Fatty Liver and Nonalcoholic Steatohepatitis

Key Points

1
Hepatic steatosis, the accumulation of triglyceride droplets in hepatocytes, is found in one third to one half of all adults in the United States and is an important cause of elevated serum aminotransferase levels (typically <250 U/L).
2
Steatosis without significant inflammation or fibrosis on biopsy is a benign hepatic condition, although it is associated with insulin resistance and indicates an increased risk for development of cardiovascular disease and type 2 diabetes mellitus.
3
Steatosis associated with substantial necroinflammatory changes identified on a liver biopsy specimen, called nonalcoholic steatohepatitis (NASH) when alcohol consumption is minimal or none, can cause progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma.
4
Nonalcoholic fatty liver disease (NAFLD) is the umbrella term that includes both steatosis without inflammation and NASH.
5
A liver biopsy is warranted to diagnose NASH or other causes of occult liver disease when elevated aminotransferase levels are unexplained, especially in a patient with obesity or type 2 diabetes mellitus, because of the risk of advanced fibrosis and cirrhosis.
6
Hepatic steatosis is reliably identified by imaging techniques when the degree of fatty infiltration is substantial. Ultrasonography reveals increased liver echogenicity, whereas noncontrast computed tomography (CT) imaging reveals decreased liver density compared with the spleen. Magnetic resonance imaging (MRI) is the most sensitive test for detecting liver fat.
7
Focal steatosis is a variant typically detected incidentally during imaging of the abdomen. The appearance is usually characteristic, although biopsy confirmation is occasionally required to exclude malignancy when the imaging appearance is atypical.
8
Lipotoxic liver injury caused by metabolites of free fatty acids likely causes NASH; steatosis may be an adaptive mechanism with temporary storage of fatty acids as triglyceride to prevent lipotoxic injury.

Overview

Terminology

1.
Nonalcoholic fatty liver disease (NAFLD) is the term used to describe excessive liver triglyceride accumulation when alcohol consumption is minimal (fewer than two to four drinks daily).
2.
No uniformly accepted term exists for NAFLD that is not NASH; terms such as fatty liver , benign steatosis, simple steatosis, and nonalcoholic fatty liver (NAFL) are commonly used.
3.
NASH is diagnosed when a liver biopsy specimen shows steatosis and characteristic necroinflammatory changes in a patient who has fewer than two to four drinks per day; the presence of fibrosis is not required, but characteristic perisinusoidal fibrosis supports a diagnosis of steatohepatitis.
4.
NASH is not a diagnosis of exclusion; it can often be found in the presence of other liver diseases such as chronic hepatitis C.

Pathogenesis

▪
NASH is thought to be a disease of lipotoxic injury to hepatocytes caused by nontriglyceride metabolites of free fatty acids.
▪
Triglyceride in the lipid droplets may actually be a protective response to store fatty acids in an inert form.
▪
The specific metabolites of free fatty acids that cause lipotoxic injury have not been fully identified. Possibilities include ceramides, diacylglycerols, lysophosphatidylcholine species, omega-oxidized fatty acids, and phosphatidic acid species.

The causes of hepatic lipotoxicity are attributable to one or more of the following abnormalities in the trafficking of fatty acids in the body:

Increased Peripheral Mobilization of Fatty Acids

▪
Adipose tissue releases free fatty acids in response to cyclic adenosine monophosphate (cAMP)–mediated signaling from glucagon, epinephrine, and adrenocorticotropic hormone; released fatty acids are transported to the liver bound to albumin in the circulation.
▪
Insulin is a major inhibitory signal that normally prevents adipose tissue lipolysis after meals; adipocyte insulin resistance allows inappropriate postprandial lipolysis in adipose tissue with release of free fatty acids into the circulation.
▪
Prolonged starvation is associated with appropriate release of fat from peripheral stores that can overwhelm the liver’s ability to handle it, thereby leading to steatosis and NASH.

Increased Hepatic Synthesis of Fatty Acids

▪
The liver disposes of excess carbohydrates, especially fructose, by converting carbohydrate to fatty acids through de novo lipogenesis.
▪
Excess carbohydrates from dietary sources (e.g., sugar-sweetened beverages) or provided parenterally (e.g., total parenteral nutrition) predispose to hepatic lipotoxicity.

Impaired Hepatic Catabolism of Fatty Acids

▪
Impaired mitochondrial beta-oxidation of fatty acids is a major factor in alcoholic steatosis and has also been shown to contribute to the development of NASH.
▪
Factors that cause microvesicular steatosis may do so through impaired mitochondrial function (e.g., valproic acid, alcohol, acute fatty liver of pregnancy).
▪
Other oxidative pathways (cytochrome P-450 omega-oxidation, peroxisomal beta-oxidation) facilitate disposal of fatty acids.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here