Multifocal Nodular Nonalcoholic Steatohepatitis

Multifocal nodular fatty infiltration of the liver mimicking metastatic disease has been reported in the literature.^1–4 Nonalcoholic fatty liver disease (NAFLD) has been associated with insulin resistance.⁵ Insulin sensitizers have been shown to improve liver biochemistry and histology in nonalcoholic steatohepatitis (NASH).^6–10 We report a case of multifocal nodular NASH in which radiologic abnormalities dramatically resolved after receiving rosiglitazone. This correlated with improvement in glycemic control, as well as with insulin sensitivity in both the fasting and fed states.

Case Report

A 59-year-old woman was evaluated for asymptomatic abnormal liver biochemistries. She had no prior or family history of liver disease, and denied history of intravenous drug abuse or blood transfusions. Past history was significant for hyperlipidemia, aortofemoral bypass, and coronary artery disease, which had been treated with coronary artery stents. Medications included a statin, niacin, and aspirin. She occasionally drank 2 glasses of wine and smoked 3–4 cigarettes a day.

Physical examination revealed a normotensive woman with truncal obesity and a body mass index (BMI) of 29.3 kg/m². She had mild hepatomegaly but no other stigmata of chronic liver disease. Laboratory studies showed serum alanine aminotransferase of 85 U/L (normal <52 U/L), aspartate aminotransferase of 72 U/L (normal <39 U/L), and alkaline phosphatase of 173 U/L (normal <126 U/L). Albumin, total globulin, and protime were normal, whereas platelet count was 133,000 μL (normal 140,000–450,000 μL). Extensive serologies for other etiologies of liver disease were negative.

Computed tomography (CT) scan revealed a 10.5-cm hypodense mass in the liver, mainly confined to the caudate lobe, as well as several smaller hypodense masses in the right lobe of the liver (Figure 1A). The findings caused concern for malignant disease involving the liver. Interestingly, however, the scan showed a blood vessel traversing the center of the mass undistorted, favoring a benign etiology of the liver mass. Magnetic resonance imaging of the liver confirmed the presence of hepatic masses. However, fat suppression techniques revealed that the masses were, in fact, multifocal fatty liver.

Figure 1.

Computed tomography scan showing multifocal nodular nonalcoholic steatohepatitis at baseline (A), and after 6 months of treatment with rosiglitazone (B).

Core liver biopsy of the mass in the caudate lobe revealed benign hepatocytes, with features of nonalcoholic steatohepatitis. Laparoscopy was elected in order to obtain multiple large tissue samples and thereby minimize sampling error¹¹; it did not reveal malignant masses within the liver. The liver showed yellowish discoloration and fibrotic changes consistent with fatty liver disease and early cirrhosis. Multiple wedge biopsies from the areas of interest in the right and left lobes of the liver were taken, for a total of 5 wedge biopsies. All biopsies showed changes consistent with nonalcoholic steatohepatitis, bridging fibrosis, and early cirrhosis.

Statin therapy was then discontinued, as were alcohol and smoking. The patient was advised to lose weight gradually through diet and exercise. Vitamin E 400 IU daily was initiated. However, after 6 months, there was no appreciable change in liver biochemistries or imaging from repeat CT scan of the liver.

Subsequent blood tests revealed that the patient's fasting glucose was elevated at 133 mg/dL (normal <99 mg/dL), and her glycohemoglobin measured 6.7% (normal <5.9%). She underwent a 2-hour glucose tolerance test to measure her insulin levels at baseline and at 30-minute intervals following a glucose load (Figure 2). Baseline homeostasis model assessment-insulin resistance (HOMA-IR),¹² which measures insulin resistance in the fasting state, measured 7.7 units (normal <2 units). The patient was, therefore, initiated on rosiglitazone 4 mg twice daily. Diet, exercise, weight loss, and vitamin E were continued.

Figure 2.

Insulin levels measured during glucose tolerance test at baseline and after rosiglitazone.

After 6 months, glycohemoglobin improved to 6.1%, and she was able to reduce her BMI to 26.6 kg/m². Fasting glucose and insulin levels also improved; this was reflected in an improved HOMA-IR score of 4.3 units, which indicated improved insulin sensitivity in the fasting state. In order to assess insulin sensitivity in response to food, a 2-hour glucose tolerance test was repeated while on rosiglitazone (Figure 2). Insulin levels were again obtained at 30-minute time intervals following a glucose load. There was marked improvement in insulin sensitivity, both in the fasting and fed states, and her liver biochemistries normalized. Repeat CT scan of the liver showed dramatic resolution of the multifocal nodular hepatic lesions (Figure 1B).

Discussion

This is the first case, to our knowledge, of multifocal nodular NASH mimicking metastatic disease that resolved with insulin sensitizers. Our patient's multifocal nodular NASH dramatically resolved after treatment with insulin sensitizers, in combination with diet, exercise, weight loss, and vitamin E. The striking resolution was largely attributed to rosiglitazone's improvement in insulin resistance and glycemic control; no change had been detected with only vitamin E, diet, and exercise. It is likely, however, that all factors worked in synergy toward the resolution.

NASH is believed to develop according to the multi-hit hypothesis, with the “first hit” being insulin resistance and the “second hit” being oxidative stress. Other contributing factors include cytokines (tumor necrosis factor [TNF]) and adipokines (adiponectin, leptin, resistin).⁵ Angiotensin may influence the progression of NASH to cirrhosis, as hepatic stellate cells contain angiotensin receptors.¹³ Thus, agents being evaluated as potential treatments of NASH also include TNF inhibitors, such as pentoxifylline,¹⁴ and angiotensin-converting enzyme inhibitors.¹³

Vitamin E, an antioxidant given to affect the “second-hit” portion of NASH development, has produced beneficial outcomes in the treatment of NASH. Vitamin E has been shown to improve liver biochemistry in children with NASH,¹⁵ steatosis but not other histologic parameters,⁶ and fibrosis but not necroinflammatory activity when combined with vitamin C.¹⁶ Another antioxidant, betaine, has also shown some effectiveness in NASH.¹⁷

Several studies have demonstrated significant biochemical and/or histologic improvement in NASH with the insulin sensitizers rosiglitazone, pioglitazone, and metformin.^6–10 Insulin sensitizers have been shown to enhance insulin sensitivity, reduce fasting insulin levels, and reduce fasting serum free fatty acid levels.^5–10 Insulin sensitizers also increase serum adiponectin levels, which correlates with a reduction in fatty liver.¹⁰ Neuschwander-Tetri and associates found that 48 weeks of rosiglitazone led to histologic resolution of NASH in 45% of patients.⁷ In another study, Sanyal and colleagues⁶ showed that pioglitazone plus vitamin E led to greater improvement in liver histologic evidence in patients with NASH than vitamin E alone. The improvement in liver histology was associated with decreases in both fasting serum free fatty acid levels and in insulin levels.⁶ Similarly, pioglitazone was shown to improve liver histology in NASH, which correlated with improvement in insulin sensitivity^8,10 and hepatic glucose production.⁸ In addition, peroxisome proliferator activator receptor agonists, which include rosiglitazone and pioglitazone, have also been shown to have anti-inflammatory and antifibrotic properties.^18,19 These studies suggest an important role for insulin sensitizers in improving the histologic changes of NASH, perhaps by a variety of mechanisms.

In summary, we describe, to our knowledge, the first reported case of multifocal nodular NASH mimicking metastatic disease that dramatically resolved with insulin sensitizer therapy. Rosiglitazone was started when diet, exercise, weight loss, and vitamin E failed to produce improvement in the patient. Radiologic abnormalities resolved with improved glycemic control and insulin sensitivity, both in the fasting and fed states. This case shows the importance of insulin resistance in the development and treatment of NASH.