Focal Fatty Liver

The case reported by Berkelhammer and associates¹ highlights an interesting aspect of nonalcoholic fatty liver disease (NAFLD), namely its distribution, the discussion of which has previously been largely confined to radiologic literature. Hepatic steatosis may be either diffuse or focal in its distribution.^2,3 Focal hepatic steatosis may be seen either in circumscribed areas near anatomical landmarks or may appear as multiple nodular areas producing a pseudotumor appearance.⁴ Typically, focal steatosis is identified in characteristic locations such as the gallbladder fossa, the medial segment near the falciform ligament, the subcapsular region, and the porta hepatis.² Aside from location, other characteristic radiographic features of focal hepatic steatosis include a wedge-shaped or geographic configuration, absence of a mass effect, and visualization of normal vascular structures coursing through these fatty regions.^2,3

The second variety of focal hepatic steatosis has been coined multifocal nodular fatty infiltration of the liver (MNFIL) and is characterized in a case series published by Kroncke and colleagues.⁴ Focal hepatic steatosis may pose diagnostic dilemma in that its hypodense appearance on computed tomography (CT) scan may make it difficult to distinguish from metastatic disease, especially in individuals with a history of malignancy. This may be particularly problematic in the case of MNFIL, in which lesions tend to be spherical or ovoid, sharply demarcated, measure from 5 mm to 2 cm in size, and number from 2 to more than 20.⁴ Magnetic resonance imaging (MRI), using the combination of in-phase (IP) and opposedphase (OP) gradient-echo imaging (low signal intensity in OP images compared with IP images), and contrast-enhanced ultrasound have both been reported to reliably distinguish MNFIL from metastatic liver disease.^4–6 However, intralesional fat cannot exclude hepatic adenomas, hepatocellular carcinoma, or, in rare cases, focal nodular hyperplasia, all of which can exhibit steatosis.⁷ Despite advances in liver imaging techniques, individual clinical assessment remains paramount in the evaluation of fatty liver lesions, with judicious use of liver biopsy in cases where diagnosis remains uncertain.

The current understanding of focal fatty liver, including prevalence, etiology, natural history, and treatment, is extremely limited. In a retrospective analysis of abdominal CT scans in 1,425 healthy adults, El-Hassan and associates found the overall prevalence of fatty infiltration to be 9.7%, with 68% being diffuse, 9% being focal and solitary, and 22% being focal and multiple in distribution.⁸ Among children and adolescents, a retrospective review of 305 consecutive contrast-enhanced abdominal CT scans found the overall prevalence of focal fatty infiltration to be 9.2%, 80% of which were described as geometric and 20% of which were described as ovoid.⁹ The prevalence increased dramatically with age in this series, with 0% up to 4 years of age, 7.3% from 5–9 years of age, 10.2% from 10–14 years of age, and 25.6% from 15–19 years of age. Although not as common as diffuse fatty liver, these data suggest that focal patterns of hepatic steatosis are not rare. Further studies are required in order to better characterize the prevalence of focal hepatic steatosis and to determine whether the epidemiology of this pattern differs from the pattern of diffuse fatty liver, which is seen more commonly among those of male gender, Hispanic ethnicity, and increasing age with central obesity and insulin resistance.¹⁰

The natural history of focal hepatic steatosis has not been studied. In the case series by Kroncke and coworkers, follow-up MRI was performed in 5 patients, 3 of whom demonstrated no change and 2 of whom had resolution. (No information was provided about the time interval between imaging studies in this series.)⁴ Of the 2 patients with resolution, 1 had undergone gastrectomy with significant weight loss. At a minimum, larger case series with serial imaging studies will be required to elucidate the natural history of these lesions.

Histologically, focal fatty change has been described in an autopsy series with 10 patients as well-demarcated, unencapsulated areas of severe and, typically, macrovesicular steatosis, surrounded by hepatic parenchyma that contains little or no steatosis.¹¹ Unlike the case described by Berkelhammer and colleagues, this autopsy series had only 1 case in which the nodule contained significant fibrosis. Likewise, another case reported by Battaglia and coworkers was described as containing macrovesicular steatosis without inflammation or fibrosis.¹² There are not enough data published regarding the histopathology of focal fatty lesions to estimate how often features of inflammation and fibrosis may be present within these lesions. It is also important to note that the patient described by Berkelhammer and colleagues had presented with asymptomatic abnormal liver biochemistries. It is unclear from published literature how often this is true among individuals with focal fatty liver and whether or not the finding of elevated aminotransferases may be indicative of more advanced histologic features within these nodules.

Although the etiology of focal hepatic steatosis is not yet established, vascular supply to the liver other than the portal vein or hepatic artery is one of the mechanisms that has been proposed to account for this finding (as well as for the finding of focal areas of fatty sparing among a diffusely steatotic liver).^12,13 This vascular supply may consist of either aberrant or normal veins that enter the liver directly, independent of the portal venous system. These veins may communicate with intrahepatic portal branches to various degrees, producing focal variation in portal venous perfusion, and may contribute to focal metabolic changes that manifest as hepatic steatosis. Three venous systems that have been recognized to produce focal fatty change on imaging studies are the cholecystic veins, the epigastric-periumbilical venous system, and the parabiliary venous system.¹³ The parabiliary system drains the head of the pancreas; it is thought that this may result in the delivery of higher concentrations of insulin than normal in the portal venous supply, thus contributing to hepatic steatosis.¹² This argument is supported by the association of NAFLD with insulin resistance and the finding that focal fatty change is seen beneath the capsule in individuals receiving intraperitoneal insulin during peritoneal dialysis.¹⁴ Altered oxygen tension due to atypical vascular supply is another potential variable that may be relevant in determining the particular histopathology present in these lesions, given the role of oxidant stress in nonalcoholic steatohepatitis (NASH).¹⁵

As our understanding of NAFLD continues to evolve, this case report demonstrates an interesting variant of what appears to be the most common cause of liver disease among both adults and children in the United States.^10,16 This case illustrates the importance of liver imaging techniques in distinguishing focal hepatic steatosis from other mass lesions in the liver, but also demonstrates the importance of histologic evaluation as the only means of establishing a diagnosis of NASH in the setting of suspected NAFLD. Although this report would suggest that focal NASH may respond to the same type of therapeutic intervention currently under study for the treatment of diffuse NASH, namely with ligands for the peroxisomal proliferator activated receptor-gamma, further research is clearly necessary to establish the appropriate course of therapy for individuals with this lesion.