Context.—Nodular hyperplasia (also referred to as nodular regenerative hyperplasia and nodular regenerative hyperplasia of the liver) is a sequel to therapy with thioguanine in patients with hematologic malignancies. Recently, 6-thioguanine has been used to treat patients with inflammatory bowel disease who have been resistant to other forms of therapy.

Objective.—To study liver biopsies from 3 patients with inflammatory bowel disease who had received thioguanine for more than a year, and who had elevated serum liver enzyme values and underwent percutaneous liver biopsy.

Design.—Percutaneous liver biopsies and histologic examinations were performed, including staining with the reticulin silver impregnation method.

Results.—All 3 patients had foci of nodular regenerative hyperplasia, which was best seen with the reticulin silver impregnation method.

Conclusions.—Thioguanine-treated inflammatory bowel disease patients are at risk for the development of nodular hyperplasia. Reticulin-stained histologic sections are necessary to recognize this change. Further studies are needed to determine the frequency and significance of this change.

In 1884, Sabourin1 described, and beautifully illustrated (Figure 1), the condition he called nodular hyperplasia of the liver. This condition is also known as nodular regenerative hyperplasia of the liver,2,3 micronodular transformation,4 and monoacinar or multiacinar regenerative nodule,5 and is ascribed to livers with small nodules, which are generally 1 mm or less in diameter and often not visible with the naked eye, unless they are extensive. Typically, minimal or no parenchymal fibrosis is present. The nodularity can be indistinct on sections stained with hematoxylin-eosin, but is well demonstrated with silver reticulin impregnation methods, which show double-cell-thick liver plates, generally around a central portal blood supply, with compression of adjacent liver cells and condensation of the surrounding reticulin framework.

Figure 1.

The illustration from Sabourin's 1884 publication.1 

Figure 1.

The illustration from Sabourin's 1884 publication.1 

Close modal

Nodular hyperplasia (NH) occurs in up to 5% of the elderly population, but shows higher prevalence in patients with a variety of systemic diseases, such as polycythemia, rheumatoid arthritis, and polyarteritis nodosa, but also in association with primary biliary cirrhosis and hepatitis C, as well as many other disorders.4,6–28 In one report, a patient with Crohn disease treated with steroids developed NH.3 Nodular hyperplasia has been reported as a phenomenon following liver transplantation,29,30 as well as after renal transplantation31 and bone marrow/stem cell transplantation.32,33 This condition has been described in children34 and even in fetal liver.35 The pathogenesis in most cases is thought to be related to relative, sublethal ischemia4,25,36,37 with reactive liver cell proliferation.

A variety of histopathologic changes, including NH, have been reported as complications of thioguanine therapy, both when it is used as a cancer chemotherapeutic agent and as an immunosuppressive agent.38–47 6-Thioguanine has been effectively used for the treatment of patients with both Crohn disease and ulcerative colitis who fail with traditional thiopurine therapy, often associated with thiopurine-related hepatotoxicity.48 

Other known antineoplastic agents associated with hepatic toxicity include mercaptopurine49 and 5-flurouracil.27 Hepatic toxicity can manifest as hepatocytic injury and cholestasis, but also can cause venoocclusive disease.44 

We recently studied 3 patients with inflammatory bowel disease who were treated with thioguanine. Each patient was treated for approximately 1 year, during which time liver test values were elevated. Liver biopsies showed early NH in each case.

Case 1

A 36-year-old man with a 28-year history of Crohn disease was treated with azathioprine and mesalamine for moderately active disease from 1995 to 1999. Thioguanine therapy was initiated in February 2000 and continued for 17 months. Liver enzyme test values were in the reference range before thioguanine therapy was initiated. Subsequently, he developed elevated liver enzyme values (Table 1) and underwent percutaneous core liver biopsy. The biopsy showed early regenerative nodule formation, seen only with a reticulin silver impregnation method (Figure 2). We found no fibrosis and no evidence of a cholangiopathy.

Table 1.

Liver Test Values

Liver Test Values
Liver Test Values
Figure 2.

Case 1. Early nodular hyperplasia with 2-cell-thick liver plates and slight compression of surrounding hepatocytes, not seen with hematoxylin-eosin (A; original magnification ×40) but apparent with reticulin silver impregnation (B; original magnification ×100)

Figure 2.

Case 1. Early nodular hyperplasia with 2-cell-thick liver plates and slight compression of surrounding hepatocytes, not seen with hematoxylin-eosin (A; original magnification ×40) but apparent with reticulin silver impregnation (B; original magnification ×100)

Close modal

Case 2

A 39-year-old man had a history of steroid-dependent ulcerative colitis for 6 years. He was treated with thioguanine, beginning in July 2000, when therapeutic levels of 6-mercaptopurine metabolite were not obtained during azathioprine therapy. Liver enzyme test results at the start of thioguanine therapy were within the reference range. He received thioguanine for approximately a year, during which time alanine aminotransferase and aspartate aminotransferase values rose, as did the alkaline phosphatase determinations (Table 1). Liver biopsy was performed approximately 1.5 years after the start of thioguanine therapy. Percutaneous liver biopsy showed focal nodule formation (best seen with reticulin) with mild Kupffer cell hyperplasia and mild portal fibrosis. We found no evidence of cholangiopathy.

Case 3

A 33-year-old man with a 20-year history of Crohn disease had undergone ileal resections on 3 occasions for complications. While receiving tacrolimus and 6-mercaptopurine, he continued to have obstructive symptoms with fistula formation. He was then treated with thioguanine and 5-aminosalicylic acid, beginning October 2000. He had symptomatic improvement. Liver enzyme values in July 2001 were elevated (Table 1), and he underwent percutaneous core liver biopsy 6 months later. The biopsy showed focal nodule formation (best seen with reticulin) with mild Kupffer cell hyperplasia and mild portal fibrosis. We found no evidence of cholangiopathy.

Thioguanine has been added to the armamentarium for the treatment of Crohn disease in those patients for whom more conventional immunomodulator therapy is of limited effectiveness.48 Thioguanine is a purine antagonist that has principally been used in the treatment of hematologic malignancies. It has been reported to cause liver cell necrosis14 and jaundice,46,50 generally in association with venoocclusive disease. Both venoocclusive disease and the Budd-Chiari syndrome have been reported in patients taking thioguanine alone or with other drugs.13,32,38–40,43,51,52 Thioguanine therapy has also been suggested as a cause of peliosis hepatis.42 

Nodular hyperplasia is an uncommon liver disorder characterized by nodules of regenerative hepatocytes, at first irregularly distributed throughout the liver but eventually becoming diffuse, in the absence of or with minimal associated fibrosis. Ranström53 and Steiner,2 who popularized the term nodular regenerative hyperplasia and defined it as a unique entity, are generally credited with the first descriptions of this condition, although it was described earlier by both Sabourin1 and Jacobi54 (Table 2). In addition, Sabourin cited an earlier description of this entity by Kelsch and Kiener in 1878. A variety of terms have been applied to this distinctive process (Table 3).

Table 2.

Landmark Articles in the Recognition of Nodular Hyperplasia of the Liver

Landmark Articles in the Recognition of Nodular Hyperplasia of the Liver
Landmark Articles in the Recognition of Nodular Hyperplasia of the Liver
Table 3.

Nodular Hyperplasia Synonyms

Nodular Hyperplasia Synonyms
Nodular Hyperplasia Synonyms

More than 250 cases of NH have been reported to date. Nodular hyperplasia showed an incidence of approximately 2.5% in a study of 2500 autopsies4 and has been identified in 0.5% of 3820 liver biopsies.10 

Clinically, NH can be present without signs or symptoms, can be associated with biochemical abnormalities in the absence of physical signs, and can also be the cause of profound portal hypertension.3,4,8,10,12,14,17,35 Clinical features of a large group of patients treated with 6-thioguanine were reported recently.55 The list of associated conditions is long4,37,56,57 (Table 4), and the presence of portal hypertension in a patient with one of these disorders should suggest the possibility of NH.

Table 4.

Nodular Hyperplasia Associations*

Nodular Hyperplasia Associations*
Nodular Hyperplasia Associations*

Macroscopically, the surface of the liver may be unremarkable or may show an almost imperceptible fine nodularity that can easily be overlooked. The nodules are usually 1 mm or less in diameter. In some cases, some of the nodules may be more prominent and can be seen bulging beneath the capsule. The cut surface of the unfixed liver may also appear relatively normal, until closely inspected with a magnifying lens. Nodular hyperplasia and early micronodular cirrhosis can be macroscopically similar in appearance, although micronodular cirrhosis is noticeably firm because of the connective tissue septa. Nodular hyperplasia, in the absence of fibrosis, has approximately the same consistency as normal liver. Micronodular cirrhosis also tends to be lighter in color. Generally, nodularity becomes more apparent after fixation.

The histopathologic features of NH are usually more easily appreciated in an explant or wedge biopsy specimen than in a needle core biopsy. The appearance of NH in a core biopsy may be quite subtle. When apparent with hematoxylin-eosin, it is generally best appreciated with low-power magnification. An approximately circular zone of normal-sized or slightly enlarged hepatocytes is seen, generally centered on portal tracts. Sinusoids are relatively indistinct. The hyperplastic area is surrounded by a rim of compressed, atrophic-appearing hepatocytes. The liver plates are either 1 or 2 cells thick. The portal tracts themselves are unremarkable. Sinusoidal spaces are compressed, but endothelial and Kupffer cells are not significantly changed.

Reticulin silver impregnation staining is particularly useful in the recognition of NH, which can be overlooked if only hematoxylin-eosin preparations are studied. The reticulin accentuates the nodular appearance, because of the condensation of the reticulin network in the peripheral rim of compressed hepatocytes. Reticulin also makes 2-cell-thick plates more obvious. Connective tissue stains, such as Masson trichrome, are less helpful because fibrosis is not classically a feature of this condition. These stains are useful, however, to document the absence of fibrosis.

The needle biopsy findings must be differentiated from partial nodular transformation and focal nodular hyperplasia (FNH)19,56 and from dysplastic foci.5 Partial nodular transformation is a rare cause of portal hypertension and is almost always perihilar and consequently rarely seen in liver biopsies, except when the perihilar lesion is deliberately biopsied. Distinguishing FNH from NH can be impossible if the typical central scar of FNH is not sampled and if the zone of compressed hepatocytes in NH is not appreciated. Similarly, the diagnosis of cirrhosis can be impossible to establish on the basis of histopathology alone when the nodular portion of cirrhosis is obtained without the fibrous septa, as is often the case when relatively small biopsy needles are used. Dysplastic foci typically show irregular margins, do not form around portal tracts, and usually do not have surrounding rims of compressed, atrophic-appearing hepatocytes.5 

Nodular hyperplasia may be overlooked when (1) a relatively small-caliber core biopsy is obtained, (2) only hematoxylin-eosin slides are studied, and (3) the pathologist is unfamiliar with this uncommon disorder. In addition, if the nodular changes are not diffuse, the diagnostic changes may be missed completely by the needle. In our cases, the nodularity was focal. Compression of adjacent hepatocytes was present, but even with reticulin stain, it was subtle. The principal feature was nodularity due to conversion to 2-cell-thick liver plates. It has been recommended that wedge biopsy or laparoscopically guided needle core biopsy be used when a diagnosis of NH is suspected.57 In our experience, as well as in the experience of others,11 percutaneous or transjugular needle biopsy can be relied on if the pathologist is sensitive to the subtle nodularity characteristic of this condition and, particularly, if the reticulin stain is routinely used.

Vascular compromise is thought to be the basis of NH.4,5,23,25,29,36,37 The hypothesis is that partial or complete portal vein obstruction, or some other cause for diminished hepatic blood flow, initially causes sublethal hepatic ischemia or hepatocellular atrophy, which is accompanied by hepatic artery dilation with subsequent increase of arterial flow, perhaps accompanied by the release of hepatotropic growth factors, leading to hepatocellular hyperplasia and the formation of nodules.37 Obliterative vascular changes were seen in all 64 cases studied at autopsy in which NH had been diagnosed.4 Nodular hyperplasia can develop in patients with congestive heart failure,2 further supporting the theory that the first step in the development of this distinctive morphologic entity is reduction of effective blood flow.

Thioguanine has been strongly implicated as a cause of vascular damage in patients who have undergone bone marrow transplantation.44,45 Early fibrosis, with deposition of collagen in the space of Disse, has been well demonstrated.45 The frequency of occurrence of NH and/or of fibrosis in inflammatory bowel disease patients undergoing treatment with thioguanine is not known and awaits a comprehensive prospective study.

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Author notes

Reprints: Stephen A. Geller, MD, Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 ([email protected])