Nonalcoholic fatty liver disease (NAFLD) has escalated to the number one liver disease in the United States.  No longer just “fatty liver, or fatty liver with focal sparing” noted as almost an afterthought on imaging reports, it has now become an epidemic problem with potential for very real morbidity and mortality.  Afflicting children and adults, its pathogenesis is multifactorial, but its increase prevalence strongly concides with the mounting Western obesity rate.  This issue of  The WCC Note commences a two-part series on hepatic steatosis, beginning with reviews of its prevalence, pathology, and clinical consequences.
 

How is nonalcoholic fatty liver disease defined?

1.  NAFLD is defined as macrovesicular steatosis in more
than 5% of hepatocytes (1) in the absence of significant
ethol consumption or other specific cause of liver disease.
2.  NAFLD encompasses a spectrum of disease, ranging from:
a.  Simple steatosis
b.  Steatohepatitis (NASH)
c.  Fibrosis and cirrhosis, to
d.  Hepatocellular carcinoma. (2)
 

How many people have fatty liver?

1. An estimated 31 million Americans, 31% of men and 16% of women have NAFLD.  It is thought to be the most plausible cause for the elevated serum aminotransferases and/or gamma glutamyl transpeptidase levels recorded in 24% of U.S. adults. (3)
2. The United States National Institutes of Health estimates that nonalcoholic steatopatitis (NASH) affects 2% to 5% of Americans, with an additional 10% to 20% having fatty liver, i.e. hepatic fat without current inflammation or liver damage. (4)
3. The true prevalence in children is not known but is reported at 2.5% to 10% and from 8%  to 80% in obese children. (5) NAFLD is reported as a common cause of liver disease in children and adolescents. (1, 6)

Who gets fatty liver?

1.  The most common associations are:
a.  Obesity is the number one cause. Eighty percent of patients with NAFLD are obese, and 80% of  obese
individuals have NAFLD
b.  Type 2 diabetes mellitus
c.  Dyslipidemia (2)
 2.  NAFLD affects children, adolescents, (1,6) and adults.  It affects boys more than girls (1) and men and women
equally. (3)
3.   Insulin resistance is reported as almost universal in adults NAFLD and highly prevalent in afflicted children
and adolescents. (1)
4.   Both genetic and environmental factors are thought to be responsible for the major ethnic variations in
prevalence.  (1) Recently, for example, variants in apolipoprotein C3 gene have shown association with
NAFLD. (7)
5.   The current Western diet, high in saturated fats and fructose, is considered highly responsible. (8)

Why does fatty liver disease occur?  What is the pathogenesis?

1. NAFLD is considered to be the liver’s manifestation of a metobolic syndrome called “syndrome X” or “insulin
resistance syndrome.”  The syndrome links NAFLD with obesity, diabetes mellitus type 2, hypertension, and
hyperlipidemia. (1)
2. Evidence points to a two-hit theory.
a.   The first hit:
i.   The  “first hit” involves accumulation of fat in the liver.
ii.  Free fatty acids (FFA) are elevated in the serum, become oversupplied to the liver, and lead to
steatosis. (2)
b.   The second hit:
i    Steatosis makes the liver vulnerable to additional biochemical insults, the “second hit.”  These include
oxidative stree, mitochondrial dysfunction, pro-inflammatory cytokines, adipocytokine imbalance,
dysregulated apoptosis, and stellate cell activation.  The result can lead to inflammation causing NASH
and fibrosis. (5, 9)
 

What is the pathology of nonalcoholic fatty liver?

1.  Liver steatosis consist of large and small vesicles of fat, predominantly
triglycerides inside hepatocytes. (3)
2.  The histology may differ between children and adult. (10)

Figure at right: Fatty liver in a 44-year -old man.
Axial contrast-enhanced CT scan shows linear high
attenuation along the hepatic surface (arrow), a finding
that represents pseudoenhancement.   The diaphragm has
attenuation of the fatty liver and thus mimics an enhanced
hepatic capsule. (14)

What is the pathology of nonalcoholic steatohepatitis
(NASH) ?1.     Steatosis, multifocal parenchymal inflammation, Mallory hyaline,
hepatocyte death from ballooning degeneration and also apoptosis, and
sinusoidal fibrosis occur. (3)

What effect does fat have on the liver?1.     NAFLD is suspected to be responsible for up to 70% of chronic hepatitis
cases of “unknown” cause.  Studies suggest that cirrhosis may eventually
develop in up to 10% to 30% of those with NAFLD. (3)
2.     NAFLD may contribute to progression of other liver diseases. (3)

What are some recent nutritionally related studies?

1.  Daily frutose ingestion by patients with NAFLD shows association with increase hepatic fibrosis. (11)
2.  In contradistinction, berry consumption has been shown to enhance liver function. (12)

What other diseases are associated with NAFLD?1.  Chronic kidney disease and retinopathy show higher prevalence in type 1 diabetic patients
who have NAFLD. (13)
2.   Hepatic steatosis is an independent marker for increased cardiovascular risk. (10)

Conclusion:  Nonalcoholic fatty liver disease has become the most common chronic liver disease
in Western children, adolescents, and adults.  It can have association with hepatitis, cirrhosis, and
hepatocellular carcinoma.

Research and reporting by Margaret D. Phillips, M.D.

Reviewer and publisher: Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

Imaging Reveals Astrocytes Can Respond to Visual Stimuli
Neurons are known as the principal functioning cells in the brain, receiving, storing, and transmitting information.  Higher-order functions such as sight, therefore, rely on neurons.  The brain’s star-shaped astrocyte cells are thought to perform functions for neurons, metabolically buffering, detoxifying, supplying nutrients, and electrically insulating them.  Astrocytes also contribute to brain barriers and play a principal role in brain repair and brain scar formation.  Until now, the ability to see had not been a role ascribed (in part) to astrocytes.  Yet researchers at the Massachusetts Institute of Technology recently documented that astrocytes do indeed respond to visual stimuli.  The authors used two-photon imaging of calcium signals in vivo, employing a ferret visual cortex model.  As reported in Science, astrocytes displayed distinct spatial receptive fields, as well as orientation and spatial associations.  The finding suggests the role of both neurons and astrocytes in vision.  This holds implications for non-invasive imaging techniques that study brain activity, such as functional MRI.

Conclusion:  Imaging shows that astrocytes join neurons as cells known to respond to visual stimuli.

MRI: CONTRAST

Alternative MRI Contrast Agent Can Deliver Therapeutic Drugs
Gadolinium has dominated the MRI contrast market since it was approved for human use 20 years ago.  More than 85 million doese had been administered by 2007, about 5 million annually.  A recent study in the Journal of the American Chemical Society reports the creation of a novel MRI contrast agent that is not gadolinium-based, but rather manganese-labeled, toroidal (doughnut-shaped) nanoparticles.  This new molecular agent can target fibrin, a constituent of a clot.  The authors, from Washington University School of Medicine, Philips HealthCare, and St. Thomas Hospital (London), state that the agent can also incorporate chemotherapeutic compounds, raising the possibility of its exhibiting both diagnostic and therapeutic utilities.

Conclusion:  A novel MRI contrast agent can not only target the fibrin in thrombus, but also deliver therapeutic compounds.

CARDIAC CT

Pericardial Fat Is Related to Calcified Coronary Artery Plaque
The U.S. Centers for Disease Control (CDC) report that an estimated 66 percent of U.S. adults and 17 percent of children and adolscents are overweight.  Inflammatory cytokines exist at higher levels in pericardial fat than in subcutaneous fat.  To assess whether pericardial fat is associated with calcified coronary artery plaque, researchers for the Multiethnic Study of Atherosclerosis examined the volume of pericardial fat on cardiac CT in 159 patients in Forsythe County, NC, and evaluated for calcified coronary artery plaque.  As reported in the research journal Obesity, pericardial fat proved significantly associated with calcified coronary artery plaque, even when adjusting for other cardiovascular risk factors, and was independent of gender and ethnicity.

Conclusion:  Pericardial fat is associated with calcified coronary artery plaque, independent of gender and ethnicity.