Bloom syndrome

* Bloom syndrome is a rare autosomal recessive disorder characterized by normally proportioned but strikingly small body size, a characteristic facies and photosensitive facial skin lesion, immunodeficiency, and a marked predisposition to development of a variety of cancers. We describe here, we believe for the first time, pronounced sclerosing hyaline necrosis with Mallory bodies in the liver of a patient with Bloom syndrome. Mallory bodies are cytoplasmic eosinophilic inclusions, which are more common in visibly damaged, swollen hepatocytes in various liver diseases but are never found in normal liver. The possible pathogenesis of this finding in Bloom syndrome is discussed.

(Arch Pathol Lab Med. 1999;123:346-350)

Bloom syndrome is an extremely rare autosomal recessive genetic disorder characterized by growth retardation, an unusual facies and a photosensitive facial skin lesion, immunodeficiency, and an increased tendency to develop neoplasms, as well as certain other less constant clinical features.1,2 Liver histopathology in this rare syndrome has not been well studied previously. Sclerosing hyaline necrosis, that is, pericentral fibrosis first described by Edmondson et al in 1963,3 is part of the morphologic spectrum of alcoholic hepatitis and represents a more extensive degree of perivenular liver cell necrosis associated with the deposition of fibrous tissue. Mallory bodies (MBs), which are eosinophilic intracytoplasmic inclusions consisting of aggregated cytokeratin protein, are never found in normal liver tissue but can be seen in association with a variety of liver diseases.45 To our knowledge, MB formation in the liver in persons with Bloom syndrome has not been reported. We describe histopathologic findings in a patient with Bloom syndrome. The patient's liver tissue showed sclerosing hyaline necrosis with MB formation where other known causes of MB formation, such as alcohol or other drug abuse or viral hepatitis, were not present.

REPORT OF A CASE

The patient was a 37-year-old white man with Bloom syndrome whose designation in the Bloom's Syndrome Registry is 21(RaRe). His accession to the registry was reported by German et all in 1977. He was the second child of 2 born to a consanguineous union. He had no remarkable health problems except asthma. His only medications prior to admission were albuterol inhaler for asthma and hydrocodone-acetaminophen for pain. He had had no recent infections. He had lived with his mother and had eaten well without unusual dietary habit until the last hospitalization. He had never drunk alcohol according to his mother. The mother also stated that the patient had had intermittent vague abdominal discomfort and loose bowel movements with asymptomatic periods in between for a year prior to his death. On August 2, 1997, he presented himself at our institution with a 4-month history of intermittent crampy lower abdominal pain, occasional diarrhea, anorexia, and a 9.1-kg weight loss over 2 months. He had also noted intermittent subjective fevers, night sweats, and cough productive of green sputum for 1 week.

Physical examination revealed a thin, cachectic white man with the characteristic facies of Bloom syndrome and short stature (142 cm, 31.5 kg) with temperature of 36.1degC, pulse of 115/min, respiratory rate of 20/min, and blood pressure of 140/92 mm Hg. He had mild right and left lower quadrant-suprapubic tenderness but no rebound tenderness or guarding. Pertinent admission laboratory results included the following: hemoglobin, 39 g/L (normal, 136-175 g/L); hematocrit, 0.13 (normal, 0.390.49); aspartate aminotransferase, 43 U /L (normal, 31-40 U /L); alanine aminotransferase, 28 U/L (normal, 3-35 U/L); alkaline phosphatase, 565 U/L (normal, 41-133 U/L); lactate dehydrogenase, 305 U/L (normal 88-220 U/L); total protein 41 g/L (normal 60-80 g/L); albumin, 19 g /L (normal, 34-47 g /L); and y-glutamyl transpeptidase, 401 U /L (normal 9-85 U /L). The white blood cell count was 3.8 x 10^sup 9^/L with 0.60 segmented neutrophils, 0.14 bands, 0.18 lymphocytes, 0.06 monocytes, and 0.02 eosinophils. Chemical analyses of the blood, other liver function test results, and coagulative test results were within normal limits. Viral hepatitis A, B, and C and human immunodeficiency virus 1 serologic test results were negative. An abdominal computed tomographic scan revealed a right iliopsoas "abscess," which was drained of 20 mL of purulent fluid.

The patient was treated with multiple broad-spectrum intravenous antibiotics but developed acute abdominal pain and discharge of feces from the psoas abscess drainage site. Exploratory laparotomy on the second day after admission revealed a perforated bowel and the right psoas abscess with ipsolateral ureteral obstruction, and right hemicolectomy was performed. The surgical specimen displayed an ulcerated cauliflower-like tumor (4.5 x 4 x 3.5 cm) in the cecum, which histologically was a moderately differentiated invasive adenocarcinoma with extension into the mesentery and right psoas muscle. Intraoperative liver biopsy was also performed; microscopy revealed central sclerosing hyaline necrosis and MB formation. The patient's hospital course was complicated by multiple asthma exacerbations and progressive respiratory failure secondary to Aspergillus sp and cytomegalovirus pneumonia. His white blood cell counts fluctuated from 7.1 to 0.3 x 10^sup 9^/L during his hospital course. The patient died on the 43rd hospital day. A complete autopsy was performed.

MATERIALS AND METHODS

The hepatic tissue taken at the time of the exploratory surgery was fixed in 10% neutral buffered zinc-formalin, embedded in paraffin, sectioned in 3- to 4-Wm thicknesses, and stained by the following methods for light microscopy: hematoxylin-eosin (HE), diatase/periodic acid-Schiff for alpha,-antitrypsin deficiency, Prussian blue stain for iron, Gordon and Sweet stain for reticulin, and Sirius red stain for collagen. Immunohistochemical staining of paraffin sections was performed using a universal second antibody kit with a biotin-streptavidin labeling system (Vector Laboratories, Inc, Burlingame, Calif) and the following commercially purchased primary antibodies: cytokeratin CAM 5.2 antibody (Becton Dickinson, San Jose, Calif) to distinguish "empty cells" and MBs; ubiquitin antibody (Dako Corporation, Carpinteria, Calif) to validate MBs; AE1/AE3 antibody (Boehringer Mannheim, Indianapolis, Ind) to localize higher molecular keratin of bile ducts; a-actin antibody (Sigma Chemical Company, St Louis, Mo) to identify activated Ito cells and proliferated vessels, and cytomegalovirus antibody (BioGenex, San Ramon, Calif) to identify cytomegalovirus.

PATHOLOGIC FINDINGS

The liver biopsy specimen consisted of a wedge-shaped red-brownish piece of liver tissue measuring 0.8 x 0.4 x 0.3 cm. Histologic examination of HE-stained sections revealed central sclerosing hyaline necrosis and empty hepatocytes with loss of cytoplasmic eosinophilia that contained MBs, mainly in the centrilobular location (Figure 1). The CAM 5.2 antibody, which normally stains cytokeratins 8 and 18 in hepatocytes, failed to stain empty hepatocytes that contained MBs focally within or adjacent to the central sclerosing hyaline areas. These cells were arranged both singly and in clusters associated focally with pericellular fibrosis. Some of these cells contained MBs of typical size, shape, and location in the cytoplasm that were stained positive by CAM 5.2 anti-cytokeratin antibody (Figure 2) and anti-ubiquitin antibody (Figure 3) with the usual immunohistochemical profile of these intracytoplasmic inclusions. Mild ductal metaplasia in periportal areas was also present focally. Adjacent hepatic parenchyma did not show fatty change. Unlike alcoholic liver pathology, neutrophils were absent around the MB-containing cells. Bridging centrilobular and periportal fibrosis and diffuse activation of stellate cells, indicated by the anti-a-actin immunostaining, were present throughout the liver tissue (Figure 4). Gram, methenamine silver fungal, and acid-fast bacilli stains failed to reveal fungal or bacterial infection in the liver specimen. The anticytomegalovirus immunostaining for the viral infection also was negative.

At autopsy the enlarged liver weighed 1730 g in this 31.5-kg individual but had a normal lobe configuration and pattern of the blood vessels and bile ducts. The cut surface was dark brown to slightly greenish without gross evidence of regenerative nodules. Extrahepatic bile ducts had no obstruction, and the gallbladder appeared normal. Liver sections showed similar histologic features as described in the biopsy specimen. The amount of MB formation was also the same as in the biopsy specimen.

COMMENT

Mallory bodies, also known as alcoholic hyalin, are refractile, eosinophilic, or slightly basophilic intracytoplasmic inclusions of hepatocytes that never are seen in normal hepatic tissue. They are a prominent feature of alcoholic liver disease and also can be seen in nonalcoholic steatohepatitis, some types of viral and drug hepatitis, hepatocellular carcinoma, obesity, diabetes, and jejunoileal bypass.45 Mallory bodies are usually found in centrilobular hepatocytes that have lost their normal immunohistochemical cytoplasmic reticular staining pattern for cytokeratins 8 and 18, so-called empty cells,45 and they usually are associated with central fibrosis (ie, sclerosing hyaline necrosis).3 Liver pathology in the rare congenital Bloom syndrome has not been described in detail previously. This patient with Bloom syndrome had a grossly enlarged liver that showed pronounced MB formation and centrilobular fibrosis (or sclerosing hyaline necrosis) on microscopy. Our observations are limited to this one case. In the present case, the MBs were mainly distributed in the centrilobular hepatocytes, similar to the distribution in alcoholic liver disease.7 The associated histopathologic finding of marked, central hyaline sclerosis in this case also is similar to the spectrum of morphology found in chronic alcoholic liver disease, in which the presence of MB and polymorphonuclear neutrophil infiltrate with concomitant fatty change is quite characteristic.4,5,7 However, unlike alcoholic liver pathology, neutrophils were absent around the MB-containing cells, although the patient had a neutrophilia (0.74) at the time of liver biopsy. The adjacent hepatic parenchyma did not show fatty change. The MBs surrounded by polymorphonuclear neutrophils found in alcoholic liver disease are associated with liver cell necrosis that was not seen in the present case. Theoretically, the polymorphonuclear neutrophils are attracted to dead hepatocytes containing MBs because MBs, when exposed to plasma, will bind complement, which in turn attracts polymorphonuclear neutrophils.4,5,7

Intestinal obstruction by the cecal adenocarcinoma, along with cachexia and low total serum protein and albumin levels, also indicates the presence of malnutrition at the time of admission, which is a known cause of MB formation.7 However, the histology of nutritional fibrosis is typically micronodular portal cirrhosis with fatty change,7 which was not seen in this patient. Direct induction of MB formation by extrahepatic abscess and/or malignancy has not yet been documented.457 Therefore, their concomitant presence in this patient cannot simply explain the MB formation. In addition, the negative viral serology and microorganism staining in the liver biopsy as well as a nearly normal aspartate aminotransferase (43 U/L) and a normal alanine aminotransferase (28 U/L) also ruled out infectious etiology of MB formation in the present case. Though several medications (including heparin, sulfasalazine, acetaminophen, allopurinol, fluconazole, prochlorperazin, oxacillin, and trimethoprim-sulfamethoxazole) that the patient received intermittently for short courses during his hospitalization have sometimes been associated with drug-induced hepatitis or hepatic necrosis, they are not responsible for the central sclerosing hyaline necrosis and MB formation because the MBs preexisted these treatments (these lesions were already present at the time of the liver biopsy, 43 days prior to death). In addition, the degree and extent of the marked fibrosis observed in centrilobular hepatic regions take years to develop. Thus, the relatively short course of his last illness could not account for the marked fibrosis in his liver.

Bloom syndrome is the consequence of homozygosity or compound heterozygosity for mutations at BLM, the Bloom syndrome gene located in chromosome band 15q26.1. It features genomic instability, so that excessive number of DNA alterations of various types accumulate in the cells of affected persons throughout intrauterine and postnatal life.2s9 This hypermutability of Bloom syndrome cells is assumed to be responsible directly or indirectly for much of the clinical phenotype, in particular the great tendency to develop neoplasms of a wide variety of histologic types and sites at unusually early ages.2?,9 Idiopathic hepatitis has been reported in several persons with Bloom syndrome, and evidence of liver toxicity by liver function tests is a common complication when cancer chemotherapy is administered to them.2 However, until now, detailed histopathologic studies of the liver in Bloom syndrome have not been reported. Recently, Nicotera et allo also demonstrated that oxygen radical production was dramatically elevated above controls in Bloom syndrome cell lines. Okadaic acid, a phosphatase (PP2a/PPl) inhibitor, has recently been shown to induce MB formation and hyperphosphorylation in drug-primed mice.ll These observations suggest that certain enzymatic abnormalities secondary to the primary defect9 of Bloom syndrome genetic instability predispose hepatocytes to hyperphosphorylation injury, resulting in MB formation and fibrosis. Thus, in persons with Bloom syndrome, somatic cells, including hepatocytes, may be more susceptible to detrimental factors, such as drugs, hypoxia, ischemia, malnutrition, and other forms of stress. The observation in this single case of Bloom syndrome of an interesting and unusual lesion in the liver indicates the need for study of additional cases to determine whether this is a consistent feature of the disorder that deserves intensive study as a model of the consequences of somatic cell mutation.

References

1. Bloom D. Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs. AJDC 1954;88:75-758.

2. German J. Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine. 1995;72:393-406.

3. Edmondson HA, Peters RL, Reynolds TB, Kuzma OT. Sclerosing hyaline necrosis of the liver in the chronic alcoholic. Ann Intern Med. 1963;59:646-673.

4. French SW, Nash J, Shitabata P, et al. Pathology of alcoholic liver disease: VA Cooperative Study Group 119. Semin Liver Dis.1993;13:154-169. 5. Jesen K, Gluud C. The Mallory body: morphological, clinical and experimental studies (part 1 of a literature survey). Hepatology 1994;20:1061-1082.

6. German J, Bloom D, Passarge E. Bloom's syndrome, V: surveillance for cancer in affected families. Clin Genet. 1977;12:162-168. 7. French SW, Eidus LB, Freeman J. Nonalcoholic fatty hepatitis: an important clinical condition. Can J Gastroenterol.1989;3:189-197.

8. Ellis NA, Groden J, Ye T-Z, et al. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell. 1995;83:655-666. 9. Ellis NA, German J. Molecular genetics of Bloom's syndrome. Hum Mol Genet.1996;5:1457-1463.

10. Nicotera T, Thusu K, Dandona P. Elevated production of active oxygen in Bloom's syndrome cell lines. Cancer Res. 1993;53:5104-5107. 11. Hu B, Yuan QX, French SW. Role of phosphotheonine in cytokeratin aggregation in drug primed mouse livers treated with okadaic acid [abstract]. Mol Biol Cell. 1997;8(suppl):64.

Accepted for publication on October 13, 1998 From the Department of Pathology, Harbor-UCLA Medical Center, University of California Los Angeles, School of Medicine (Drs Wang, Cornford, and French), and the Laboratory of Human Genetics, New York Blood Center, New York, NY (Dr German).

Reprints: Samuel W. French, MD, Department of Pathology, HarborUCLA Medical Center, 1000 W Carson St, Torrance, CA 90509.

Copyright College of American Pathologists Apr 1999
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