Non-alcoholic fatty liver disease
Editor in Chief: Elliot Tapper, M.D., Beth Israel Deaconess Medical Center
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Overview and Impact
Template:DiseaseDisorder infobox
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease in the absence of excessive alcohol use that begins as fatty accumulation in the liver (hepatic steatosis). A fatty liver does not necessarily disturb the function of the liver, but by varying mechanisms and insults, it may progress to inflammation of the liver. When inflammation occurs in this setting, the condition is then called NASH - Non-alcoholic steatohepatitis. NASH, in turn, may progress to fibrosis and, later, cirrhosis. Studies of serial liver biopsies estimate a 26-37% rate of hepatic fibrosis and 2-9% rate of cirrhosis in less than 6 years. [1][2] At present, estimates are that between 30- 90 million Americans have some degree of NAFLD and 5-6% have NASH. [3]
NAFLD/NASH was first described in a 1980 series of obese, non-alcoholic patients of the Mayo Clinic.[4] Since that seminal description, our understanding of NAFLD has progressed minimally. [5] The disease is most closely associated with the increasing obesity, insulin resistance, type two diabetes mellitus and hyperlipedmia endemic to the developed world. Roughly half of all patients with NAFLD, however, do not meet criteria for metabolic syndrome. [6]
Epidemiology
Estimates are that between 30- 90 million Americans have some degree of NAFLD and 5-6% have NASH. [3] A Japanese study estimates the prevalence of NAFLD in that country at 31 per 1000 and found an incidence of approximately 10% - 308 new cases of NAFLD in a group of 3,147 patient followed over 414 days.[7]. 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.[8][9]
Some have suggested a genetic or sociocultural component to NAFLD spectrum disease.[10] As a part of the Dallas Heart Study,[11] 2,240 patients - 1,105 african-americans, 401 hispanics and 734 caucasians - received abdominal MRI's from which we can infer the presence of steatosis. Hepatic steatosis was found in 45% of hispanics (both men and women), 33% of caucasians (42% of men, 24% of women) and 24% of african-american (23% of men, 24% of women). This pattern may hold true in children as well. In a San Diego study of 742 consecutive autopsies of children victims of trauma over 10 years, fatty liver was found in 9.6% of all children, 38% of the obese, 12% of hispanics, 10% of asians, 8.6% of caucasians and 1.5% of african-americans.[12]
Pathophysiology
The exact cause is still unknown. However both obesity and insulin resistance likely play a strong role in this disease process. The exact reasons and mechanisms by which this disease progresses from one entity to the next is a subject of much research and debate. One such debated mechanisim proposes a "second hit", or further injury, enough to cause change that leads from hepatic steatosis to hepatic inflammation. Oxidative stress, hormonal imbalances and mitochondrial abnormalities may be potential causes for this "second hit" phenomenon.
Secondary causes
NAFLD can also be caused by the following medications (termed secondary NAFLD):
- Amiodarone
- Antiviral drugs (nucleoside analogues)
- Aspirin / NSAIDS
- Corticosteroids
- Methotrexate
- Nifedipine
- Perhexiline
- Tamoxifen
- Tetracycline
- Valproic acid
Signs, Symptoms and associations
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. In that respect, NASH is becoming an increasingly common indication for liver transplantation. [13] As awareness of this condition spreads, it has been regarded as a major cause of cryptogenic cirrhosis of the liver.[14] The diagnosis of cryptogenic cirrhosis is usually made in patients with similar clinical characteristics to those with NAFLD spectrum disease. Cryptogenic cirrhotics tend to be women, aged 63 (+/- 11) years who are obese and type 2 diabetics. [10]. Moreover, there are case reports of patients with NASH who received serial liver biopsies where there was a progression to cirrhosis with a dissapearance of the histologcal stigmatia of NASH. Without the index biopsy, these patients' cirrhosis would have been classified as cryptogenic.[15][16]
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.[17]
Diagnosis
Disturbed liver enzymes are common. Typically, one finds a 2-4 fold elevation of the ALT above normal limit and an AST/ALT ratio of less than 1. 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. Imaging is often ordered in the workup of suspected NAFLD. Ultrasound has sensitivities approaching 100%, but a 62% positive predictive value. Problematically, ultrasound of fatty liver reveals a hyperechoic echotexture - a so-called 'bright liver' - that can often be indistinguishable from fibrosis. Computed tomography is reported to be 93% sensitive with a 76% positive predictive value. A biopsy of the liver is considered the gold standard in diagnosis. Classically, biopsy reveals macrovesicular steatosis, inflammation, ballooning degeneration, zone 3 perivenular/periportal/perisinusoidal fibrosis and, finally, mallory bodies.[18] [19][16]
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.[20]
Treatment
Trials are presently being conducted to optimise treatment of NASH. No standard treatment has yet emerged as the "gold standard". General recommendations include improving metabolic risk factors and reducing alcohol intake.
A large number of treatments have been studied for NAFLD. While many may improve biochemical markers, such as alanine transaminase levels, most have not been shown to reverse the histological abnormalities or reduce clinical endpoints:[21]
- Weight loss: gradual weight loss, and possibly bariatric surgery, may improve the process in obese patients.
- Insulin sensitisers (metformin and rosiglitazone but more markedly pioglitazone) have shown efficacy in some studies.
- Antioxidants and ursodeoxycholic acid, as well as lipid-lowering drugs, have little benefit.
References
- ↑ 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.
- ↑ 3.0 3.1 McCullough, AJ. Thiazolidinediones for NASH. NEJM 2006;355(22):2361-2363.
- ↑ Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434-438. PMID 7382552.
- ↑ Day, CP. Non-alcoholic steatohepatitis (NASH): where are we now and where are we going? Gut. 2002 May; 50(5): 585–588.
- ↑ Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–S112.
- ↑ Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;143(10):722–8
- ↑ 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.
- ↑ 10.0 10.1 Caldwell et al. Has natural selection in human populations produced two types of metabolic syndrome (with and without fatty liver). J of Gastroenterology and Hepatology 2007;22(S1):S11-S19
- ↑ Browning et al. Prevalence of Hepatic Steatosis in an Urban Population in the United States: Impact of Ethnicity. Hepatology 2004;40:1387-1395.
- ↑ Schwimmer et al. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118;1388-93.
- ↑ Choudhury J, Sanyal A. Clinical Aspects of Fatty Liver Disease. Semin Liver Dis 2004; 24: 349-362.
- ↑ Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 2003;289:3000-4. PMID 12799409.
- ↑ Yoshioka Y, Hashimoto E, Yatsuji S. “NASH: cirrhosis, hepatocellular carcinoma and burnt-out NASH.” J Gastroenterol 2004;39;1215-1218
- ↑ 16.0 16.1 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
- ↑ Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol 2003;37:340-3. PMID 14506393
- ↑
- ↑ Angula P. Nonalcoholic Fatty Liver Disease. NEJM. 2002 346(16):1221-31
- ↑ Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol 2003;37:340-3. PMID 14506393
- ↑
External links
- Medscape article on NASH.
- MEDICINENET article on Steatosis.
- NIH page on Nonalcoholic Steatohepatitis