLD and NASH. Until RCTs with histological endpoints prove their efficacy, statins should not be used to specifically treat NASH.

Ursodeoxy cholic acid is not recommended for the treatment of NAFLD or NASH.

Omega-3 fatty acids is not recommended for the specific treatment of NAFLD or NASH but they may be considered as the first line agents to treat hypertriglyceridemia in patients with NAFLD.

Patients with NAFLD should not consume heavy amounts of alcohol.

Foregut bariatric surgery is not contraindicated in otherwise eligible obese individuals with NAFLD or NASH (but with- out established 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. Do need to repeat liver biopsy in patients with NAFL or NASH.

To see a Specialist:

Patients with steatohepatitis on liver biopsy be followed by a hepatologist.

Patients with nonalcoholic fatty liver without steatohepatitis can be followed by a primary care physician, provided the diagnosis is clear.

Patients who develop cirrhosis and have complications (eg, ascites, variceal bleeding) or a model for end-stage liver disease (MELD) score ≥10 will be referred for a liver transplantation evaluation.

Management of Gastroparesis

What is Gastroparesis?

Gastroparesis is slow emptying of the gastric contents presenting as nausea, vomiting, early satiety, and postprandial fullness. Many patients may be asymptomatic.

Epidemiology: Difficult to estimate its true prevalence due to asymptomatic in many people and its vague presentation common to many other diseases like nausea, vomiting. One study estimates the prevalence as 20 to 40 percent of diabetic patients might have gastroparesis.

Clinical Presentation:

Symptoms can be nausea, vomiting, early satiety, bloating and postprandial fullness

Diagnosis of Gastroparesis:

Diagnosis of gastroparesis is based on the combination of symptoms of gastroparesis, absence of gastric outlet obstruction or ulceration, and delay in gastric emptying.

Delay in gastric emptying need to be confirmed is required for the diagnosis of gastroparesis. Scintigraphic gastric emptying of solids is the standard for the evaluation of gastric emptying and the diagnosis of gastroparesis.  e most reliable method and parameter for diagnosis of gastroparesis is gastric retention of solids at 4 h measured by scintigraphy. Studies of shorter duration or based on a liquid challenge result in decreased sensitivity in the diagnosis of gastroparesis.

Rule out other condition that can cause Gastroparesis:

Condition that can mimick gastroparesis like thyroid dysfunction, neurological disease, prior gastric or bariatric surgery, and autoimmune disorders should be ruled out before diagnosing and treating gastroparesis.

Diabetes and Gastroparesis:

Markedly uncontrolled ( > 200 mg / dl) glucose levels may aggravate symptoms of gastroparesis and delay gastric emptying. Hence, good glycemic control should be a target for therapy; this may improve symptoms and the delayed gastric emptying.

Medication and Gastroparesis:

Medication-induced delay in gastric emptying, particularly from narcotic and anticholinergic agents and GLP-1 and amylin analogs among diabetics, should be considered in patients before assigning an etiological diagnosis. Narcotics and other medications that can delay gastric emptying should be stopped to establish the diagnosis with a gastric emptying test.

Gastroparesis can be associated with and may aggravate GERD. Evaluation for the presence of gastroparesis should be considered in patients with GERD that is refractory to acid-suppressive treatment.

Alternative approaches for assessment of gastric emptying include wireless capsule motility testing and 13 C breath testing using octanoate or spirulina incorporated into a solid meal; they require further validation before they can be considered as alternates to scintigraphy for diagnosis of gastroparesis.

Medications that a ect gastric emptying should be stopped at least 48 h before diagnostic testing; depending on the pharmacokinetics of the medication, the drug may need to be stopped > 48 h before testing. (Strong recommendation, high level of evidence) 11. Patients with diabetes should have blood glucose measured before starting the gastric emptying test, and hyperglycemia treated with test started a er blood glucose is < 275 mg / dl. (Strong recommendation, moderate-high level of evidence) 12.  e presence of rumination syndrome and / or eating disorders (including anorexia nervosa and bulimia) should be considered when evaluating a patient for gastroparesis.  ese disorders may be associated with delayed gastric emptying, and identi-  cation of these disorders may alter management. (Strong recommendation, moderate-high level of evidence) 13. CVS de ned as recurrent episodic episodes of nausea and vomiting should also be considered during the patient history.  ese patients may require alternative therapy. (Conditional recommendation, moderate level of evidence) 14. Chronic usage of cannabinoid agents may cause a syndrome similar to CVS. Patients presenting with symptoms of gastroparesis should be advised to stop usage of these agents. (Conditional recommendation, low level of evidence) 15.  e  rst line of management for gastroparesis patients should include restoration of  uids and electrolytes, nutritional support and in diabetics, optimization of glycemic control. (Strong recommendation, moderate level of evidence) 16. Oral intake is preferable for nutrition and hydration. Patients should receive counseling from a dietician regarding consumption of frequent small volume nutrient meals that are low in fat and soluble  ber. If unable to tolerate solid food, then use of homogenized or liquid nutrient meals is recommended. (Conditional recommendation, low level of evidence) 17. Oral intake is the preferable route for nutrition and hydration. If oral intake is insu cient, then enteral alimentation by jejunostomy tube feeding should be pursued (a er a trial of nasoenteric tube feeding). Indications for enteral nutrition include unintentional loss of 10 % or more of the usual body weight during a period of 3 – 6 months, and / or repeated hospitalizations for refractory symptoms. (Strong recommendation, moderate level of evidence) 18. For enteral alimentation, postpyloric feeding is preferable to gastric feeding because gastric delivery can be associated with erratic nutritional support. (Conditional recommendation, low level of evidence) 19. Enteral feeding is preferable to parenteral nutrition. (Conditional recommendation, low level of evidence) 20. Good glycemic control should be the goal. Since acute hyperglycemia inhibits gastric emptying, it is assumed that improved glycemic control may improve gastric emptying and reduce symptoms. (Conditional recommendation, moderate level of evidence) 21. Pramlintide and GLP-1 analogs may delay gastric emptying in diabetics. Cessation of these treatments and use of alternative approaches should be considered before initiation of therapy for gastroparesis. (Conditional recommendation, low level of evidence) 22. In addition to dietary therapy, prokinetic therapy should be considered to improve gastric emptying and gastroparesis symptoms, taking into account bene ts and risks of treatment. (Strong recommendation, moderate level of evidence) 23. Metoclopramide is the  rst line of prokinetic therapy and should be administered at the lowest e ective dose.  e risk of tardive dyskinesia has been estimated to be < 1 % . Patients should be instructed to discontinue therapy if they develop side e ects including involuntary movements. (Moderate recommendation, moderate level of evidence) 24. For patients unable to use metoclopramide, domperidone can be prescribed with investigational new drug clearance from the FDA and has been shown to be as e ective as metoclopramide in reducing symptoms without the propensity for causing central nervous system side e ects; given propensity of domperidone to prolong corrected QT interval on electrocardiogram, a baseline electrocardiogram is recommended and Clinical Guideline: Management of Gastroparesis - ajg2012373... https://dl.dropbox.com/s/s4f74j3sdn3fwqe/ajg2012373a.pdf?to... 16 of 20 3/24/13 12:13 PM The American Journal of GASTROENTEROLOGY VOLUME 108 | JANUARY 2013 www.amjgastro.com 34 Camilleri et al . Rhythm. Dr Abell NIH GPCRC is an investigator, consultant, and licensor for Medtronic; is a consultant and investigator for Rhythm. Dr Sha has received support from Salix Pharmaceuticals. Dr Gerson is a consultant for Takeda, Santarus, and IntroMedic . REFERENCES 1 . Grades of Recommendation, Assessment, Development, Evaluation (GRADE) Working Group . Grading quality of evidence and strength of recommendations . BMJ 2004 ; 328 : 1490 – 4 . 2 . Camilleri M , Bharucha AE , Farrugia G . Epidemiology, mechanisms, and management of diabetic gastroparesis . Clin Gastroenterol Hepatol 2011 ; 9 : 5 – 12 . 3 . Tack J , Bisschops R , Sarnelli G . Pathophysiology and treatment of functional dyspepsia . Gastroenterology 2004 ; 127 : 1239 – 55 . 4 . Sarnelli G , Caenepeel P , Geypens B et al. Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia . Am J Gastroenterol 2003 ; 98 : 783 – 8 . 5 . Choung RS , Locke GR III , Schleck CD et al. Risk of gastroparesis in subjects with type 1 and 2 diabetes in the general population . Am J Gastroenterol 2012 ; 107 : 82 – 8 . 6 . Talley NJ , Young L , Bytzer P et al. Impact of chronic gastrointestinal symptoms in diabetes mellitus on health-related quality of life . Am J Gastroenterol 2001 ; 96 : 71 – 6 . 7 . Punkkinen J , F ä rkkil M , M ä tzke S et al. Upper abdominal symptoms in patients with Type 1 diabetes: unrelated to impairment in gastric emptying caused by autonomic neuropathy . Diabet Med 2008 ; 25 : 570 – 7 . 8 . Hyett B , Martinez FJ , Gill BM et al. Delayed radionucleotide gastric emptying studies predict morbidity in diabetics with symptoms of gastroparesis . Gastroenterology 2009 ; 137 : 445 – 52 . 9 . Jung HK , Choung RS , Locke GR III et al.  e incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006 . Gastroenterology 2009 ; 136 : 1225 – 33 . 10 . Parkman HP , Yates K , Hasler WL et al. Similarities and di erences between diabetic and idiopathic gastroparesis . Clin Gastroenterol Hepatol 2011 ; 9 : 1056 – 64 . 11 . Cherian D , Parkman HP . Nausea and vomiting in diabetic and idiopathic gastroparesis . Neurogastroenterol Motil 2012 ; 24 : 217 – e103 . 12 . Cherian D , Sachdeva P , Fisher RS et al. Abdominal pain is a frequent symptom of gastroparesis . Clin Gastroenterol Hepatol 2010 ; 8 : 676 – 81 . 13 . Hasler WL , Wilson L , Parkman HP et al. Importance of abdominal pain as a symptom in gastroparesis: relation to clinical factors, disease severity, quality of life, gastric retention, and medication use . Gastroenterology 2010 ; 138 (Suppl 1) : S-461 . 14 . Hasler WL , Parkman HP , Wilson LA et al. Psychological dysfunction is associated with symptom severity but not disease etiology or degree of gastric retention in patients with gastroparesis . Am J Gastroenterol 2010 ; 105 : 2357 – 67 . 15 . Maleki D , Locke III GR , Camilleri M et al. Gastrointestinal tract symptoms among persons with diabetes mellitus in the community . Arch Intern Med 2000 ; 160 : 2808 – 16 . 16 . Bredenoord AJ , Chial HJ , Camilleri M et al. Gastric accommodation and emptying in evaluation of patients with upper gastrointestinal symptoms . Clin Gastroenterol Hepatol 2003 ; 1 : 264 – 72 . 17 . Parkman HP , Yates K , Hasler WL et al. Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity . Gastroenterology 2011 ; 140 : 101 – 15 . 18 . Soykan I , Sivri B , Sarosiek I et al. Demography, clinical characteristics, psychological pro les, treatment and long-term follow-up of patients with gastroparesis . Dig Dis Sci 1998 ; 43 : 2398 – 404 . 19 . Bityutskiy LP , Soykan I , McCallum RW . Viral gastroparesis: a subgroup of idiopathic gastroparesis — clinical characteristics and long-term outcomes . Am J Gastroenterol 1997 ; 92 : 1501 – 6 . 20 . Vassallo M , Camilleri M , Caron BL et al. Gastrointestinal motor dysfunction in acquired selective cholinergic dysautonomia associated with infectious mononucleosis . Gastroenterology 1991 ; 100 : 252 – 8 . 21 . Debinski HS , Kamm MA , Talbot IC et al. DNA viruses in the pathogenesis of sporadic chronic idiopathic intestinal pseudo-obstruction . Gut 1997 ; 41 : 100 – 6 . 22 . Frantzides CT , Carlson MA , Zografakis JG et al. Postoperative gastrointestinal complaints a er laparoscopic Nissen fundoplication . JSLS 2006 ; 10 : 39 – 42 . treatment withheld if the corrected QT is > 470 ms in male and 450 ms in female patients. Follow-up electrocardiogram on treatment with domperidone is also advised. (Moderate recommendation, moderate level of evidence) 25. Erythromycin improves gastric emptying and symptoms from delayed gastric emptying. Administration of IV erythromycin should be considered when IV prokinetic therapy is needed in hospitalized patients. Oral treatment with erythromycin improves gastric emptying also. However, the long-term e ectiveness of oral therapy is limited by tachyphylaxis. (Strong recommendation, moderate level of evidence) 26. Treatment with antiemetic agents should occur for improvement of associated nausea and vomiting but will not result in improved gastric emptying. (Conditional recommendation, moderate level of evidence) 27. TCA can be considered for refractory nausea and vomiting in gastroparesis but will not result in improved gastric emptying and may potentially retard gastric emptying. (Conditional recommendation, low level of evidence) 28. Intrapyloric injection of botulinum toxin is not recommended for patients with gastroparesis based on randomized controlled trials. (Strong recommendation, high level of evidence) 29. GES may be considered for compassionate treatment in patients with refractory symptoms, particularly nausea and vomiting. Symptom severity and gastric emptying have been shown to improve in patients with DG, but not in patients with IG or PSG. (Conditional recommendation, moderate level of evidence) 30. Gastrostomy for venting and / or jejunostomy for feeding may be performed for symptom relief. (Conditional recommendation, low level of evidence) 31. Completion gastrectomy could be considered in patients with PSG who remain markedly symptomatic and fail medical therapy. (Conditional recommendation, low level of evidence) 32. Surgical pyloroplasty or gastrojejunosotomy has been performed for treatment for refractory gastroparesis. However, further studies are needed before advocating this treatment. Partial gastrectomy and pyloroplasty should be used rarely, only in carefully selected patients. 33. Acupuncture can be considered as an alternative therapy.  is has been associated with improved rates of gastric emptying and reduction of symptoms.