Non-alcoholic fatty liver disease overview
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Editor in Chief: Elliot Tapper, M.D., Beth Israel Deaconess Medical Center, C. Michael Gibson, M.S., M.D. [1]
Overview
Nonalcoholic fatty liver disease [NAFLD] is due to the deposition of extra fat in liver cells that is not caused by alcohol. It is normal for the liver to contain some fat. However, when there is more than 5 -10 percent of the liver’s weight is fat, then it is called a fatty liver (steatosis).NAFLD is marked by inflammation that can progress to irreversible damage.NAFLD is similar to the damage caused by alcohol consumption in most of the cases. It is estimated that in united states approximately 80 to 100 million people are affected with NAFLD. NAFLD most commonly affects people in the age group 2-19 and 40-50 years.It is most commonly seen in Hispanic population when compared to Caucasian and African American populations.
Historical Perspective
- NAFLD is relatively new concept first introduced in 1980.
Classification
- Based on histology it is classified into the non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH).NAFL mostly considered as a benign condition but recent studies show it can progress to NASH up to 44%. The more severe form of NAFLD is called non-alcoholic steatohepatitis (NASH).[1]
- One of the leading cause for cirrhosis in adults in united states is NASH. Almost 25 percent of adults with NASH may lead to cirrhosis.
- On the other hand, NASH progress to fibrosis that can lead to cirrhosis and hepatocellular cancer (HCC).[2]
- Rate of progression does not correlate with body mass index (BMI) or hyperlipidemia
Pathophysiology
- It is thought that pathophysiology of NAFLD is multifactorial that includes numerous genetic, dietary, metabolic and hormonal factors.
- Most experts believe that NAFLD is a 2 hit hypothesis.
- The first hit resulting in increased fat accumulation especially triglycerides within the hepatocyte and increases the risk of liver injury.
- On the second hit inflammatory cytokines causes mitochondrial dysfunction and oxidative stress which in turn lead to steatohepatitis and/or fibrosis.[3].
- Free fatty acids (FFA) play very crucial role in damaging the liver indirectly by either undergoing β-oxidation or are esterified with glycerol to form triglycerides, leading to hepatic fat accumulation.
- Now there is new evidence that FFA is directly causing the liver damage by increasing the oxidative stress by upregulation of TNF-alpha expression via a lysosomal pathway.
- Oxidative stress inhibits the replication process in the mature hepatocytes, Results in the proliferation of progenitor (oval ) cell population and later they differentiate into hepatocyte-like cells. Now both the oval and hepatocyte-like cells play a very important role in the process of fibrosis and hepatocellular carcinogenesis.[3]
- Alterations in MTP/apoB synthesis and secretion have been implicated as one of the potential mechanisms in the pathogenesis of NAFLD which in turn leads to a decreased capacity for lipid export
- Normally triglycerides are transported from the liver in the form of VLDL particles which are then formed by the incorporation of triglyceride into apolipoprotein B (apoB) by microsomal transfer protein (MTP).[5]
Causes
- Common causes in the development of NAFLD is related to obesity which will result in insulin resistance and metabolic syndrome.[6][7]It is estimated that approximately 80% of the obese people suffer from NAFLD.[8]
- Patients who are having type 2 diabetes mellitus are more prone to develop Nafld[9][10]
- Less commonly Patients with hypertension and dyslipidemia are also associated with developing NAFLD
Differentiating Non-alcoholic fatty liver disease from Other Diseases
Epidemiology and Demographics
Estimates are that between 30 - 90 million Americans have some degree of NAFLD and 5-6% have NASH. [11]In the third National Health and Nutrition Examination Survey (NHANES III), the peak prevalence of NAFLD in men occurred in the fourth decade and in the sixth decade for women.[12][13]
Risk Factors
Screening
Natural History, Complications and Prognosis
NASH may progress to fibrosis and, later, to cirrhosis. Studies of serial liver biopsies estimate a 26-37% rate of hepatic fibrosis and 2-15% rate of cirrhosis in less than 6 years. [14][15][16] In 2001, NASH represented 2.9% of the indications of liver transplantation.[17] The impact of NAFLD is manifest at each step along the spectrum of the disease. Studies in the United States and Sweden have revealed that both simple steatosis as well as steatohepatitis significantly reduce life expectancy, even when the diagnosis is made in children.[18][19]
Diagnosis
Diagnosis Criteria
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alcoholic related diseases
Monitor severity of the disease
| Offer Enhanced Liver Fibrosis Test (ELF) | |||||||||||||||||||||||
| (>10.51) ELF Positive | (<10.51) ELF Negative | ||||||||||||||||||||||
| Indicating advanced fibrosis and risk of progression to cirrhosis | Typically Benign -- Advanced fibrosis unlikely | ||||||||||||||||||||||
| Refer the patient to Heptologist | |||||||||||||||||||||||
- On negative ELF test offer retest for every 3 years for adults and 2 years for children.
History and Symptoms
Most patients with NAFLD have no or few symptoms. Infrequently patients may complain of fatigue, malaise and dull right upper quadrant abdominal discomfort. Mild jaundice can rarely be noticed. More commonly it is diagnosed as a result of abnormal liver function tests during routine blood tests. Often following an asymptomatic course, the disease may present first with cirrhosis and/or the complication of portal hypertension.
Physical Examination
Laboratory Findings
Elevated liver function tests are common. Typically, one finds a 2-4 fold elevation of the ALT above normal limit and an ALT/AST ratio of greater than 1.[20] This ratio is imperfect, as AST tends to rise with the degree of fibrosis.[21] Furthermore,high ALT values within the reference range (less than 40 IU) are still predictive of NAFLD/NASH.[22] Another blood test that can be elevated is the ferritin. Typically, and except in very advanced disease, the liver's synthetic function is intact with normal albumin and INR. When considering NAFLD, other tests are generally performed, including those for associated conditions (e.g. glucose, hemoglobin A1C) and those to distinguish this disease from viral hepatitis. Additionally, autoimmune causes are ruled out with serology. TSH is warranted, as hypothyroidism is more prevalent in NASH patients.[23]
Imaging Findings
CT
Imaging is often ordered in the workup of suspected NAFLD. Ultrasound and computed tomography have sensitivities between 93-100%, but 62-76% positive predictive values. Problematically, ultrasound of fatty liver reveals a hyperechoic echotexture - a so-called 'bright liver' - that can often be indistinguishable from fibrosis and generally cannot reliably delineate NAFLD from NASH.[24] Computed tomography is less sensitive, rarely detecting steatosis when fatty infiltration is less than 33%, but is potentially more specific.[25] Statistics are similar for MRI, however using advanced MR techniques, some groups have been able to both quantify steatosis and differentiate steatohepatitis from steatosis.[26][27]
Other Diagnostic Studies
A biopsy of the liver is still considered the gold standard in diagnosis. This is especially true for those patients with elevated liver enzymes for whom a non-invasive workup is inconclusive; 34% of these patients, in one series, were found to have NASH.[28] Classically, biopsy reveals macrovesicular steatosis, inflammation, ballooning degeneration, zone 3 perivenular/periportal/perisinusoidal fibrosis and, finally, mallory bodies.[29][30] Unfortunately, however, a standard biopsy is only able to sample a volume that is 1/50,000th of the liver, underscoring substantial room for sampling error.
Treatment
Medical Therapy
- Trials are presently being conducted to optimize treatment of NASH. No standard treatment has yet emerged as the gold standard.
- General recommendations include improving metabolic risk factors - weight loss, treating diabetes, managing lipids - and reducing alcohol intake.
- Moringa Oleifera (MO), a plant from the family Moringacea is a major crop in Asia and Africa, the leaves of these plant have been studied extensively and it has shown to be beneficial in NAFLD and in prevention and alleviation of NAFLD.[31]
Surgery
Primary Prevention
Secondary Prevention
References
- ↑ "American Liver Foundation - Non-Alcoholic Fatty Liver Disease".
- ↑ "Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. - PubMed - NCBI".
- ↑ 3.0 3.1 Dowman JK, Tomlinson JW, Newsome PN (2010). "Pathogenesis of non-alcoholic fatty liver disease". QJM. 103 (2): 71–83. doi:10.1093/qjmed/hcp158. PMC 2810391. PMID 19914930.
- ↑ Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ (2004). "Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway". Hepatology. 40 (1): 185–94. doi:10.1002/hep.20283. PMID 15239102.
- ↑ "Apolipoprotein synthesis in nonalcoholic steatohepatitis - Charlton - 2002 - Hepatology - Wiley Online Library".
- ↑ "Nonalcoholic Fatty Liver Disease".
- ↑ Sung KC, Jeong WS, Wild SH, Byrne CD (2012). "Combined influence of insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes". Diabetes Care. 35 (4): 717–22. doi:10.2337/dc11-1853. PMC 3308286. PMID 22338098.
- ↑ "Nonalcoholic fatty liver disease".
- ↑ "Nonalcoholic Fatty Liver Disease".
- ↑ "Nonalcoholic Fatty Liver Disease & NASH | NIDDK".
- ↑ McCullough, AJ. Thiazolidinediones for NASH. NEJM 2006;355(22):2361-2363.
- ↑ Ong JP et al. Epidemiology and Natural History of NAFLD and NASH. Clin Liver Dis 11 (2007) 1–16
- ↑ Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the united states. Gastroenterology 2003;124(1):71–9.
- ↑ Adams LA, Sanderson S, Lindor KD, et al. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005;42(1):132–8.
- ↑ Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease:a clinical histopathological study. Am J Gastroenterol 2003;98(9):2042–7.
- ↑ Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865-73.
- ↑ Charlton M et al. Frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease. Liver Transpl 2001;7:608-614
- ↑ Adams et al. The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study. GASTROENTEROLOGY 2005;129:113–121
- ↑ Feldstein AE et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 2009;58:1538–1544
- ↑ Powell et al. The Natural History of Nonalcoholic Steatohepatitis: A Follow-up Study of Forty-two Patients for Up to 21 YearsHEPATOLOGY 1990; 11: 74-80
- ↑ Sorbi et al. The Ratio of Aspartate Aminotransferase to Alanine Aminotransferase: Potential Value in Differentiating Nonalcoholic Steatohepatitis From Alcoholic Liver DiseaseAm J Gastroenterol 1999;94:1018–1022
- ↑ Chang Y et al. Higher Concentrations of Alanine Aminotransferase within the Reference Interval Predict Nonalcoholic Fatty Liver Disease. Clinical Chemistry 2007;53(4):686–692
- ↑ Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol 2003;37:340-3. PMID 14506393
- ↑ MIshra P et al. Abdominal Ultrasound for Diagnosis of Nonalcoholic Fatty Liver Disease (NAFLD). Am J Gastroenterol 2007;102:2716–2717).
- ↑ Saadeh et al. The Utility of Radiological Imaging in Nonalcoholic Fatty Liver Disease. GASTROENTEROLOGY 2002;123:745–750
- ↑ Taouli B et al. Advanced MRI Methods for Assessment of Chronic Liver Disease. AJR 2009; 193:14–27.
- ↑ McPherson S et al. Magnetic resonance imaging and spectroscopy accurately estimate the severity of steatosis provided the stage of fibrosis is considered. J Hepatol. 2009;51(2):389-97
- ↑ Skelly et al. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol 2001;35:195-9
- ↑ Angula P. Nonalcoholic Fatty Liver Disease. NEJM. 2002 346(16):1221-31
- ↑ Brunt EM, Janney CG, Di Bisceglie AM et al. Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions. Am. J. Gastroenterol. 1999; 94(9):2467-2474
- ↑ Vergara-Jimenez M, Almatrafi MM, Fernandez ML (2017). "Bioactive Components in Moringa Oleifera Leaves Protect against Chronic Disease". Antioxidants (Basel). 6 (4). doi:10.3390/antiox6040091. PMID 29144438.