Fatty Liver Disease: Alcoholic and Nonalcoholic
Maxwell L. Smith, MD
16.1 INTRODUCTION
This chapter covers the spectrum of fatty liver disease from sim-ple steatosis to severely active steatohepatitis. The chapter begins with general definitions and discussion germane to most cases of steatosis and steatohepatitis, regardless of the etiology. This is followed by a review of specific diseases, including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), drug-induced fatty liver disease, Wilson disease, overlap diseases, and diffuse microvesicular steatosis.
16.2 DEFINITIONS
Simply defined, fatty liver disease is the accumulation of lipid droplets in the cytoplasm of hepatocytes. Steatosis is divided into macrovesic-ular and microvesicular steatosis based on the size of the fat droplets. Macrovesicular steatosis contains large centrally located fat droplets that displace the nucleus to the periphery of the hepatocyte (Fig. 16.1), whereas microvesicular steatosis involves small droplets of lipid not displacing the nucleus. Also of note, there is a diagnostic distinction between true microvesicular steatosis and simply smaller droplets of steatosis, which are seen in the majority of cases of macrovesicular steatosis. For this reason, authors sometimes use the term mixed large-droplet and small-droplet steatosis in the setting of typical fatty liver disease (alcoholic, nonalcoholic, and others) (Fig. 16.2), but reserve the term microvesicular steatosis for cases of diffuse microvesicular steatosis (Table 16.1). The mixed pattern is considered to be part of the normal findings in macrovesicular steatosis and should not be confused with microvesicular steatosis. The distinction is important because there are significant differences in the differential diagnosis between macrovesicular steatosis and diffuse microvesicular steatosis (Table 16.2). True microvesicular steatosis shows diffuse involvement of the hepatocyte cytoplasm by small droplets of lipid, giving the cytoplasm a bubbly appearance (Fig. 16.3). This pattern of injury is much less common than macrovesicular steatosis. Whereas steatosis is the accumulation of lipid in the cytoplasm, steatohepatitis includes the presence of active injury such as lobular inflammation and ballooning degeneration of hepatocytes.
 Figure 16.1 Steatosis seen in fatty liver disease. Large-droplet steatosis with single large cytoplasmic fat droplets displacing the hepatocyte nucleus to the periphery of the cell. Also called macrovesicular steatosis. |
 Figure 16.2 Steatosis seen in fatty liver disease. Small-droplet steatosis seen in routine fatty liver disease is characterized by smaller cytoplasmic fat droplets that may be multiple and do not displace the nucleus to the periphery. Over time, these droplets coalesce and will become large droplets. |
16.3 GENERAL PATHOLOGIC APPROACH
The recognition of steatosis is straightforward in practice. Identifying the etiology of the steatosis requires clinical and serologic correlation. If no clinical data are available, a descriptive diagnosis with a differential is often as far as the pathologist can go (Table 16.3). One of the major distinctions to make is between the presence of steatosis alone and the presence of a superimposed steatohepatitis. Compared to steatohepatitis, steatosis alone is considered a benign disease that will not progress to cirrhosis and has a lower risk for hepatocellular carcinoma (HCC). In contrast, steatohepatitis is a progressive fibrotic liver disease that can lead to cirrhosis and increased risk for HCC. Although this is a useful dichotomy for clinical management, in reality
there is a spectrum of biologic disease ranging from simple steatosis to active steatohepatitis.
there is a spectrum of biologic disease ranging from simple steatosis to active steatohepatitis.
Table 16.1 Definitions in fatty liver disease | ||||||||||||||||||
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Distinguishing simple steatosis from steatohepatitis
Lobular inflammation and hepatocellular injury are the key features distinguishing simple steatosis from steatohepatitis.1 Either extreme of the spectrum of steatosis and steatohepatitis is easy to recognize. The key questions become how much steatosis is sufficient to be called abnormal, what are the criteria for ballooning degeneration, and how much inflammation should be required. A definitive diagnosis of steatohepatitis requires both steatosis and hepatocyte injury.
By generally accepted definition, the normal liver may show up to less than 5% macrovesicular steatosis
(Fig. 16.4). In this setting, the steatosis is often randomly distributed and may have both small and large droplets of fat. Vary rarely, in severe alcoholic hepatitis, the degree of steatosis may approach this lower limit of normal. However, in this setting, there also tends to be diffuse ballooning degeneration, Mallory hyaline formation, and neutrophilic inflammation suggesting the underlying disease process.
(Fig. 16.4). In this setting, the steatosis is often randomly distributed and may have both small and large droplets of fat. Vary rarely, in severe alcoholic hepatitis, the degree of steatosis may approach this lower limit of normal. However, in this setting, there also tends to be diffuse ballooning degeneration, Mallory hyaline formation, and neutrophilic inflammation suggesting the underlying disease process.
Table 16.2 Differential diagnosis of fatty liver disease | ||||||
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 Figure 16.3 Microvesicular steatosis. True microvesicular steatosis characterized by innumerable fine lipid droplets filling the hepatocyte cytoplasm giving it a foamy appearance. Because of the fine cytoplasmic vacuoles, often the cell membranes appear accentuated. |
Table 16.3 Sample reports, assuming the pathologist does not have clinical history | ||||||||||||||||||
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Ballooning degeneration is described as swollen hepatocytes (usually greater than 2 to 3× normal size) with voluminous clear to rarified cytoplasm and small bits of eosinophilic material (Fig. 16.5). The eosinophilic material represents degenerated cytoskeleton filaments. This material can coalesce and form large ropy structures of Mallory hyaline (Fig. 16.6). Balloon cells do not have lipid droplets and must be distinguished from swollen hepatocytes with a single large fat droplet. This is best done by looking at high power for the fine fragments of cytoskeletal remnants that would not be seen within a large fat droplet. If a case has steatosis, lobular inflammation, and pericellular fibrosis, it is more likely to show ballooning when compared with cases lacking these other features. Despite this clear definition of ballooning degeneration, there will be cells that everyone will agree show ballooning but other cells will generate
disagreement. The hepatocytes that are the most likely to cause disagreement usually have one or more of the above features missing (Fig. 16.7). Some cells are only slightly swollen and have some cytoplasmic clearing but lack Mallory hyaline. In these equivocal settings, a trichrome stain may be useful because the ballooning cells are usually surrounded by delicate pericellular fibrosis (Fig. 16.8). A periodic acid-Schiff (PAS) with diastase stain can highlight scattered ceroid laden macrophages that may be used as an indirect marker for past foci of hepatocyte injury (Figs. 16.9 and 16.10), but this can occur in any type of hepatitic injury. Other conditions that can lead to swollen and rarefied hepatocytes include cholestatic conditions (sepsis, duct obstruction, and drug reaction) and conditions associated with increased glycogen deposition (glycogenic hepatopathy and anorexia nervosa).
disagreement. The hepatocytes that are the most likely to cause disagreement usually have one or more of the above features missing (Fig. 16.7). Some cells are only slightly swollen and have some cytoplasmic clearing but lack Mallory hyaline. In these equivocal settings, a trichrome stain may be useful because the ballooning cells are usually surrounded by delicate pericellular fibrosis (Fig. 16.8). A periodic acid-Schiff (PAS) with diastase stain can highlight scattered ceroid laden macrophages that may be used as an indirect marker for past foci of hepatocyte injury (Figs. 16.9 and 16.10), but this can occur in any type of hepatitic injury. Other conditions that can lead to swollen and rarefied hepatocytes include cholestatic conditions (sepsis, duct obstruction, and drug reaction) and conditions associated with increased glycogen deposition (glycogenic hepatopathy and anorexia nervosa).
 Figure 16.4 Minimal macrovesicular steatosis. This liver biopsy from a patient with autoimmune hepatitis showed minimal steatosis (less than 5%). It is not necessary to comment on this degree of steatosis in the report. |
 Figure 16.5 Hepatocyte ballooning. Hepatocyte with ballooning degeneration characterized by cytoplasmic swelling, rarefication, lack of fat droplets, and small fragments of eosinophilic material (arrow). Nearly everyone would agree this represent ballooning degeneration. |
 Figure 16.6 Mallory hyaline. Mallory hyaline is characterized by large ropy eosinophilic cytoplasmic inclusions representing coalesced cytoskeleton filaments (arrows). These are often seen in the cytoplasm of ballooning hepatocytes. |
 Figure 16.7 Equivocal hepatocyte ballooning. This cell shows mild swelling and some cytoplasmic rarefication (arrow). Is this a hepatocyte undergoing ballooning degeneration? Not everyone will agree. It may not be prudent to base a diagnosis of steatohepatitis on only a single cell with this morphology. |
 Figure 16.8 Pericellular fibrosis. Ballooning hepatocytes with “chicken-wire” pericellular fibrosis (trichrome stain). |
 Figure 16.9 Ceroid laden macrophages. These are Kupffer cells that reside in the sinusoidal spaces and are responsible for phagocytizing dead hepatocytes (arrow). They are recognized as gray to brown cells with abundant foamy cytoplasm. |
Lobular inflammation is a characteristic feature of steatohepatitis. In steatohepatitis, the inflammation is predominantly lymphocytic but rarely can show neutrophils, most commonly in the setting of alcohol or drug effects (Figs. 16.11 and 16.12). The inflammation consists of scattered clusters of cells or single cells scattered throughout the lobule, but can be more prominent in areas of hepatocyte injury or ballooning degeneration. Taking all of the features together, one can often appreciate a component of lobular disarray and injury in steatohepatitis that is
missing in steatosis alone. Sometimes this low-power gestalt approach can be a helpful supplement to individual criteria scrutinized at medium or high power.
missing in steatosis alone. Sometimes this low-power gestalt approach can be a helpful supplement to individual criteria scrutinized at medium or high power.
 Figure 16.10 Ceroid laden macrophages. PAS with diastase stains can highlight ceroid laden macrophages in the sinusoidal spaces. Some use the presence of ceroid laden macrophages as indirect evidence of hepatocyte ballooning degeneration in fatty liver disease. PAS, periodic acid-Schiff. |
 Figure 16.11 Lobular inflammation in steatohepatitis. Clusters of neutrophils can be seen to the right of a few ballooning hepatocytes in this cases of alcoholic steatohepatitis. |
Estimating the degree of steatosis
Pathologists may spend a significant amount of time perseverating over the exact percentage of steatosis on liver biopsies. The perceived quantitative percentage score given in each case may drive this behavior. In reality, the reproducibility of this quantitative scoring process is poor, and pathologists tend to overestimate the degree of steatosis when compared with morphometric studies.2 It is best to think of the scoring in terms of mild, moderate, and severe steatosis, based on the estimated fat percentage as 5% to 33%, 34% to 67%, and >67%, respectively. Overall fat percentage should be estimated at low power using a 4× or 10× objective. The percentage being estimated was originally defined as the percent of hepatocytes with macrovesicular (large droplet) steatosis.1 However, several other studies have used the surface area of fat within the biopsy. Either approach works fine and should lead to the same final fat score. Studies have shown improved estimation of steatosis using guideline images.3 Examples of mild, moderate, and severe steatoses are shown in Figures 16.13, 16.14, and 16.15 for reference, respectively.
 Figure 16.12. Lobular inflammation in steatohepatitis. This case of nonalcoholic steatohepatitis has a lymphocytic lobular infiltrate. |
 Figure 16.13 Mild steatosis. Estimating the amount of fat in liver biopsies can be challenging and is best done by thinking about it in terms of mild moderate or severe amount of fat. Mild steatosis has more than 5% but less than 33%. |
 Figure 16.14 Moderate steatosis. Moderate steatosis has more than 34% but less than 66%. |
 Figure 16.15 Severe steatosis. Severe steatosis shows more than 67% macrovesicular steatosis. |
Grading activity in steatohepatitis
The nonalcoholic fatty liver disease activity score (NAS) was introduced in 2005 as a way to grade the degree of activity in cases of nonalcoholic steatohepatitis4 (Table 16.4). Only features with high interobserver agreement (kappa values ranging from 0.5 to 0.79) and those independently associated with a diagnosis of nonalcoholic steatohepatitis were included in the NAS. The features include steatosis (scored 0 to 3), ballooning degeneration (scored 0 to 2), and lobular inflammation (scored 0 to 3). The scoring system is based on the unweighted sum of all three scores and thus ranges from 0 to 8. There is general agreement that most biopsies with NAS scores of 0 to 2 do not represent nonalcoholic steatohepatitis, whereas biopsies with NAS scores of 5 to 8 do represent nonalcoholic steatohepatitis.4 Biopsies with NAS scores of 3 or 4 may represent simple steatosis or nonalcoholic steatohepatitis depending on the presence or absence of all three histologic features. Other grading systems have been developed but the NAS is the most widely used.
Table 16.4 Nonalcoholic fatty liver disease activity score4 | ||||||||||||||||||||||||
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Grading systems should not take the place of thorough histologic assessment in the reporting of liver biopsies with fatty change. Many have argued strongly that scoring systems were developed for clinical trials and have less of a role in the clinical record.5 Scoring systems do have advantages in that they assure assessment and reporting of all of the pertinent features associated with fatty liver disease. They also provide standard criteria for reporting and for communication with clinicians. Although the NAS was developed for cases of NAFLD, in common practice it is often applied to all biopsies with fatty disease, because the etiology is rarely known at the time of sign-out (Table 16.3). The decision to use a scoring system, regardless of the disease process, should be made in conjunction with input from the clinicians ordering the liver biopsy.
Staging fibrosis in steatohepatitis
In 1999, Brunt et al.1 proposed a fibrosis staging system for NAFLD to take into account the unique centrilobular and subsinusoidal patterns of fibrosis (other synonyms include sinusoidal fibrosis and pericellular fibrosis) seen in nonalcoholic steatohepatitis. The staging system was revised in 2005 and incorporated into the NAS staging system, with modifications of the Stage 1 fibrosis to include a substage with portal fibrosis alone
(Table 16.5).4 Histologic examples of the four fibrosis stages are shown in Figures 16.16, 16.17, 16.18, and 16.19. Note that even fine subsinusoidal fibrosis that bridges from central to portal or central to central regions is sufficient for Stage 3 fibrosis. This fibrosis staging system is quite helpful as the majority of the other fibrosis staging systems were developed for chronic viral hepatitis and do not take into account the unique fibrosis patterns seen in early stages of steatohepatitis associated fibrosis. Similar to the NAS grade, the NAS stage is often applied to all cases because the etiology is often unknown at the time of sign-out.
(Table 16.5).4 Histologic examples of the four fibrosis stages are shown in Figures 16.16, 16.17, 16.18, and 16.19. Note that even fine subsinusoidal fibrosis that bridges from central to portal or central to central regions is sufficient for Stage 3 fibrosis. This fibrosis staging system is quite helpful as the majority of the other fibrosis staging systems were developed for chronic viral hepatitis and do not take into account the unique fibrosis patterns seen in early stages of steatohepatitis associated fibrosis. Similar to the NAS grade, the NAS stage is often applied to all cases because the etiology is often unknown at the time of sign-out.
Table 16.5 Nonalcoholic steatohepatitis clinical research network fibrosis staging systema | ||||||||||||||||||
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 Figure 16.16 Fibrosis Stage 1a. Stage 1a fibrosis shows fine early subsinusoidal fibrosis in zone 3 and normal appearing portal areas. |
 Figure 16.17 Fibrosis Stage 2. Stage 2 fibrosis shows portal, focal periportal, and Zone 3 subsinusoidal fibrosis but no definite bridging fibrosis. |
 Figure 16.18 Fibrosis Stage 3. Stage 3 fibrosis is seen, with clear bridging fibrosis and some early architectural distortion. |
 Figure 16.19 Fibrosis Stage 4. Stage 4 fibrosis is seen, with clear regenerative nodules. |
16.4 ALCOHOLIC FATTY LIVER DISEASE
Clinical features
Alcohol-associated liver disease may be encountered in anyone exposed to excessive amounts of alcohol because alcohol is a direct hepatotoxin. The exact amount of alcohol required to induce liver disease is variable from one person to the other because of genetic susceptibility, comorbid conditions, and exposure to other hepatotoxins. As low as 40 g/day of alcohol for men and 20 g/day for women has been reported to increase risk of fibrosis. Nearly everyone who has excessive exposure will develop steatosis, which is reversible, whereas approximately 30% of individuals will develop steatohepatitis, with an increased risk of fibrosis, cirrhosis, and HCC. Excessive alcohol may affect several other organ systems, including the nervous system, gastrointestinal system, and cardiovascular system. Patients with cirrhosis secondary to alcohol can show any of the typical consequences of cirrhosis, including portal hypertension, splenomegaly, esophageal varices, and ascites.
Laboratory findings
Alcohol-related liver disease causes elevations of both aspartate transaminase (AST) and alanine transaminase (ALT); however, AST is usually increased at least 2× the ALT. The levels of alkaline phosphatase (ALP) are usually only mildly elevated, whereas γ glutamyltransferase (GGT) can show marked elevations. Although there are many exceptions, an AST to ALT ratio of greater than 2, along with an elevated GGT out of proportion to the ALP, can raise the possibility of alcohol as an etiology. In advanced disease, there may be synthetic dysfunction with low albumin and a prolonged international normalized ratio.
Imaging
Imaging studies can be useful in establishing the presence and distribution of steatosis. Ultrasound is widely used as a noninvasive method but has low sensitivity for lower amounts of fat. Ultrasound cannot detect fat levels below 15% to 20%. Magnetic resonance imaging (MRI) is more sensitive in quantifying the amount of fat (Figs. 16.20 and 16.21). Hepatic fat content can also be estimated with multi-echo gradient-recalled-echo MRI, known as Liver Imaging of Phase-related signal Oscillation and Quantification (LIPO-Quant). Most of the time, the fat accumulation occurs diffusely throughout the liver. However, in a minority of cases, the fat accumulates in particular areas; a phenomenon termed focal fatty infiltration. The medial segment of the left lobe of the liver is a common site and this can mimic a mass lesion. There are no imaging studies that can reliably distinguish steatosis from steatohepatitis.6 There has been significant recent interest in the use of transient elastography for noninvasive means of fibrosis monitoring. However, both steatosis and active inflammation decrease the accuracy of transient elastography, limiting its usefulness in the setting of alcoholic liver disease.7
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