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Related Subjects: | Chronic liver disease | Cirrhosis | Alkaline phosphatase (ALP) | Liver Function Tests | Ascites Assessment and Management | Budd-Chiari syndrome | Autoimmune Hepatitis | Primary Biliary Cirrhosis | Primary Sclerosing Cholangitis | Wilson disease | Hereditary Haemochromatosis | Alpha-1 Antitrypsin (AAT) deficiency | Non alcoholic steatohepatitis (NASH) | Spontaneous Bacterial Peritonitis | Alcoholism and Alcoholic Liver Disease | Liver Transplantation

NASH is a diagnosis of exclusion once viral, alcohol and other causes of liver disease are excluded. It is the main cause of previously termed cryptogenic cirrhosis. There is a risk of hepatocellular cancer

About

• Fat is deposited within the liver
• Abnormal LFTs and liver biopsy in whom alcohol intake is not to blame

Defining

• Fatty liver and no inflammation: Non-alcoholic fatty liver (NAFL)
• Fatty liver and inflammation : Non-alcoholic steatohepatitis (NASH)
• Both can progress to cirrhosis

Histology

• NAFL: macro vesicular steatosis
• NASH: steatosis, inflammation, ballooning, Mallory's hyaline, fibrosis, cirrhosis, liver failure

Incidence

• NAFLD is seen in 20-30% of population
• The most common liver disease in the world
• High prevalence in the obese, T2DM populations
• It is probably underestimated as a cause for cirrhosis.
• USA NAFLD seen in 35% population and 2-7% NASH and matches with obesity

Associations

• Central "apple type" obesity, insulin resistance
• Type 2 diabetes mellitus or prediabetes
• Dyslipidaemia and Insulin resistance
• Hypertension, Metabolic syndrome
• Minor associations: HIV (Disease or medications), Hispanic, Sleep apnoea, Hypothyroidism, PCOS

Risks of progression

• Obesity BMI > 30 kg/m2
• Type 2 Diabetes mellitus
• Aged 45-50+
• AST/ALT > 1

Pathophysiology

• Two hit hypothesis states that dysregulation of fatty acid metabolism leads to steatosis, which is the first hepatic insult in NAFLD. Steatosis is associated with several cellular adaptations and altered signalling pathways, which render hepatocytes vulnerable to a second hit.
• The second insult may be one or more environmental or genetic perturbations, which cause hepatocyte necrosis and inflammation and activate the fibrogenic cascade, thereby leading to fibrosis and cirrhosis in a minority of patients with NAFLD

Differential to exclude

• Alcoholic liver disease: Less than 2 drinks per day
• Exclude Prednisone and Tamoxifen and Amiodarone
• Hepatitis B/C but may have both
• Alpha 1 antitrypsin, Wilson's disease, Haemochromatosis

Clinical

• Largely asymptomatic noted only on blood test
• Obesity, Fatigue, Hepatomegaly
• Pain in RUQ may suggest liver capsule stretch
• Liver disease, sleep apnoea is common
• Liver failure and transplant evidence
• Commonly have heart disease and cancers

Progression assessed by biopsy/Fibroscan

• No fibrosis F0 ? Initial F1 ? Intermediate F2 ? Advanced F3 ? Cirrhosis F4
• NASH takes 7 years for each stage (28 years in total)
• NAFL takes 14 years for each stage (56 years in total)
• Hepatocellular cancer x 7 risk even without cirrhosis

Investigations

• FBC,U&E, AST/ALT less than x 2 upper limit (ALT>AST) and may be normal
• Fatty liver seen on USS and MRI and CT
• The ELF test is a non-invasive blood test that measures three direct markers of fibrosis: hyaluronic acid (HA), procollagen III amino-terminal peptide (PIIINP), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). The ELF test, in conjunction with other laboratory and clinical findings, can be used to assess the risk of progression to cirrhosis and LREs in patients with chronic liver disease. Diagnose people with advanced liver fibrosis if they have an ELF score of 10.51 or above and NAFLD.
• Liver biopsy to assess NASH vs NAFLD, To assess fibrosis and exclude other causes in high risk patients. Issues are that disease may over/underestimate disease which may be patchy. Patients are often obese so challenging procedure. Can be expensive and has risks including death in a small number.
• Transient elastography (Fibroscan): based on USS and helps to show how stiff the liver is and so how fibrosed. Can be inaccurate with recent alcohol, fatty can overestimate fibrosis. Operator experience.

Be aware that in people with type 2 diabetes, NAFLD is a risk factor for atrial fibrillation, myocardial infarction, ischaemic stroke and death from cardiovascular causes.

Management

• Dietary advice for "Metabolic syndrome". Avoid fruit juice or carbonated sugar beverages. Exercise 2 hours slit between 3 times per week.
• Loose weight - this is key even gastric banding and other bariatric surgery needs to loose 7-10% weight
• Pioglitazones for those with T2DM
• Be aware that people with NAFLD who are taking statins should keep taking them. Only consider stopping statins if liver enzyme levels double within 3 months of starting statins, including in people with abnormal baseline liver blood results.
• Vitamin E 800 IU/day recently shown to be beneficial
• Liver transplant even for those with HCC

References

• Non-alcoholic fatty liver disease (NAFLD): assessment and management NICE guideline [NG49]Published date: 06 July 2016
• Nonalcoholic Fatty Liver Disease: Review