Micronodular Transformation (Nodular Regenerative Hyperplasia) of the Liver: A Report of 64 Cases Among 2,500 Autopsies and a New Classification of Benign Hepatocellular Nodules IAN R. WANLESS From the Department of Pathology, Toronto Western Hospital and the University of Toronto, Toronto, Canada

Nodular regenerative hyperplasia is defined by hepatocellular nodules distributed throughout the liver in the absence of fibrous septa between the nodules. Most reports have been single cases so that the prevalence and clinical significance of nodular regenerative hyperplasia is uncertain. In this study, the hepatic histology of 2,500 consecutive autopsies was reviewed. A spectrum of nodular transformation was found with nodular regenerative hyperplasia present in 2.6% of autopsy livers and qualitatively similar but lesser degrees of nodular transformation in a further 10.2%. Nodular transformation was also seen in 47% of livers with cirrhosis and 69% with incomplete cirrhosis. Obliteration of many small portal veins was seen in all cases with nodular regenerative hyperplasia, but only 4.7% of these had evidence of portal hypertension. The prevalence of various clinical states was compared in nodular regenerative hyperplasia and in controls. The results confirm, extend and quantify the spectrum of associated diseases. Nodular regenerative hyperplasia occurs in 5.6% of individuals over age 80 and with increased frequency in patients with systemic arteritis, polymyalgia rheumatica, massive tumor infiltration and mineral oil deposition. Nodular regenerative hyperplasia appears to be the hepatic analogue of arterial and arteriolar nephrosclerosis. A new classification of nodular transformation is proposed that encompasses the spectrum of lesions described here and the previously defined entities of focal nodular hyperplasia, partial nodular transformation and “cirrhosis telangiectasia hepatis.” The major conclusion is that nodular regenerative hyperplasia is a secondary and nonspecific tissue adap-

tation to heterogeneous distribution of blood flow and does not represent a specific entity. (HEPATOLOGY 1990; 11:787-797.)

Nodular regenerative hyperplasia (NRH)of the liver is a condition characterized by diffuse micronodular transformation of the hepatic parenchyma without fibrous septa between the nodules (1-4).This lesion may be associated with features of portal hypertension and subclinical cholestasis. In most previously published cases, patients have had a chronic systemic disease such as rheumatoid arthritis, a lymphoproliferative disorder o r a myeloproliferative disorder that antedated the diagnosis of liver disease. The exact pathogenesis of NRH is not established. It has been suggested that obliteration of portal veins may initiate the nodular transformation (4). Recently, NRH has been associated with systemic arteritis (5, 6 ) . Most of the literature concerning NRH has been reported from clinical research units, usually as single case reports. The absence of a control group has allowed the opportunity for bias toward symptomatic cases and has prevented adequate evaluation of possible etiological factors. To overcome these difficulties, a retrospective study of consecutive autopsies was undertaken that revealed a spectrum of lesions that cannot be easily conceptualized using the existing nomenclature. Therefore, a new classification of nodular transformation is proposed. MATERIALS AND METHODS A total of 2,535 consecutive and complete adult autopsies

performed at Toronto Western Hospital between 1973 and 1986 was reviewed. Cases were excluded if the glass slides of Received September 12, 1989; accepted December 18, 1989. liver tissue were insufficient because of tumor infiltration ( 14 This work was presented in part at the 75th Annual Meeting of the cases), severe autolysis (one case) or if the slides were lost (20 International Academy of Pathology and has been published in abstract form cases). The remaining 2,500 cases were assessed for the (Lab Invest 1986;54:67A). presence of architectural abnormalities including regional A detailed bibliography, includinga list of the cases tabulated in the literature variation in hepatocyte size and the presence of nodularity. review, may be obtained from the author on request. Zone I11 atrophy with congestion in a pattern typical of chronic This work is dedicated to Dr. Aron M. Rappaport, friend and forebear. passive congestion was ignored in this study. Address reprint requests to: Dr. I.R. Wanless, Department of Pathology, Micronodular transformation was diagnosed if the parenToronto Western Hospital, 399 Bathurst Street, Toronto, Canada, M5T 2S8. 31/1/20066 chyma contained hepatocellular nodules less than 3 mm in 787

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TABLE1. Architectural abnormalitiesin 2,500 consecutive autopsies tabulated according to proposed classification Proposed classification

synonyms”

Number

Percentage ~

Focal atrophy without nodules Nodular transformation, type 1 (ischemic) Micronodular transformationb, grade 1-2 Micronodular transformation, grade 3 Macronodular transformationd Nodular transformation with fibrous septa Nodular transformation with cirrhosis

Nodular transformation, type 2 (hyperemic) Nodular transformation, type 2, solitary Nodular transformation, type 2, multiple Nodular transformation, type 3 (neoplastic)

Focal atrophy, infarct of Zahn

305

12.2

Focal atrophy, hyperplasia Nodular regenerative hyperplasia (2)’ Partial nodular transformation (24)’ Adenomatous or hyperplastic changes in incomplete septal cirrhosis (9) Adenomatous (22) or hyperplastic (23) changes in cirrhosis

256 64 2 36

10.2 2.6 0.08 1.4

64

2.6

14 7 0

0.6 0.3 0

Focal nodular hyperplasia (25)’ Multiple focal nodular hyperplasia (26) “Cirrhosis hepatis telangiectasia” (27, 28Y Adenomatosis (29, 30)

0

0

“These synonyms reflect historical, and not necessarily current, usage. *Nodules predominantly less than 3 mm diameter and fibrous septa grade 0 to 1. “Alsomiliary hepatocellular adenomatosis (l),adenomatous hyperplasia (31), nodular transformation (3), noncirrhotic nodulation (32). dNodules predominantly larger than 3 mm diameter and fibrous septa grade 0 to 1. Type 1 has nodules arising because of ischemic atrophy in internodular tissue; type 2 has nodules arising because of focal hyperemia resulting from arterial enlargement. ‘Also adenoma (33). W s o hamartoma, focal cirrhosis (34). #Also atypical cirrhosis or pseudocirrhosis of hereditary hemorrhagic telangiectasia.

diameter that were not surrounded by fibrous tissue. Nodular transformation was graded 0 to 3 + according to the degree of contrast between nodular and internodular tissue. When nodules were present but indistinct or only occasionally distinct, the liver was graded 1+ or 2 . Livers were graded 3+if the nodularity was distinct in most areas examined and was considered comparable with published cases of NRH. Livers were also graded for the presence of fibrous septa: 0 = no septa, 1 = occasional septa not surrounding nodules, 2 = occasional septa, some surrounding nodules ( = incomplete cirrhosis), 3 = septa surrounding many nodules ( = cirrhosis). Sixty-four cases having grade 3 nodular transformation and grade 0 to 1 septa were called NRH. Cases of nodular transformation with nodules larger than 10 mm were classified as macronodular transformation and excluded; one of these was published separately as partial nodular transformation (7). Various morphological parameters were semiquantitated (grade 0 to 3 + except arterial changes and dysplasia as grade 0 to 2 + ) by examination of one hematoxylin and eosin or hematoxylin-phloxine-saffron-stained slide of each case of NRH and an equal number of age-matched and sex-matched controls not having cirrhosis or nodular transformation. Each parameter was determined on a separate day. Parameters examined included obliterative portal venopathy (81,hyaline arteriolosclerosis, arterial fibrosis without hyaline change, mineral oil granulomata and hepatocellular “dysplasia.” Dysplasia was defined as nuclear enlargement and hyperchromatism with irregular contour of nuclear membranes. In a separate study, obliterative portal venopathy in livers with NRH was compared with that in cases having milder degrees of nodular transformation. For this comparison, each NRH case was matched for age and sex with three cases having moderate, mild and no micronodular transformation, respectively. The slides of the four groups were graded blindly.

+

To test the significance of various clinical associations, the prosector’s summary of the hospital charts of the 64 NRH cases and of 420 consecutive adult autopsies without NRH (controls)were reviewed for age, sex and evidence of hepatic or systemic diseases. Hypertension was defined as a diastolic pressure 3 100 mm Hg. A random subset of 120 controls was assessed in more detail for various autopsy and clinical parameters. Coronary and aortic atherosclerosis was graded according to the prosectors’ descriptions. Myocardial infarct was defined by a focal scar recognizable by gross inspection or a substantial focus of acute necrosis on microscopic examination. Cases of NRH were subdivided into five groups based on associated disorders: immune complex diseases (NRH-11, lymphoproliferative disorders (NRH-2), myeloproliferative disorders (NRH-3), massive hepatic metastases found at autopsy (NRH-4) and none of these (NRH-5). The complete hospital record for each patient with NRH was reviewed for additional clinical findings, including liver function tests. The literature was reviewed. The cases reported in detail having diffcse hepatic involvement with nodules predominantly less than 3 mm in diameter (i.e., excluding partial nodular transformation) are shown later in Table 5.

RESULTS Architectural abnormalities were found in 833 of the 2,500 autopsies. The abnormalities presented a continuous spectrum that was arbitrarily divided into entities using a new classification (Table 1). Nodular transformation was recognized by regions of atrophy juxtaposed to normal or hyperplastic regions with a curved contour and no intervening fibrous septum. Nodular transformation was seen in 69% of livers with incomplete cirrhosis. Nodular transfor-

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100

Percent of cases

OPV

Grade 1

50

0

FA G r a d e 2 Bl G r a d e 3

0

1

2

3 INRHI

InOrmslJ

Micronodular transformation (grade)

FIG. 1. Prevalence of obliterative portal venopathy (OPV) in livers with various grades of nodular transformation that were age-matched and sex-matched to the 64 cases with NRH (nodular transformation grade 3).

FIG. 2. Liver slice showing uniform micronodular transformation. The nodules measure 1 to 2 mm in diameter. (Bar = 5 mm.)

TABLE 2. Histological features of liver in NRH and controls"

Obliterated portal veins Hyaline arteriosclerosis Arterial fibrosis Mineral oil deposits Dysplasia

Controls

NRH-all

=-I

NRH-2

NRH-3

NRH-4

NRH-5

Grade

(N= 64)

(N = 64)

(N = 7 )

(N = 5 )

(N =

( N =7 )

(N = 44)

2-3 + 1-2+ 1-2+ 2-3 + 2t

24 (38) 41 (64) l(1.6) 12 (19) 11 (17)

57 (89)' 41 (64) 12 (19)' 21 (33) 9 (14)

5 (71) 3 (43) 4 (57)' 2 (29)

5 (100)' 3 (60) 3 (60)' 1(20) 1(20)

1(100) 0 (0) O(0) O(0) O(0)

7 (loold 104) O(0) O(0) 1(14)

39 (89)b 34 (77) 5 (11) 18 (41y 7 (16)

0 (0)

1)

NRH- 1 = Immune complex diseases (includes rheumatoid arthritis, 2; Felty's syndrome, 2; polyarteritis nodosa, 1; progressive systemic sclerosis, 1;systemic lupus erythematosus, 1); NRH-2 = lymphoproliferative disease (includes chronic lymphatic leukemia, 2; Waldenstrom's macroglubulinemia, 2; myeloma, 1; lymphoma, 1); NRH-3 = myeloproliferative disease; NRH-4 = massive metastatic liver disease; NRH-5 == Other. "The numbers in parentheses are percentages. bp < 0.001. cp < 01.05. dp < 0.01. =p < o1.002. fp < 0.02.

mation was also seen within the cirrhotic nodules in 69% of livers with macronodular cirrhosis, 45% of those with mixed macronodular and micronodular cirrhosis and in 39% of micronodular cirrhosis. After exclusion of cases with cirrhosis or incomplete cirrhosis, micronodular transformation was found in 320 cases, 64 of which had sufficient nodularity (grade 3) to warrant the diagnosis of NRH. Obliterative changes in portal veins were seen in all livers with nodular transformation. The percentage of livers having severe obliterative portal venopathy was proportional to the degree of nodular transformation (Fig. 1). Hepatic Morphology o f NRH (Micronodular Transformation Grade 3). Formalin-fixed wet tissue was available for review in 22 cases with NRH. The typical

gross appearance of NRH was seen in all of these cases (Fig. 2). The capsular surfaces were finely granular with surface elevations less pronounced than in cases of

micronodular cirrhosis. The nodules were usually paler than the rest of the parenchyma. On cut section, most of the nodules were less than 2 mm in diameter. Microscopically,the nodules were composed of benignappearing hepatocytes often arranged in double-cell plates (Fig. 3) (4).The hepatocytes between nodules were atrophic with scanty cytoplasm. Hepatocyte nuclei within nodules were often smaller and more uniform than nuclei between nodules. When the nodules in NRH were compared with the nodular transformation within individual cirrhotic nodules, the cytological and architectural appearances were identical. Various histological features in NRH and controls were semiquantitated and summarized in Table 2. Portal vein obliteration (grades 2 or 3) was present in 89% of cases and in 38%of controls (p < 0.001) (Figs. 4 and 5 ) . Fibrosis of arteries was found more often in NRH cases than in controls (19 vs. 1.6%,p < 0.002). Arterial

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TABLE 3. Clinical and autopsy features in present series and in literature

Organ weights" Myeloproliferative diseases excluded Liver, males Liver, females Spleen, males Spleen, females Liver, varices absent Liver, varices present Spleen, varices absent Spleen, varices present Splenomegalyb Myeloproliferative diseases Liver, males Liver, females Spleen, males Spleen, females Other features' hcitesd Varices Variceal hemorrhage Death from variceal hemorrhage

NRH

Control

1,475 (34) 1,294 (21) 211 (33) 167 (22)

1,390 (57) 1,293 (54) 178 (59) 141 (52)

NFlH in literature

1,550 (20) 1,232 (17) 526 (17) 440 (20) 1,559 (20) 1,221 (17) 409 (18) 546 (19) 41% 2,632 (3) 2,144 (5) 1,389 (4) 1,071 (5)

4.7 1.6 0 0

2.5 0 0

0

26 54 19 21'

"Weightsin grams. Number of cases in parentheses. 'Splenomegaly = clinical splenomegaly or spleen weight > 200 gm. 'Percentage of cases. N = 120 for controls. dAscites = peritoneal fluid > 300 ml not explained by congestive heart failure, local peritoneal disease, massive hepatic tumor or cirrhosis. 'Percentage of 62 deaths.

fibrosis was especially common in NRH patients having immune complex diseases (NRH-1) or lymphoproliferative diseases (NRH-2) (63% and 80%, respectively). One patient in group NRH-1 had acute arteritis and arterial fibrosis. In contrast, the prevalence of hyaline arteriosclerosis was equal in NRH and controls. The arterial fibrosis involved arteries between 40 and 160 pm in diameter in seven cases with NRH and larger arteries (300to 600 pm) in two cases (one with temporal arteritis and the other with rheumatoid arthritis and hyperviscosity). The small artery fibrosis was characterized by intimal or medial fibrosis, or both, with loss of muscle fibers and loss of definition of the margins between intima and media (Figs. 6,7 and 8).The large artery lesions were characterized by marked intimal fibrous thickening without disruption of the internal elastic lamina. Definite arterial fibrosis was typically seen in only a few arteries of a large autopsy section. Mineral oil deposits were more commonly seen in the NRH group than in controls (64% vs. 41%, p c 0.02). Deposits were especially prominent in group NRH-5 (Table 2). Hyperchromatism of nuclei was present focally in 78% of NRH cases and 75% of controls. Mild dysplasia was present in 14% of NRH cases and 17% of controls. Severe dysplasia was not seen in any case or control. Tissue evidence of cholestasis was present in 10 cases of NRH, six of which had massive hepatic metastases. The weights of livers, spleens and hearts were no different from those of controls (Table 3). Clinical Features of NRH. The percentages of cases

and controls having selected diseases are listed in Table 4. The NRH cases were older than the controls. The calculated percentage of autopsy patients 80 or more years of age having NRH was 5.3%. Although the numbers are too small in most disease groups for statistical analysis, the prevalence of NRH was apparently increased among patients with various forms of immune-mediated diseases, chronic lymphatic leukemia, macroglobulinemia, Hodgkin's disease and massive metastatic carcinoma. Among the four patients younger than 60 yr, three had one of these diseases: rheumatoid arthritis (two), agnogenic myeloid metaplasia (one). There was no association with atherosclerosis, congestive heart failure, hypertension, diabetes mellitus or obesity. One patient had HCC associated with hemochromatosis. Four patients probably had used alcohol moderately. Three patients had a clinical history of polymyalgia rheumatica, two of them had cranial nerve symptoms but normal temporal artery biopsy specimens. NRH was diagnosed before death in one patient who also had esophageal varices and ascites. This was the only patient with documented esophageal varices but these were asymptomatic. Endoscopy was performed on only five of the 64 patients. Ascites was noted clinically in eight patients and was explained by abdominal malignancy or severe congestive failure in all but three cases. In one of these three, the ascites was transient and not present at autopsy and in another ascites was massive and longstanding. Hepatosplenomegaly was noted clinically in four

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FIG.3. Micrograph of liver with nodular transformation showing a portion of a nodule (top) 0.8 mm in diameter that contains a portal tract with widely patent portal vein. The nodule is demarcated by atrophy rather than by fibrosis. An isolated duct is present in the atrophic area (bottom). (Hematoxylin-phloxine-saffron, x 160.)

FIG.4. Micrograph of liver with nodular transformation showing a nodule (top right) and a portal tract with obliterated portal vein in the atrophic perinodular tissue. A few mineral oil droplets are present in the portal tract. (Hematoxylin-phloxine-saffron,x 140.)

patients, hepatomegaly in another five and splenomegaly in another four. All but two of these patients had diseases commonly associated with organomegaly (lymphoma, heart failure, metastatic liver disease, Felty’s syndrome and agnogenic myeloid metaplasia). Liver function tests were normal in most patients tested. Alkaline phosphatase was elevated to more than 1.5 times the upper limit of normal in 22 of 62 patients (35%) but in only seven patients (11%) could this elevation not be explained by liver metastases, moderate to severe congestive heart failure or duct obstruction. Only four patients had unexplained alkaline phosphatase greater than twice the upper limit of normal. One of these with acute arteritis in the liver had an alkaline phosphatase level of 204 IU/L (Nc loo), a bilirubin level of 3 mg/dl, and an AST level of 55 IUD,. The other three had normal AST, and one had mild hyperbilirubinemia and transiently elevated plasma ammonia.

Clinical history of vasculitis correlated with the presence of hepatic arterial fibrosis. Of the four patients with arterial fibrosis in NRH-1, all had clinical evidence of vasculitis (skin rash or nailbed infarcts in three, multiorgan disease in one). Of the three cases with arterial fibrosis in NRH-2, two had glomerulonephritis (one with skin rash). Of the five with arterial fibrosis in NRH-5, one had polymyalgia rheumatica but no clinical evidence of vasculitis. REVIEW OF THE LITERATURE Approximately 180 cases of NRH are reported in the literature. Of these, 135 were reported with individual case histories and are summarized in Tables 3 and 5 and 69 cases had immunological diseases, including 30 with rheumatoid arthritis, 8 with systemic lupus erythematosus, 5 with progressive systemic sclerosis, and 12 with a monoclonal gammopathy . Of those with rheumatoid arthritis, 25 had Felty’s syndrome. Fourteen had a

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FIG.5. Portal tract with obliterated portal vein. The largest vessel present is one-quarter the diameter of a normal portal vein. (Hematoxylin-phloxine-saffron, x 410.)

myeloproliferative disorder. Forty cases had miscellaneous conditions including kidney transplants (11 cases), toxic oil syndrome (five cases) and diverse conditions of uncertain relevance. Systemic disease was not mentioned in 10 cases. Examination of Table 5 reveals many cases with evidence of small vessel disease in various organs. Cutaneous or deep vasculitis was present in 12, Raynaud’s phenomenon in 12, pulmonary hypertension in 7, and glomerulonephritis in 12. The patients with monoclonal gammopathies often had evidence of small vessel injury with cryoglobulinemia or hyperviscosity. Recent portal vein thrombi were noted in 5 cases. Kidney transplantation had been performed on 16 patients. Six patients had veno-occlusive lesions, often with marked focal sinusoidal dilatation (“peliosis”). Clinical evidence of portal hypertension was the major complication with varices reported in 54% and ascites in 26%. Variceal hemorrhage was reported in 19% of the cases and was the cause of death in 21% of the patients who died.

FIG.6. Small hepatic arteries from a patient with NRH who died with active polyarteritis nodosa. (A) Acute arteritis in 145-pm diameter vessel. Note inflammatory distortion of the adjacent duct (arrows) (H & E, ~ 2 7 0 . (B) ) Healing arteritis in 155-pm diameter vessel. (HPS, original magnification x 310.)

Liver function tests were reported for 106 cases. Alkaline phosphatase was elevated in 59%, AT.,T or AST in 28% and jaundice was mentioned in 11%of cases. DISCUSSION This study reveals that NRH occurs as part of a spectrum of architectural changes known as nodular transformation. As summarized in the proposed classification (Table 1>,this spectrum has several dimensions,

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TABLE4. Percentage of patients having various conditions NRH con7ml Relative ~

n

Age < 60yr Age 60-79yr Age > = 80 yr Percent men Felty’s syndrome Progressive systemic sclerosis Agnogenic myeloid metaplasia Polyarteritis nodosa Polymyalgia rheumatica Chronic lymphocytic leukemia Waldenstrom’s disease Systemic lupus erythematosus Rheumatoid arthritis Hodgkin’s disease Lymphocytic thyroiditis Non-Hodgkin’s lymphoma Congestive heart failure* All cancer Hypertension* Diabetes mellitus type 11* Myeloma Massive liver metastases Infarcts of brain, kidney, or spleen* Coronary artery disease, severe* Atherosclerotic aortic aneurysm* Pulmonary embolus* Myocardial infarct*

=

64

6.2 48.4 45.3 57.8 3.1 1.6 1.6 1.6 3.1 3.1 3.1 1.6 6.2 3.1 4.7 4.7 31.2 42.2 20.3 12.5 1.6 12.5 37.5 45.3 12.5 15.6 35.9

n

=

420”

24.3 53.6 22.1 55.7 0 0 0 0 0.2 0.5 0.5 0.2 1.2 0.7 1.9 3.8 30.0 41.0 20.8 12.9 1.9 5.2 35.0 47.5 13.3 17.5 50.8

ratio

p Value

0.26 0.90 2.05 1.04 Increased Increased Increased Increased 13.1 6.56 6.56 6.56 5.25 4.38 2.46 1.23 1.04 1.03 0.97 0.97 0.82 2.39 1.07 0.95 0.94 0.89 0.71

< 0.01 c: 0.001

< 0.05

< 0.05

“For conditions marked*, the control group contained 120 consecutive autopsies aged 2 60 yr.

including severity and extent of liver involvement, size of nodules, degree of fibrous septation and type of vascular lesion. The common factor in all parts of this spectrum is an apparent heterogeneity of hepatic blood supply. In focal nodular hyperplasia and “cirrhosis telangiectasia hepatica” (of hereditary hemorrhagic telangiectasia), the primary abnormality appears to be a focal augmentation of arterial blood flow. In the remaining conditions there is obliteration of portal veins, documented semiquantitatively in this study and by morphometry in an earlier study (4). It has been suggested that, in NRH and partial nodular transformation, portal vein obliteration leads to atrophy of hepatocytes in the supplied acini (4, 7). It follows from this suggestion and from the present study that a small number of portal vein lesions will lead to small foci of atrophy, probably without nodule formation. If a larger number of portal veins is obliterated, the acini with intact portal venous supply will stand out in relief as more or less spherical nodules. When many portal veins are obliterated, portal hypertension occurs. Because nodularity is present in many cases that have no clinical evidence of portal hypertension, nodularity is a more sensitive indicator of portal venous obliteration than is clinical portal hypertension. One can also conclude from this observation that compression of vessels by nodules is not likely to be responsible for portal hypertension in patients with NRH.

The degree of fibrous septation is determined by the amount of necrosis and acinar fibrosis occurring during the active phase. Necrosis is probably minimal during the development of pure NRH and prominent in cirrhotogenic conditions such as CAH and alcoholism. Nodular transformation often occurs within the nodules bound by fibrous septa in cirrhosis, probably because of variable blood supply in the cirrhotic nodules. This is a major source of diagnostic confusion, especially with small biopsies. The qualitative similarity of the nodules of NRH and those of incomplete and complete cirrhosis has been noted by others (9-11). Two features of the present study are the relative absence of selection bias and the inclusion of a control group. The results suggest that the collected literature concerning NRH is biased toward cases having symptoms or abnormal liver function tests. Only 1 of 64 cases in this series had documented varices, compared with 73 of 135 in the literature. Similarly, unexplained alkaline phosphatase elevation was noted in only 11%of the present series, compared with 59% of cases in the literature. Hepatomegaly is probably not an integral feature of NRH, although it may occur, especially in the myeloproliferative syndromes. Rather, the liver weights in this study and in the literature are normal. Furthermore, the livers with NRH in the presence of varices tend to be smaller than the livers not associated with varices. This

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TABLE 6. Summary of conditions associated with 136 cases of NRH in the literature Diagnosis

Immunological disorders Rheumatoid arthritis

Number

Comments

30

25 Felty’s syndrome, 6 vasculitis (3 cutaneous, 5 deep), 2 hyperviscosity syndrome, 1 cryoglobulinemia, 1 amyloid, 3 Rsynaud’s phenomenon, 3 pulmonary hypertension, 3 pulmonary fibrosis, 2 glomerulonephritis, 1diabetes 1thyroiditis, 2 glomerulonephritis, 4 vasculitis (2cutaneous, 2 deep), 2 pulmonary hypertension, 1 hyperviscosity, 3 Raynaud’s phenomenon, 1 kidney transplant with VOD 4 Raynaud’s phenomenon, 2 CRST, 1 vasculitis (cutaneous and deep) Diabetes mellitus

Systemic lupus erythematosus

8

Progressive systemic sclerosis

5

Raynaud’s phenomenon Polyarteritis nodosa Glomerulonephritis Membranous Membranoproliferative Cryoglobulinemia Goodpasture’s Chronic Monoclonal gammopathy, I& or IgA IgM (Waldenstrom’s disease) Myasthenia gravis Idiopathic thrombocytopenic purpura Hashimoto’s thyroiditis PBC Myeloproliferative disorders Agnogenic myeloid metaplasia Chronic myeloid leukemia Polycythemia rubra Vera Primary thrombocythemia Miscellaneous End-stage renal disease

1 1

12

Toxic oil syndrome Diabetes mellitus Portal vein thrombosis Primary pulmonary hypertension Others”

5 3 3 2 17

2 1 1 1

2

Kidney transplant, azathioprine Kidney transplant 2 kidney transplants, one peliosis

8 4 2 1 1 1

1 POEMS, 1 pulmonary hypertension, 2 amyloid 2 cryoglobulinemia and vasculitis, 1 CLL, 2 lambda, 2 kappa 2 azathioprine

6 4 3

1hydroxyurea 4 busulfan-thioguanine, 1 portal vein thrombosis 1 portal vein thrombi

1 Raynaud’s phenomenon

1

11 with transplantation (usually treated with azathioprine), 1 diabetes, 2 VOD/peliosis, 1VOD, 2 peliosis 1 pulmonary hypertension, 2 PSS-like, 1VOD

1pulmonary embolihnfarcts

VOD = veno-occlusivedisease; CRST = a syndrome comprised of calcinosis cutis, Raynaud’s phenomenon, scleroderma and telangiectasis; POEMS = a syndrome comprised of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes; CLL = chronic lymphatic leukemia; PSS = progressive systemic sclerosis. “One each of carcinoma of rectum, Down syndrome, tuberculosis, Krabbe’s disease, bacterial endocarditis, mitral valve disease, myocardial infarct, cerebral infarct, peripheral vascular diseasehypertension,hyperthyroidism, hypothyroidism, lymphomatoid granulomatosis, polycystic renal disease, hepatic adenoma, HCC, alcohol abuse, CAH.

would be expected if NRH is a result of ischemic atrophy. This study confirms the association of NRH with immune complex, lymphoproliferative and myeloproliferative disorders. This study includes the first report, to my knowledge, of NRH with polymyalgia rheumatica. Also noted in this study are associations with advanced age and massive metastatic carcinoma. Each of these associations provides an independent clue to the pathogenesis of NRH. The association with immunological diseases may be explained by the presence of hepatic arteritis causing obliteration of the small arteries and their adjacent portal veins (the “menage a foie” phenomenon) (12). Similarly, gammopathies may be causative via arteritis secondary to insudation of monoclonal proteins (13).

Because most patients with peliosis or veno-occlusive disease had kidney transplants, it was suggested that azathioprine might be the cause of these vascular lesions (14,15). Further evidence that toxins may produce NRH is supported by the report of cases with chronic myelogenous leukemia treated with busulfanthioguanine (16). In addition, patients with the toxic oil syndrome often have NRH and cutaneous and pulmonary vascular lesions (17). Examination of NRH cases having massive metastases revealed that the carcinoma usually invaded multiple small portal veins. The mechanism of the association of NRH with chronic lymphatic leukemia (CLL)is not certain. One previously reported case had a coexistent monoclonal gammopathy (12) but this was

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FIG.8. Portal tract vessels showing marked intimal fibrosis of an artery (bottom) and adjacent portal vein. The vein has two lumina separated by a fibrous bridge (arrow), suggesting that arteritis had caused local portal vein inflammation with secondary thrombosis and recanalization. This patient also had healed arteritis in the gallbladder. (HPS, original magnification x 190.)

FIG.7. This patient was a woman who presented at age 64 with an IgG-lambda monoclonal serum protein and rapidly progressive crescentic glomerulonephritis. She was maintained on dialysis and died 8 yr later with multiple myeloma. The liver showed NRH at autopsy. (A) renal arteriole (40-pm diameter) at first presentation showing large intimal insudate. (HPS, original magnification x 1,100.) (B) Hepatic arteries (85 and 100 pm diameter) at autopsy showing intimal and medial fibrosis. (HPS, original magnification x 240.)

not documented in the present two cases with CLL. The portal tract infiltrates may contribute to portal vein obliteration and the rare occurrence of portal hypertension with CLL (18). The association of NRH with age may be related to portal venous lesions occurring in the majority of elderly individuals (81, possibly as a result of multiple small

thrombi or a reaction to mineral oil deposits (19).A role for alcohol abuse may exist in the pathogenesis of NRH. Of the four patients with suspected alcoholism in this series, one had massive ascites and one had transient encephalopathy and splenomegaly. I have seen several cases of NRH in alcoholics with portal hypertension not included in this series. It is possible that incomplete cirrhosis in the recovering alcoholic can undergo resorption of the more delicate fibrous septa, leaving irreversible vascular obliteration accompanied by nodular transformation and recognized as NRH. The importance of portal venous lesions in the pathogenesis of NRH has been stressed because of the close association of NRH with histological evidence of portal vein lesions. However, it is possible that arterial lesions are also important. Atrophy of an acinus is more likely to develop if both the arterial and venous supply are impaired; in this situation compensatory dilatation of the artery cannot ameliorate the ischemia produced

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by a venous lesion. Thus arteriosclerosis of aging might that are identical to those seen in micronodular transact in concert with portal vein lesions occurring by formation. The differentiation of macronodular and chance in the same acinus. NRH may be the hepatic micronodular transformation is helpful in distinequivalent of arterial and arteriolar nephrosclerosis guishing lesions caused by portal vein thrombosis from related to advanced age. The low prevalence of NRH those caused by portal tract inflammation. Macrocompared with nephrosclerosis may be caused by the nodular transformation type 2 can usually be diagnosed dual blood supply in the liver. by the prominence of large arteries in the lesions. Recently, it has been noted that NRH may be Adenomatosis may be very difficult to separate from accompanied by veno-occlusive lesions or peliosis, or nonneoplastic nodular transformation; the regular arboth, often in patients receiving azathioprine for kidney rangement of vascular structures in an acinar pattern transplantation or in patients who have received bone suggests the latter. marrow transplants. It is known that nodular changes Acknowledgments: I thank Ron Adams and Jimmy may occur in Budd-Chiari syndrome (20) and that intrahepatic portal venous thrombosis may follow he- Choi for their technical assistance. patic venous obstruction. There are thus several mechREFERENCES anisms by which heterogeneity of blood flow in the 1. Ranstom S. Miliary hepatocellular adenomatosis. Acta Pathol microvasculature may arise. Microbiol 1953;33:225-229. It has been suggested that NRH may be a preneo- 2. Steiner PE. Nodular regenerative hyperplasia of the liver. Am J plastic change in the hepatocytes (3, 31, Sogaard PE. Pathol 1959;35:943-953. Hum Path01 1981;12:1052, Correspondence). However, 3. Stromeyer FW, Ishak KG. Nodular transformation (nodular “regenerative” hyperplasia) of the liver. Hum Pathol 1981;12: in the present series, the one case of HCC occurring in 60-71. a patient with NRH also had hemochromatosis. Another 4. Wanless IR, Godwin TA, Allen F, Feder A. Nodular regenerative patient with nodular transformation and HCC had hyperplasia of the liver in hematologic disorders: a possible response to obliterative portal venopathy. Medicine 1980;59: incomplete cirrhosis, probably related to hepatitis B 367-379. virus infection. This case, excluded from the present Y, Ohta G, Sasaki K. Nodular regenerative hyperplasia study, could easily have been misclassified as NRH. 5. Nakanuma of the liver associated with polyarteritis nodosa. Arch Pathol Lab Dyskaryotic changes of dysplasia were seen as often in Med 1984;108:133-135. controls as in NRH. Much of the regional heterogeneity 6. Reynolds WJ, Wanless IR. Nodular regenerative hyperplasia of the liver in a patient with rheumatoid vasculitis: a morphometric of liver cell size seen in livers with cirrhosis, fibrosis, study suggesting a role for hepatic arteritis in the pathogenesis. CAH and adjacent to neoplasms (22, 23) may also be a Rheumatol 1984;11:838-842. result of the heterogeneity of blood flow rather than a 7. JWanless IR, Lentz JS, Roberts EA. Partial nodular transformation preneoplastic change. Neoplastic nodular transforof liver in an adult with persistent ductus venosus. Arch Pathol mation (adenomatosis, nodular transformation type 3) Lab Med 1985;109:427-432. appears to be much less common than nodular trans- 8. Wanless IR, Bernier V, Seger M. Intrahepatic portal sclerosis in patients without history of liver disease: an autopsy study. Am J formation accompanying irregular blood flow. Path01 1982;106:63-70. The proposed classification for nodular transfor9. Sciot R, Staessen D, Van Damme B, Van Steenbergen W, Fevery mation was designed to simplify the above concepts with J , De Groote J , Desmet VJ. Incomplete septal cirrhosis: histological aspects. Histopathology 1988;13:593-603. a uniform nomenclature. This classification recognizes four major points: (a) a spectrum of nodular transfor- 10. Weinbren K, Mutum SS. Pathological aspects of diffuse nodular of the liver. J Pathol 1984;143:81-92. mation exists in which NRH is the most severe histo- 11. hyperplasia Nakanuma Y, Ohta G. Nodular hyperplasia of the liver in primary logical manifestation, (b) nodular transformation in biliary cirrhosis of early histological stages. Am J Gastroenterol 1987;82:8-10. NRH, incomplete cirrhosis and cirrhosis is qualitatively the same and differs only in the amount of fibrous 12. Wanless IR. Understanding non-cirrhotic portal hypertension: menage a foie [Editorial]. HEPATOLOGY 1988;8:192-193. septation, (c) most cases can be divided into one of two 13. Wanless IR, Solt LC, Kortan P, Deck JHN, Gardiner GW, groups, depending on the size of the nodules, and (d) Prokipchuk EJ. Nodular regenerative hyperplasia of the liver some cases with large nodules occur by a different associated with macroglobulinemia: a clue to the pathogenesis. Am J Med 1981;70:1203-1209. pathogenesis whereby the vascular abnormality causes focal hyperemia rather than ischemia of the paren- 14. Katzka DA, Saul SH, Jorkasky D, Sigal H, Reynolds JC, Soloway RD. Azathioprine and hepatic venocclusive disease in r e n d chyma. transplant patients. Gastroenterology 1986;90:446-454. Several practical points arise from this classification. 15. Morales JM, Prieto C, Colina F, Mestre MJ, Lopez I, Perez-Sola A, A small biopsy may allow diagnosis of nodular transforSolis Herruzo JA, et al. Nodular regenerative hyperplasia of the liver in renal transplantation. Transplant Proc 1987;19: mation but may not allow a complete diagnosis. For 3694-3696. complete diagnosis, the tissue must be sufficient to 16. Key NS, Kelly PMA, Emerson PM, Chapman RWG, Allan NC, quantitate fibrous septa. The problem is occasionally McGee JOD. Oesophageal varices associated with busulphaninsoluble because NRH, incomplete cirrhosis and comthioguanine combination therapy for chronic myeloid leukaemia. Lancet 1987;2:1050-1052. plete cirrhosis may occur in different regions of the same liver. Macronodular transformation cannot be diag- 17. Solis-Herruzo JA, Vidal JV,Colina F, Santalla F, Castellano G. Nodular regenerative hyperplasia of the liver associated with the nosed without examination of large quantities of tissue toxic oil syndrome: report of five cases. HEPATOLOGY 1986;6: or by gross examination of the liver because macro687-693. nodules are often composed of many smaller nodules 18. Papadakis MA, Busch MP, Arieff AI. Hepatorenal syndrome

Vol. 11, No. 5, 1990

19. 20. 21.

22. 23.

24. 25. 26.

NODULAR REGENERATIVE HYPERPLASIA

complicating chronic lymphocytic leukemia. Am J Med 1986; 80~320-322. Wanless IR, Geddie WR. Lipogranulomata in liver and spleen: an autopsy series. Arch Pathol Lab Med 1985;109:283-286. Simon DC, Olsen JO. The development of regenerative nodules in Budd-Chiari syndrome demonstrated by liver scan. Clin Nucl Med 1985;10:374-375. Bretagne J-F, Deugnier Y, Launois B, Gosselin M, Ferrand B, Gastard J . Hyperplasie nodulaire regenerative, carcinome hepatocellulaire et contraceptifs oraux. Gastroenterol Clin Biol 1984; 8:768-769. Peters RL. Pathology of hepatocellular carcinoma. In: Okuda K, Peters RL, eds. Hepatocellular carcinoma. New York Wiley, 1976~107-168. Popper H, Thung SN, McMahon BJ, Lanier AP, Hawkins I, Alberts SR. Evolution of hepatocellular carcinoma associated with chronic hepatitis B virus infection in Alaskan Eskimos. Arch Pathol Lab Med 1988;112:498-504. Sherlock S, Feldman CA, Moran B, Scheuer PJ. Partial nodular transformation of the liver with portal hypertension. Am J Med 1966;40:195-203. Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal 1985;6:1194-1200. nodular hyperplasia of the liver. HEPATOLOGY Wanless IR, Albrecht S, Bilbao J , Frei JV,Heathcote EJ, Roberts EA, Chiasson D. Multiple focal nodular hyperplasia of the liver

27. 28.

29. 30. 31. 32. 33. 34.

797

associated with vascular malformations of the brain and liver and neoplasia of the brain: a new syndrome. Mod Pathol 1989; 2:456-462. Wanless IR, Gryfe A. Nodular transformation of the liver in hereditary hemorrhagic telangiectasia. Arch Pathol Lab Med 1986;110:331-335. Martini GA. The liver in hereditary haemorrhagic teleangiectasia: an inborn error of vascular structure with multiple manifestations: a reappraisal. Gut 1978;19:531-537. Lui AFK, Hiratzka LF, Hirose FM. Multiple adenomas of the liver. Cancer 1980;45:1001-1004. Flejou J-F, Barge J , Menu Y, Degott C, Bismuth H, Potet F, Benhamou J-P. Liver adenomatosis: an entity distinct from liver adenoma? Gastroenterology 1985;89:1132-1138. Gindhart TD, Cimis FkJ,Mosenthal WT, Longnecker DS. Adenomatous hyperplasia of the liver. Arch Pathol Lab Med 1979;103: 34-37. Smith JC. Noncirrhotic nodulation of the liver. Arch Pathol Lab Med 1978;102:398-401. Klemperer P. Cavernous transformation of the portal vein: its relation to Banti’s disease. Arch Pathol Lab Med 1928;6:353-377. Benz EJ, Baggenstoss AH. Focal cirrhosis of the liver: its relation to the so-called hamartoma (adenoma, benign hepatoma). Cancer 1953;6:743-755.