Inflammatory bowel disease presenting as liver disease during childhood

Volume 97 Number 5

B r i e f clinical and laboratory observations

index, the ratio between the counts obtained in stimulated versus Unstimulated LC. Interferon production was measured in rubella virus antigen stimulated as well as unstimulated LC: microplates with monolayers of FS7 cells were inoculated with serial dilutions of LC supernatant fluid and challenged with vesicular stomatitis virus. A human reference interferon preparation was included in each series of titrations? RESULTS

AND DISCUSSION

Rubella infection was documented in the mother by seroconversion (the H A I titer of < 1:8 on first day of rash, increased to 1:32 four days later), by the presence of rubella specific IgM (on the fourth day o f rash), and by isolation of rubella virus from pharynx (on the first day of rash), and urine (throughout the first four day s o f illness). Green et aP documented that virus may be present in blood and pharyngeal secretions for up to one week before onset of rash. Comparable data do not exist for h u m a n milk since this is the first reported isolation. Rubella virus was detected in the milk for the first three days after Onset of rash, a period in which the milk did not contain measurable rubella antibody. On the fifth day, rubella antibody was found in the milk ( H A I titer of 1:8). Titers increased for the following five days ( H A I titer of 1:256) and then decreased nine days after onset of the rash (HAl titer of 1:16). Rubella antibody in milk was exclusively IgA. Although no clinical manifestations appeared in the infant, rubella infection was confirmed by isolation of virus in the pharynx at age 15 days, by a serum rubella H A ! titer of 1:64 two months after the mother's illness, and by documentation of rubella-specific cellular i m m u n e responses to rubella virus at the s a m e time (stimulation index of 5.0 and an interferon titer of 1:24). This rePort , along with our previous description of the presence and transmission of rubella vaccine virus

775

(HPV77DE5 strain) in milk of a w o m a n immunized postpartum ~ demonstrate that rubella virus must be included in an increasing list of agents potentially transmitted by breast-feeding (e.g., cytomegalovirus, herpes virus). 7, 8 On the basis of limited experience, rubella in the newborn infant appears to be a mild disease. We express our thanks to the mother for her consent in providing us with the repeatedly collected specimens from her and her baby. Special thanks to Ms. Franny Alexander for her enthusiastic and skillful help; the excellent secretarial help of Ms. Debby Robinson is highly appreciated.

REFERENCES 1. Center for Disease Control: A procedural guide to the performance of the standardized rubella hemagglutinationinhibiton test, United States Department of Health, Education and Welfare, Mental Services and Mental Health Administration, Center for Disease Control, Atlanta, Ga., October, 1970. 2. Buimovici-Klein E, Weiss KE, and Cooper LZ: Interferon production in lymphocyte cultures after rubella infection in humans, J Infect Dis 135:380, 1977. 3. Buimovici-Klein E, Vesikari T, Santangelo CF, and Cooper LZ: Study of the lymphocyte in vitro response to rubella antigen and PHA by a whole blood method, Arch Virol 52:323, 1976. 4. Buimovici-Klein E, and Cooper LZ: Immunosuppression and isolation of rubella virus from human lymphocytes after vaccination with two rubella vaccines, Infect Immun 25:352, 1979. 5. Green RH, Balsamo MR, Giles JP, Krugman S, and Mirick GS: Studies of the natural history and prevention of rubella. Am J Dis Child 110:348; 1965. 6. Buimovici-Klein E, Hite RL, Byrne T, and Cooper LZ: Isolation of rubella virus in milk after postpartum immunization, J PEDIATR91:939, 1977. 7. Hayes K, Danks DM, Gibas H, and Jack T: Cytomegalovirus in human milk, N Engl J Med 287:177, 1972. 8. Dunkle ML, Schmidt RR, and O'Connor MD: Neonatal herpes simplex infection possibly acquired via maternal breast milk, Pediatrics 63:250, 1979.

Inflammatory bowel disease presenting as liver disease during childhood William Kane, M.D., Kenneth Miller, M.D,, and Harvey L. Sharp, M.D.,* Minneapolis, Minn. From the Department of Pediatrics, University of Minnesota Health Sciences Center. Supported by The National Cystic Fibrosis Foundation Fellowship, The Mogol Intestinal Research Fund for Children, and the Beckman Liver Research Fund. *Reprint address: Box 279 Mayo, Universityof Minnesota Health Sciences Center, Minneapolis, MN 55455.

0022-3476/80/110775 +04500.40/0 9 1980 The C. V. Mosby Co.

PATHOLOGIC ALTERATION of the liver is c o m m o n in )atients with inflammatory bowel disease but is usually Abbreviations used IBD: inflammatory bowel disease SKSD: streptokinase-streptodornase PHA: phytohemagglutinin

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Brief clinical and laboratory observations

The Journal of Pediatrics November 1980

Table. Pertinent laboratory data

l

Alkaline phosphatase SGOT Bilirubin Sedimentation rate Albumin IGG Anti-smooth muscle antibody Fluorescent anti-nuclear antibody Serum complement C'H50 units/ml B1A T cells

Normal vahte

Patient 1 initial evaluation

Patient 2 initial evaluation

< 220 IU/1 7-27 IU/I < 0.4/1.1 mg/dl 1-20 mm at 1 hr 3.5-4.8 gm/dl 520-1,800 mg/dI 0 0

759 50 0.5/0.5 69 2.88 4,275 1:30 Negative

1,400 28 0.1/0.8 105 2.45 2,320 1:10 Negative

Negative

45

40

120

32 + 6 164 + 8 mg/dl 5O-78% 750-3,000/mm :'

PHA Skin test

175 6O 2,493

Patient 3 7 months* 854 158 0.3/0.6 71 3.5 4,040

Patient 4 initial evaluation 1,012 24 0.2/0.5 89 2.60 2,720 1:40 Anti DNP 1:8 Anti DNA 1:2 134

324 55 522 Normal Pos. SKSD

m

Pos. Candida

47 !,576 Normal Pos. Histo.

*First time liver enzymes obtained. Had had abnormal sedimentation rate since November 1972.

not of clinical significance.' The lesion of pericholangitis may involve the portal triads in 70% and fat accumulation in the hepatocytes may occur in 50% of adult patients with IBD, but only 10% develop symptoms of liver disease, and less than 5% develop cirrhosis. Other liver diseases associated with IBD include chronic active hepatitis, sclerosing cholangitis, and carcinoma of the biliary tree. The development of cirrhosis is felt to be a manifestation of severe, extensive, and longstanding IBD. In contrast, we are reporting four patients who were initially evaluated for undefined severe liver disease and had little historical evidence of IBD. MATERIALS

AND METHODS

Skin tests used in evaluating the cell-mediated immunity of these children included intermediate PPD, histoplasrain, coccidioidin, candida, and streptokinase-streptodornase. T cells and phytohemogglutinin studies were performed by methods previously reported, 2, :~ and antis m o o t h muscle antibody titers were done by Dr. T. S. Edgington at the Scripps Clinic and Research Foundation accord{ng t o t h e method described by Dr. Robert Nakamura. 4 N o n e of these patients had alphal-antitrypsin deficiency as determined by normal trypsin inhibitory capacities and Pi typing. Wilson disease was excluded in each of these patients on the basis of normal slit-lamp ophthalmologic examinations, serum copper and ceruloplasmin concentrations, an d urinary excretion of copper with and without penicillamine. Liver tissue was frozen in isopentane precooled in liquid nitrogen and sectioned at 4

microns in a Lipshaw cryostat. Immunofiuorescent studies were carried out according to methods previously described ~, ~ and were negative in all four patients. Studies for HBsAg and rheumatoid factor, and L E preparations were negative in all four patients. CASE REPORTS Patient 1 developed a recurrent skin rash at 689 years of age, characterized by erythematous papular lesions from 1 to 5 mm in diameter; some had serpiginous borders and clear central areas which would progress to hives or bullae. Prior to this, growth and development had been normal. His private physician obtained the following laboratory results upon noting hepatomegaly: an absolute eosinophil count of 4,250 eosinophils/mm 3 (34% of i2,500 WBC/mm3), elevated serum liver enzyme concentrations, increased serum immunoglobulin values, and an erythocyte sedimentation rate of 68 mm at one hour. He was referred to us with the tentative diagnosis of visceral larva migran s. o n initial evaluation, the liver was palpated 3 cm below the right costal margin. Liver function studies are listed in the Table. He never developed any pulmonary or neurologic manifestations, but after failing to gain weight during the next five months, he was admitted to the hospital for diagnostic evaluation. A complete review of gastrointestinal symptoms was negative except forthe recent onset of occasional abdominal pain. Physical examination demonstrated the liver edge 8 cm below the fight costal margin and the spleen 3 cm below the left costal margin. A percutaneous liver biopsy specimen showed an acute and chronic inflammatory reaction in the portal areas, bile duct proliferation, and loose connective iissue circularly arranged around the bile ducts. Adjacent portal areas were connected by collagen but central veins were uninterrupted. In some areas the hepatocytes were arranged in acinar formation. Immunologic

Volume 97 Number 5 data are summarized in the Table. While in the hospital, blood was noted in his stools for the first time; barium enema and proctoscopy were consistent with ulcerative colitis and an upper gastrointestinal series with small bowel follow-through was normal. Multiple stool cultures for Salmonella, Shigella, and examinations for ova and parasites were negative. At time of panproctocolectomy the liver was described as grossly cirrhotic. Open liver biopsy showed essentially the same findings as previously reported except for more acute inflammation. Grossly, the resected rectum and colon showed continuous involvement from the rectosigmoid to the ileocecal valve, with a granular, edematous mucosa and multiple small ulcerations. Microscopically, there were superficial ulcerations, crypt abscesses, pseudopolyps, and marked lymphocytic and plasma cell infiltration of the lamina propria and submucosa. The muscular layers and serosal surface were normal, and no granulomas were seen. Patient 2, an 11-year-old boy, was seen by his private physician in November, 1973, for complaints of abdominal pain, decreased appetite, and minimal diarrhea of recent onset. Weight and height had been on the fiftieth percentile prior to this illness. After developing hepatomegaly, a liver scan showed multiple filling defects. Complete upper and lower gastrointestinal roentgenograms were normal. Although the serum SGOT and bilirubin values were normal, serum alkaline phosphatase activity was elevated. Exploratory laparotomy revealed an enlarged finely nodular liver, a normal gallbladder, and a dilated common bile duct surrounded by enlarged lymph nodes. The spleen was enlarged but without visual evidence of portal hypertension, and the bowel appeared normal. With the diagnosis of cirrhosis of unknown etiology, he was transferred to us on the first postoperative day. On arrival here, he had diffuse lymphadenopathy and a liver edge 2 cm below the right costal margin. Laboratory data at the time of admission are summarized in the Table. The operative liver biopsy showed normal hepatocytes, but a marked acute inflammation around and in the slightly proliferated bile ducts which were encircled by extensive loose connective tissue. There was bridging connective tissue between portal areas but no involvement of the central vein. Immunofluorescent studies were negative. Upper gastrointestinal and complete small bowel roentgenograms were again normal but a repeat barium enema one month later showed diffuse, symmetric serration of the bowel margins by shallow mucosal ulcers throughout the entire length of the colon. Proctoscopy and rectal biopsy showed mild chronic inflammation of the mucosa. Patient 3 was first seen in December, 1972, at 12 years of age, following a three-month history of weight loss, lethargy, migratory polyarthritis, and intermittent urticarial skin lesions which progressed to purpura. Skin biopsy was consistent with "vasculitis." Before the onset of this disease his weight and height were at the fortieth percentile. Although his symptoms responded initially to corticosteroid therapy, they recurred when the dose was tapered and discontinued. In March, 1973, he was admitted for evaluation, denying abdominal pain, diarrhea, or bloody stool. Physical examination was unremarkable except for a hard liver edge 4 cm below the right costal margin, a spleen palpable 4 cm below the left costal margin, and residual skin rash. Laboratory data are summarized in the Table. Bilateral renal, superior

Brief clinical and laboratory observations

777

mesenteric and hepatic arteriograms revealed only unusual tortuosity of the hepatic arteries without microaneurysms. Percutaneous liver biopsy showed marked fibrosis extending around liver lobules with bile duct proliferation, some chronic inflammation, but no vasculitis or good central veins seen. Three months later, after ten total months of disease, he developed crampy abdominal pain and intermittent diarrhea. Barium enema showed edema and spicutation of the rectal mucosa, and colonoscopy showed diffuse, continuous, friable, edematous, and granular mucosa extending from the rectum for 70 cm, without frank ulceration. Rectal biopsy showed a diffuse infiltration of the mucosa by lymphocytes and plasma cells, and there were small lymphoid aggregates in the lamina propria and submucosa. Multiple stool specimens for Salmonella, Shigella, and ova and parasites were negative, and upper gastrointestinal and complete small bowel roentgenograms were normal. Patient 4, a 14-year-old girl, presented in July, 1974, with a three-month history of anorexia, fever, easy fatiguability, right upper quadrant pain, and a 7-pound weight loss. Prior to this illness, her height and weight had been at the fortieth percentile. Evaluation by her physician revealed hepatosplenomegaly and anemia. Liver biopsy attempts obtained inadequate tissue, and she was sent here With a diagnosis of cirrhosis of unknown etiology. One week prior to admission here, she developed daily fevers up to 39~ Detailed history revealed the recent onset of intermittent diarrhea with bright red blood on two occasions, the last time being the day prior to admission. Physical examination revealed a hard liver 8 cm below the right costal margin and the spleen 2 cm below the left costal margin. Pertinent laboratory data are listed in the Table. Percutaneous liver biopsy revealed cirrhosis with marked bile duct proliferation and a mixed inflammatory reaction in the portal areas with occasional nests of lymphoid aggregates. Barium enema and upper gastrointestinal series with small bowel follow-through were normal, but proctoscopy showed a diffusely inflamed, finely granular, easily friable rectal and sigmoid mucosa with multiple small ulcerations. Colonoscopy showed continuous involvement by this process to 45 cm and beyond. DISCUSSION Each o f these patients was evaluated for severe liver disease a n d h a d little historical or clinical evidence for IBD. However, colonic disease, not always severe, was present. M e a s u r e m e n t s o f alkaline p h o s p h a t a s e were the best indicators of liver disease associated with IBD. However, 5' nucleotidase m i g h t h a v e b e e n a more specific liver function test if available. N o n e of the patients h a d either pruritus or a n elevated serum b i l i r u b i n concentration. Nevertheless, endoscopic retrograde cholangiography or transhepatic c h o l a n g i o g r a p h y m i g h t h a v e d e m o n strated lesions in the biliary tree. 7 T h e liver p a t h o l o g y was characterized by m a r k e d pericholangitis a n d b r i d g i n g portal fibrosis a n d / o r cirrhosis. N o i m m u n o l o g i c event was d o c u m e n t e d in any o f these patients. Follow-up a n d therapeutic i n t e r v e n t i o n for these four, plus two other

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Brief clinical and laboratory observations

patients, is the subject o f a recent abstract. ~ W e recomm e n d t h a t all patients with liver disease of u n k n o w n etiology should h a v e I B D excluded by (1) a t h o r o u g h history o f bowel symptoms; (2) b a r i u m e n e m a ; (3) u p p e r gastrointestinal series with small bowel follow-through; (4) proctoscopy with rectal biopsy; a n d (5) colonscopy if the previous e x a m i n a t i o n s are unrevealing, We thank Drs. Robert Schulenberg, James Dover, Charles Rogers, J. Nevin Isenberg, and Arnold S. Leonard, Professor and Head of Pediatric Surgery at the University of Minnesota, for participating in the care of these patients.

The Journal of Pediatrics November 1980

3.

4.

5.

6.

7.

REFERENCES 1. Kern F Jr: Hepatobiliary disorders in inflammatory bowel disease, in Popper H, and Schaffner F, editors: Progress in fiver diseases, New York, 1976, Grune & Stratton, Inc., pp 575-589. 2. Fleisher TA, Luckasen JR, Sabad A, et ah T & B lymphocyte subpopulations in children, Pediatrics 55:162, 1975.

8.

Luckasen JR, White JG, and Kersey JH: Mitogenic properties of a calcium ionophore, A23187, Proc Natl Acad Sci USA 71:5088, 1974. Nakamura RM: Immunopathology: Clinical laboratory concepts and methods, Boston, 1974, Little, Brown & Company. Westberg NG, Naff GB, Boyer JT, et al: Glomerular deposition of properdin in acute and chronic glomerulonephritis with hypocomplementemia, J Cfin Invest 50:642, 1971. Michael AF, Drummond KN, Good RA, et ah Acute poststreptococcal glomerulonephritis: Immune deposit disease, J Clin Invest 45:237, 1966. Werlin SL, Gficklich M, Jona J, and Starshak RJ: Sclerosing cholangitis in childhood, J PEDIATR 96:433, 1980. Freese D, Latimer JS, Gilberstadt S, Kane W, and Sharp H: Therapeutic response of the pericholangitis in the liver lesion associated with inflammatory bowel disease, Gastroenterology 78:1168, 1980.

Protein-losing enteropathy in a boy with systemic lupus erythematosus Masato Tsukahara, M.D.,* Kiyosato Matsuo, M.D., and Hideyuki Kojima, M.D., Ube, Japan

P R O T E I N - L O S I N G ENTERO, PATHY in systemic lupus erythematosus has b e e n described in only four p a t i e n t --all adults b e t w e e n 23 a n d 59 years of age. ~-' W e describe a 12-year-old J a p a n e s e boy with SLE initiated as proteinlosing e n t e r o p a t h y that r e s p o n d e d to corticosteroid therapy. CASE REPORT A 12-year-old Japanese boy was admitted with a six-month history of easy fatigability and blurred vision, and a two-week history of progressive edema with a 5.5 kg weight gain. There was no history of medication, diarrhea, or chronic illness that could have been related to the present disease. No corticosteroids had been given before admission. Physical examination revealed generalized edema and ascites. The breath sounds were diminished at the right base. Neither enlargement of the subcutaneous lymph nodes nor hepatomegaly was noted. Urinalysis revealed trace proteinuria and normal urinary sediment. The erythrocyte sedimentation rate was 66 ram/hour. Serum electrophoresis revealed the following values: total pro-

From the Department of Pediatrics, Yamaguchi University School of Medicine. *Reprint address': Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan 755.

tein, 4.2 gm/dl; albumin, 1.32 gm/dl; a,-gtobulin 0.17 gm/dl (normal 0.15 to 0.28 gm/dl); a~-globulin 1.28 gm/dl (normal 0.24 to 0.68 gm/dl); fl-globufin, 0.55 gm/dl (normal 0.52 to 1.03 gm/dl); and y-globulin, 0.86 gm/dl (normal 0.79 to 1.78 gm/dl). The serum cholesterol concentration was 320 mg/dl (normal 130 to 200 mg/dl), serum C3 19.1 mg/dl (normal 64 to 116 mg/dl), C4 was 12.0 mg/dl (normal 17 to 49 mg/dl), and the serum IgG concentration was 800 mg/dl (normal 881 to 1,837 mg/dl). Values for 24-hour urine protein excretion ranged between 15 and 90 mg/day. The liver function tests were normal, as were the blood urea nitrogen and creatinine values. Abbreviations used SLE: systemic lupus erythematosus ~'I-PVP: radioiodinated polyvinylpyrrofidone A chest radiograph revealed a massive right pleural effusion. Thoracocentesis was performed, and 10 ml of straw-colored transudate was removed. Upper gastrointestinal roentgenograms showed mild coarsening of the folds in the stomach and duodenum. He had a low-grade fever for the first ten hospital days, then developed a fever of 39 to 40.5 ~ for six days. His edema, pleural effusion, and ascites progressed, and the fiver became palpable 4 cm below the right costal margin, despite the use of oral diuretics and repeated infusions of albumin. A daily dose of 40 mg (1.5 mg/kg) of prednisolone was started on the twentieth

0022-3476/80/110778 + 03500.30/0 9 1980 The C. V. Mosby Co.