Updated: 03/17/08 04:01 PM
HOME HEAL EDUCATE RESEARCH DIRECTORY OUTREACH


Authors: W. Volwiler, R.A. Willson, A.M. Larson, and J.D. Ostrow
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P. Diseases of Hepatic Cell Injury



Massive hepatic necrosis (unusual)


Remarkable capacity of liver to regenerate 		  As a group, these disorders are characterized by diffuse or multifocal hepatocyte damage with accompanying inflammatory reaction. They vary in degree from an injury so mild that the illness is subclinical, to massive lysis of liver cells (fulminant hepatic necrosis) with gross shrinkage of the liver. When the liver cell injury is so massive and severe that significant cellular regeneration cannot occur in time, the condition is rapidly fatal. The regenerative efficiency of the hepatocytes is so miraculous, however, that most of these conditions heal with limited residual damage, albeit with some distortion of lobular architecture.



Spectrum of sequelae after hepatocyte injury


Cirrhosis may develop 		  Between these two extremes is a spectrum of sequelae having varying degrees of a) imperfect hepatocyte restoration; b) continuing hepatic cell necrosis with reactive smoldering inflammation; and c) fibrous scarring. If these processes are sufficient and/or prolonged, the lobular architecture and vasculature become distorted, producing cirrhosis. The time schedule for the development of cirrhosis is widely variable.

1. Viral Hepatitis (see section U.1 for further details)

Multiple viruses can cause hepatitis



Transmission via infected feces, blood, plasma or other secretions. 		  Acute or chronic inflammation of the liver caused by transmissible agents (viruses) which can damage the hepatocytes directly and/or generate an immunologic response that is inimical to the liver. Multiple varieties exist, each having its characteristic length of incubation period, clinical and laboratory features, illness duration, and degree of severity (See Table 8, Section U). The viruses are transmitted from their often persistent sites of residence in the lower digestive tract & feces, in blood plasma or certain of its fractionated products, or in other body secretions. With potent strains of virus, as little as 1/1,000 of a drop of infective plasma may transmit the illness.

Most patients only suffer flu-like symptoms; only a small proportion become jaundiced   The most common signs and symptoms, generalized malaise and fever, are usually proportionate to the severity of inflammation and liver cell necrosis. Most patients experience only a "viral-like" syndrome. In more severe cases, anorexia, nausea, and even vomiting may be seen. Jaundice, due to impairment of hepatic bilirubin transport, occurs in less than 10% of cases, and often develops as the flu-like symptoms subside. Palpable hepatomegaly may result from liver swelling secondary to inflammation and edema. Rapid stretching of the liver's capsule (Glisson's capsule) may yield tenderness to pressure on the liver and pain in the epigastric and right upper quadrant regions. In a limited number of more severe cases, the signs of acute hepatic failure develop.

High transaminases are principal lab abnormality   Laboratory detection of an acute diffuse hepatic injury is concerned chiefly with identifying a) interference with excretory efficiency of hepatic substances (e.g., bilirubin); b) exaggerated "leak" of intracellular hepatic enzymes into plasma (e.g., AST, ALT); and c) failure of hepatocytes to synthesize plasma proteins of short lifespan (especially clotting factors of the prothrombin complex).

2. Drug-induced Hepatitis and Cholestasis

  a. Role of the liver in drug metabolism
(Review Figure 10)

The liver is designed to detoxify lipophilic, protein-bound xenobiotics   The liver is the major organ for metabolism and excretion of drugs and toxins that are introduced into the body, especially the lipophilic xenobiotics that are carried in plasma bound to proteins and thus cannot be excreted by the kidney. In what is usually a two-step process, the liver converts most drugs to more polar products that are then available for excretion in bile and/or, due to weaker binding to plasma protein, in the urine. These processes involve a variety of cytosolic and membrane-bound enzymes; the latter are found mainly in the smooth endoplasmic reticulum. Each agent has its characteristic metabolic pathway(s) involving one or more of these enzyme systems.

  b. Factors that influence drug metabolism

Heredity, age, nutrition, other drugs and liver disease affect drug metabolism  
  1. Genetic polymorphisms in drug metabolizing enzyme activities.


  2. Age: infants may show considerable immaturity in the activity of drug metabolizing enzymes. Activity declines in the elderly.


  3. Nutrition: severe malnutrition may deplete the supply of detoxification (Stage II) cofactors, such as glutathione.


  4. Other drugs: may either inhibit or enhance (induce) metabolism of another drug (see next section). Alcohol can do both, accounting for the adage, "alcohol and drugs do not mix." (See d, below)


  5. Underlying liver disease: In both acute and chronic liver disease, the impaired Phase I metabolism may prolong the disposal rate of many drugs, causing excessive therapeutic or toxic effects. In cirrhosis, orally-administered drugs often bypass the liver in porto-systemic shunts, leading to excessive plasma levels.
  c. Inhibition and induction of drug metabolism




Drugs may inhibit and/or induce the monooxygenase cytochromes in the S.E.R. 		  Compounds (including hormones, e.g., estrogens) that share common binding sites on transporters or enzymes may competitively inhibit each others' transport or metabolism. The inhibition may affect binding to plasma proteins, hepatocyte uptake, binding to cytosolic storage proteins, oxidation, conjugation, or biliary secretion. Many toxins, drugs and hormones are inducers, at the transcriptional level, of the expression of drug-metabolizing enzymes, especially the cytochrome P450 and P448 monooxygenases of the smooth endoplasmic reticulum (S.E.R.).

  d. Biotransformation reactions influence drug toxicity

Stage I reactions may produce toxic derivatives; stage II (conjugation) reactions detoxify.



Overload or impairment of conjugation can lead to toxicity. 		  Stage I (mainly oxidative) reactions may convert some drugs (e.g., acetaminophen) into very toxic metabolites. By contrast, the conjugated products of stage II reactions are usually too polar to diffuse across cell membranes, rendering them inactive (unless they affect enzymes bound to plasma membranes) and unabsorbable from the intestine. The supply of cofactors regulates the phase II conjugation of the toxic metabolite. When the formation of toxic metabolites overloads the capacity of the conjugating system to inactivate them, toxicity occurs. This explains why many drugs, that are not toxic in therapeutic doses, become toxic when higher doses are ingested or conjugation is impaired by depletion of cofactors.

  e. ABC transporters export drugs from cells

Drug resistance due to ABC proteins that export xenobiotics from cells.   Most cells, including the hepatocyte, have transporters that span the plasma membranes and export xenobiotics into the plasma, bile or urine, protecting cells from excessive accumulation of toxic compounds. These ABC transporters possess ATP-Binding Cassette sequences that mediate the hydrolysis of ATP, providing the energy for the export processes. These transporters are often up-regulated by the xenobiotics that they export, enhancing protection against toxicity but also diminishing therapeutic efficacy of the drug.

  f. Classification of hepatic drug reactions

Two classes and five histological types of hepatic drug reactions




Ductules, canaliculi or hepatocytes may be primarily affected



Mixed syndromes may occur in an individual patient 		  Injury to hepatocytes may be classified into two major types according to the mechanism of injury: i) direct chemical reactions; and ii) drug hypersensitivity reactions. In some cases (i.e. chlorpromazine), both types of mechanisms are involved.

Individual drugs tend to produce a characteristic histological pattern of hepato-biliary damage, usually classified into one of five clinico-pathologic syndromes: a) cholestasis (.e.g. estrogens, anabolic steroids); b) cholestasis with reactive inflammation (e.g., erythromycin esters, chlorpromazine); c) generalized hepatitis with liver cell necrosis of varying degrees, simulating viral hepatitis or massive acute hepatocellular necrosis (e.g., halothane, isoniazid); d) chronic active hepatitis (e.g., alpha-methyl dopa, oxyphenisatin); and e) tumors (vinyl chloride, birth control pills, and androgens). A given patient may, however, show features of several syndromes.




Direct toxic injury is predictable and dose-dependent 		  i. Direct toxic injury (chemical reactions-predictable)

Agents that are directly hepatotoxic in humans are usually injurious to hepatocytes of most mammalian species. The latent period between the exposure and onset of the reaction is brief and fairly uniform. The severity of the injury is roughly proportional to the dose, and occurs predictably in most individuals exposed to sufficient doses.



Cell damage due to covalent binding of toxic compound to proteins or DNA 		  Although the damage may predominantly affect hepatocytes or cholangiocytes, some of these toxic compounds may also damage other organs (especially the kidneys). In each instance, the compound itself, or one of its stage I metabolites, interacts (usually rapidly) with one or more intracellular constituents (e.g., proteins, DNA) impairing enzyme function or cell proliferation, respectively, often resulting in cell death. The details of this sequence have been elucidated for only a few drugs, however (most notably isoniazid, acetaminophen and chlorpromazine).




Acetaminophen toxicity is due to its phase I metabolite, and is enhanced by chronic alcohol consumption. 		  Since toxicity is determined by the concentration of the reactive metabolite, the susceptibility of individuals to the drug is determined by factors that affect the balance between rates of formation of the metabolite (Stage I) and its detoxification (conjugation, Stage II). These factors were discussed in sections b, c and d, above. For example, chronic alcohol consumption increases the toxicity of acetaminophen by two mechanisms: up-regulation of CYP2E1 (the cytochrome P450's that forms the toxic intermediate) and depletion of glutathione, the cofactor for conjugation of the toxic intermediate.

Drugs that primarily cause hepatocellular injury   Common examples of agents that primarily cause hepatocellular injury are ethanol (discussed separately in section 3), isoniazid, acetaminophen, carbon tetrachloride, chloroform, phosphorus, azathioprine, 6-mercaptopurine, and mushroom (Amanita) toxins.

Damage to canaliculi and/or ductules.

Impaired net biliary secretion of various components of bile

Dislocation of ABC transporters from canalicular membrane 		  Agents that cause cholestasis primarily affect canalicular transporters or damage the ductules, leading to obstruction and/or increased permeability of the ductules. In either case, net biliary secretion is impaired for bile salts, cholesterol, phospholipids, bile pigments, porphyrins, and exogenous agents (such as biliary contrast agents and drugs). The pattern of impaired secretion is determined mainly by which ATP-dependent, canalicular transporters are affected, most often BSEP (the bile salt export pump) and/or MRP2 (the multispecific organic anion transporter). As with other forms of cholestasis, the mechanism is dislocation of the transporters from the canalicular membrane to subapical vesicles.




Injury is reversible 		  Little inflammation or gross liver cell degeneration occurs, and the retained cholephiles accumulate in the hepatocyte, rather than forming "bile plugs" in the canalicular lumen. All effects are usually reversible after discontinuing the inciting agent, although jaundice may take weeks to months to resolve.

Drugs primarily causing cholestasis



Injury is dose-related with individual variation 		  Common examples of drugs producing primarily canalicular cholestasis are: ethinyl estradiol, anabolic steroids (17α-alkyl androgens), and the immunosuppressant, cyclosporin. Ductular damage is less common, and often caused by tropical plant toxins. As with direct hepatocellular toxicity, the degree of cholestasis is roughly dose-related, may be due to a toxic intermediate formed in phase I reactions, and the pattern tends to be characteristic of each drug. Although all humans are susceptible, individuals vary widely in their manifestations of these effects, because of the same factors that affect hepatocellular toxicity.

  ii. Drug hypersensitivity (immunogenic)
reacations (unpredictable)

Hypersensitivity is unpredictable and independent of drug dose   The principal characteristic of this group of adverse hepatic reactions is the apparent unpredictability of injury in individual subjects. Hepatic drug reactions of this type are recognized more frequently and the list of drugs implicated is sizable. The reactions are often species-specific and cannot be reproduced experimentally in laboratory mammals. There is no constant relationship between the size of the dose and the occurrence of severity of the drug reaction. The latent period between exposure to the drug and the sensitivity reaction is quite variable (sometimes as long as three or four weeks after the last drug contact), and recovery after discontinuing the drug may sometimes take many months.

Hypersensitivity reactions involve autoimmune reactions to drug-protein adducts   In hypersensitivity reactions, the cells are damaged by immunogenic adducts of the drug or its metabolites with proteins, causing autoimmune-like damage to the liver and other organs. This accounts for the skin rashes, joint pain and inflammation, fever, and eosinophilic leukocytosis that often accompany the liver damage. Histologically, the liver shows varying degrees of injury to hepatocytes, canaliculi and/or intrahepatic bile ducts.

3. Ethanol and the Liver – Alcoholic Liver Disease

  a. Ethanol metabolism

In humans, the liver is the chief site of ethanol metabolism and involves two pathways, both of which convert ethanol to acetaldehyde.

Alcohol dehydrogenase   i.) Alcohol dehydrogenase, a constitutive (non-inducible) enzyme in the cytosol of the hepatocyte and gastric mucosa that uses NAD+ as a cofactor.

MEOS, inducible by ethanol   ii. Microsomal ethanol-oxidizing system (MEOS), a specific microsomal cytochrome P450 in the hepatocyte that is induced by ethanol and uses NADP+ as a cofactor. MEOS normally accounts for only 25% of ethanol metabolism, but becomes the predominant enzyme due to its induction with chronic alcohol ingestion. This induction is nonspecific, in that other drug-metabolizing enzymes are also enhanced. This is a major factor in the increased tolerance of the chronic alcoholic to alcohol itself as well as to certain sedative agents and other drugs metabolized by the microsomal cytochromes.

  b. Mechanisms of ethanol cytotoxicity

i.) Formation of toxic acetaldehyde

Acetaldehyde is the toxic metabolite of ethanol   The first metabolite of ethanol, acetaldehyde is a major factor in ethanol hepatotoxicity, and its rate of conversion to acetate by the enzyme, aldehyde dehydrogenase, is important in determining the development of alcoholic liver disease. Some of the toxic actions of acetaldehyde are due to its ability to acetylate proteins, both inactivating the proteins and generating immunogenic adducts that trigger autoimmune liver damage.

Synthesis, oxidation and export of lipids is affected







Mitochondrial damage is prominent 		  The most dramatic manifestation of alcohol toxicity is the rapid accumulation of fat in the liver, caused by multiple effects of ethanol. The fatty acids that accumulate are derived mainly from the diet.

  1. Increase in acetate and ratio of NADPH/NADP+, secondary to ethanol oxidation, resulting in increased fatty acid synthesis.


  2. Mitochondrial damage, resulting in striking ultrastructural changes including swelling and distorted cristae, with an associated decrease in fatty acid oxidation.


  3. Impaired export of lipoproteins from hepatocytes due to impaired apoprotein synthesis and damage to the cytoskeletal elements involved in transcellular movement of lipids. The damage to cytokeratin also results in formation of the characteristic alcoholic hyaline (Mallory bodies) in liver cells.
  c. Stages of alcoholic liver disease and modulating factors (Fig. 19)

Alcoholic liver disease: rising incidence and a multistage process   The incidence of alcohol-related liver disease continues to increase and is paralleled by the greater consumption of ethanol. It has been estimated that in some large urban centers, cirrhosis of the liver is at least the third most frequent cause of death between ages 25 and 65, with alcoholic and viral liver diseases as the major causes.

In humans, the excessive use of ethanol commonly results in a) fatty liver, b) alcoholic hepatitis, and/or c) fine nodular cirrhosis.



Figure 19
The Spectrum of Alcoholic Liver Disease

Fatty liver and alcoholic hepatitis may be reversible; cirrhosis is usually not reversible.   The exact interrelationships among these pathological states are not clear, but they appear to represent progressive stages in the development of long-term alcoholic liver disease. Fatty liver and hepatitis are reversible with abstinence, cirrhosis less so. Although fatty liver invariably develops with excessive ethanol ingestion, alcoholic hepatitis and cirrhosis occur only in about 20% of even heavy drinkers.





Injury worse in women than in men


Role of malnutrition is unclear 		  The mechanisms related to the transition between these three entities and the reasons for the differences in individual susceptibility are incompletely understood. Genetic, constitutional, and dietary factors are believed to play a role. Women are more sensitive to alcohol-induced liver injury than are men. Although the association of malnutrition with chronic alcoholism is well recognized, the extent to which this malnutrition contributes to the development of alcoholic liver disease remains unclear. Experimental evidence, both in man and the baboon, demonstrates that severe liver injury can be produced by prolonged alcohol ingestion in the absence of dietary deficiencies.

Release of cytokines by endotoxin-activated Kupffer cells   Chronic alcohol ingestion causes enhanced absorption of endotoxin from the gut. This in turn activates Kupffer cells to release pro-inflammatory cytokines (e.g. TNF-α and interleukin-1β), which may cause the leukocyte infiltration and cell necrosis that characterize the progression of hepatic steatosis to alcoholic hepatitis.

Ethanol dose x time determines incidence of cirrhosis   Susceptibility to alcoholic liver disease is largely determined by the amount, duration and constancy of ethanol consumption, apparently independent of the type of alcoholic beverage consumed. Above a certain threshold intake, the incidence of cirrhosis is linearly related to daily dose x time. The fat content of the liver can increase 3-fold with a single overnight binge. More prolonged ethanol ingestion can produce clinically-significant fatty liver within several weeks. Acute alcoholic hepatitis may require several months, and well-established fine nodular cirrhosis may require more than ten years of daily consumption of 300 gm of ethanol.

  d. Spectrum of alchoholic liver disease (Fig. 19)

i. Alcoholic fatty liver (steatosis)

Stages of steatosis (fatty liver)   Fat accumulates in the hepatocytes first as tiny droplets, which coalesce progressively until the entire cell may consist mostly of a single large vesicle of stored triglyceride with the nucleus and residual cytoplasm pushed to the cell margins; these cells microscopically resemble an adipose cell (macrovesicular fat). Such swollen cells may compress the sinusoids, causing reversible portal hypertension. Adjacent liver cells may rupture, merging their fat into large fatty cysts enveloped by their contiguous nuclei and other cell fragments.





Fatty liver is mostly reversible with abstinence 		  As its fat content increases, the liver progressively enlarges, sometimes becoming enormous (3-4 times normal size) and filling most of the abdomen. Except for the fatty cysts, the fatty vacuolization of hepatocytes is potentially reversible. In a given patient, the fat content (and size) of the liver may fluctuate for years without progressing to the more serious forms of alcoholic liver disease, and can disappear completely with abstinence.

ii. Alcoholic hepatitis



Mallory bodies are characteristic but not diagnostic 		  Impressive features in alcoholic hepatitis include a) ballooning and death of hepatocytes, b) intracytoplasmic deposits of altered fibrillar cytokeratin ("alcoholic hyaline" or "Mallory bodies"), that are typical of, but not unique to, alcoholic liver disease, c) infiltration of leukocytes (PMNs), and d) reactive proliferation of fibrous tissue. Varying degrees of fatty vacuolization of the hepatocyte occur also.

Damage is mainly centrilobular (acinar zone 3)   The accumulation of fat and destruction of liver cells are spotty, but occur initially and most severely in perivenous zone 3 (centrilobular). The Mallory bodies stain intensely with eosin, but differ from the round eosinophilic bodies seen in acute viral hepatitis. They are frequently perinuclear, and appear first as tiny droplets that later coalesce into ropy strands and amorphous clumps.

Polymorphs are the characteristic inflammatory cells   Inflammatory cells both infiltrate the portal triads and collect within the lobule around the debris of dying hepatocytes. In contrast to acute viral hepatitis, the invading leukocytes are characteristically polymorphonuclear, but some lymphocytes and macrophages may appear also. As the acute injury subsides, the necrosis and Mallory bodies disappear, but an infiltrate of lymphocytes lingers in the portal triads.

iii. Fibrosis and cirrhosis; the role of stellate cells

Fibrosis is due to condensation of reticulin plus new collagen synthesis by Stellate Cells   As small groups of hepatocytes die off, there is a local condensation of their supporting reticulin fibers, plus synthesis of new collagen by activated, proliferating Stellate Cells in the space of Disse. The new collagen fibrils form a barrier to diffusion of large molecules (including plasma albumin and its ligands) to the surface of the hepatocytes ("capillarization of the sinusoids"). Strands of new collagen later insinuate themselves between hepatocytes, and the irregular fibrous fingers gradually isolate groups of liver cells into small nodules without relevance to lobular architecture. The residual hepatocytes attempt to generate new liver cells, forming micronodules.

iv. Patterns of cirrhosis

Cirrhosis is the end stage if high alcohol intake continues   With continued alcoholism, progression of the foregoing processes results in diffuse cirrhosis of very small nodular type, the final step in the spectrum of alcoholic liver disease. Over time, parenchymal remodeling can transform micronodular into macronodular cirrhosis, indistinguishable from cirrhosis due to other causes.

Patterns of necrosis determine patterns of scarring   Occasionally, other patterns of the fibrous scarring are observed: a) septal scars may form, often connecting perivenous (centrilobular) zones of adjacent acini; and b) if extensive, massive necrosis of hepatocytes occurs regionally, the supporting framework collapses and the residual collagenous structures from multiple adjacent lobules condense, resulting in broad scars. Large nodules of residual hepatic tissue may remain between such thick post-necrotic scars. A mixed small and large nodular cirrhosis is the result.

4. Nonalcoholic Fatty Liver Disease (NAFLD)

  Nonalcoholic fatty liver disease represents a spectrum of liver disease which includes benign steatosis (fatty liver), nonalcoholic steatohepatitis (NASH), isolated portal fibrosis, and cirrhosis with resultant liver failure. It resembles alcohol-induced liver disease, but occurs in the absence of significant alcohol intake. Whether steatohepatitis is alcohol-related or not is often difficult to determine – there is no uniform agreement as to what “significant” alcohol intake is. Most agree, however, that steatohepatitis which occurs in the setting of alcohol consumption of over 20-40 g/day in men and 20 g/day in women constitutes alcoholic steatohepatitis and not NAFLD. NAFLD is defined as fat accumulation in the liver exceeding 5% to 10% by weight. This is generally estimated as the percentage of fat-filled hepatocytes seen by light microscopy. Recently, a grading and staging system for NAFLD/NASH has been proposed (Table 6).

NAFLD is probably the most common cause of liver disease in many countries, including the United States. Obese patients have a 60% prevalence of Grade 1 NAFLD, a 20% prevalence of grade 3 NAFLD/NASH, and 2-3% have cirrhosis. 75% of type 2 diabetics have some form of fatty liver disease. About 70% of patients with “cryptogenic” hepatitis are now believed to have NAFLD. Gender distribution is equal and even persons of normal body weight develop NAFLD. Certain drugs (i.e., methotrexate, amiodarone, tamoxifen) and surgical procedures (i.e., intestinal bypass for weight loss) have also been associated with NAFLD/NASH. Clinical predictors of more advanced disease remain to be adequately elucidated but have traditionally included female gender, age >40 to 50 years, obesity, diabetes, and dyslipidemia (particularly hypertriglyceridemia).

Grade 1, mild Benign NAFLD (simple steatosis)
Steatosis: Mainly macrovesicular, ranges from <33% to 66% of lobules
Ballooning: Occasionally observed; zone 3 hepatocytes
Lobular Inflammation: Scattered and mild acute (polymorphs) and chronic inflammation (mononuclear cells)
Portal Inflammation: None or mild
Grade 2, moderate NAFLD (steatosis with lobular inflammation)
Steatosis: Any degree, usually mixed macrovesicular and microvesicular
Ballooning: Present in zone 3
Lobular Inflammation: Polymorphs may be noted associated with ballooned haptocytes and/or pericellular fibrosis; ± mild chornic inflammation
Portal Inflammation: None; mild to moderate
Grade 3, severe Florid Steatohepatitis - NASH
Steatosis: Usually >66% (zone 3 or panacinar); commonly mixed steatosis
Ballooning: Predominantly zone 3; marked
Lobular Inflammation: Scattered acute and chronic inflammation; polymorphs may be concentrated in zone 3; areas of perisinusoidal fibrosis
Portal Inflammation: Mild or moderate; not predominant or marked
Staging
Stage 1: zone 3 perivenular, perisinusoidal, or pericellular fibrosis, focal or extensive
Stage 2: same as stage 1, plus focal or extensive portal fibrosis
Stage 3: bridging fibrosis, focal or extensive
Stage 4: cirrhosis with or without residual perisinusoidal fibrosis

Table 6
Proposed Grading/Staging of NAFLD/NASH

  The pathophysiology of NAFLD/NASH is poorly understood. NAFLD/NASH is often associated with metabolic syndromes (obesity, diabetes, hyperlipidemia, polycystic ovarian disease, peroxisomal diseases, mitochondrialopathies, Wilson’s disease, abetalipoproteinemia), many of which have either abnormal fat metabolism and/or mitochondrial injury/dysfunction. NAFLD/NASH is also commonly associated with insulin resistance. While these mechanisms probably play a fundamental role in development in NAFLD/NASH, it is not yet known whether they are causal.

NAFLD/NASH may be suspected based upon imaging studies (ultrasound, CT scan) suggesting hepatic steatosis or when liver enzymes elevations are found and there is no other identifiable reason for liver disease. Liver biopsy remains the gold standard for diagnosis and is extremely helpful in defining the stage of disease. Exercise and diet remain the cornerstone of therapy. Avoidance of alcohol may be prudent. Recent randomized controlled studies suggest no benefit to Ursodeoxycholic acid. Use of antioxidants is being evaluated. Medications directed at insulin resistance (i.e., thiazolidinediones) have shown promise and are being evaluated in larger trials.

Lack of longitudinal studies hinders our understanding of the prognosis of NASH. The 5- and 10-year survival is estimated at 67% and 59% respectively. Based on few numbers of patients, it is estimated that the risk of class 3 NAFLD/NASH for developing increased fibrosis over 5 years is 25% and for developing cirrhosis is 15%. Classes 1 and 2 may have a more benign course, although there are reports that these patients are also at risk for progression. There is also a significantly increased risk for the development of hepatocellular carcinoma in the subset of patients who progress to cirrhosis. Many patients with advanced disease are poor liver transplant candidates because of comorbid medical conditions, however, successful transplant can prolong life. As our understanding of the pathophysiology of NAFLD improves, broader treatment options should be available.

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