PLASMA-CELL HEPATITIS

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Case Report with ImmunologicStudies

Thomas S. Bumbalo, M.D., Joseph A. Bellanti, M.D., and Kornel L. Terplan, M.D.

)epartments of Pediatrics and Pathology, University of Buffalo School of Medicine, and Children's Hospital, Buffalo

I N 1956 Bearn et al.1 reported an interest ing clinical syndrome observed predomi nantly in young females. These patients showed features of chronic liver disease ac companied by marked hyperglobulinemia, febrile episodes and, in some cases, by arthritis and amenorrhea. Biopsy specimens of the liver usually revealed microscopic findings of post-necrotic cirrhosis with large numbers of plasma cells in the inflammatory infiltrates. Although a high mortality oc curred with this syndrome, the use of ster oids was followed by striking improvement in some cases. Since the original description several detailed reports of similar cases have been added.2-5

Our case, that of a young female, seems to exhibit features of this syndrome of â€œ¿plasma-cellhepatitis.â€• This diagnostic label has been suggested by Page and Good.4

History

fever. The patient was seen on the day prior to admission by her private physician, who noted her to be toxic, febrile and icteric, with hepatosplenomegaly and a cardiac murmur. There was no known ex posure to infectious hepatitis or â€œ¿hepatic toxins.â€• She had received a fourth polio myelitis immunization 6 months previously.

First Hospitalization

The presumptive diagnosis at the time of admission was infectious hepatitis and pos sible rheumatic fever.

PHYSICAL FINDINGS: Physical examination

revealed a fairly well-developed, well-nour ished, icteric young white female in no acute distress. The temperature was 102Â°F (38.9Â°C); pulse, 128/minute; and respira tions, 20/minute. The weight was 45.3 kg. The skin and sclerae were moderately icteric and the pharynx was inflamed. The liver was palpable 2 cm below the right costal margin, as was the spleen tip. There was a grade 2 systolic murmur localized to the lower left sternal border.

LABORATORY FINDINGS: Laboratory stud

ies revealed a hemoglobin concentration of iO.i gm/iÂ® ml, leukocyte count of 7,400/ mm3, with a normal differential count, and a platelet count of 357,000/mm3. Urinalysis revealed normal findings. Nasopharyngeal and throat cultures revealed beta-hemolytic streptococci, and antistreptolysin-O titer was 125 units/ml, and C-reactive protein was not detected. Roentgenographic find ings of the chest, and electrocardiographic findings, were within normal limits. The sedimentation rate was 57 mm/hr, uncor rected (34 mm/hr, corrected); the bilirubin CASE REPORT

A i23@-year-old white female was hos pitalized at the Buffalo Children's Hospital on October 10, 1960, with fatigability, weight loss of 4 to 5 months' duration, and joint pains, with low-grade fever of one week's duration. The patient had always been in good health until May, i960, when she began to tire easily, with accompany ing anorexia and a weight loss of i2 lb. (5.4

kg).

In September, 1960, she had an infection of the upper respiratory tract, associated with myalgia. During the week prior to ad mission she complained of pain in her hands, ankles and knees without swelling or redness of the joints but with low-grade

ADDRESS: (T.S.B., Office) 354 Lincoln Parkway, Buffalo 16, New York.

PxnIATlucs, February 1962 19i

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concentration was 2.2 mg/i00 ml, of which 0.8 mg was â€œ¿direct-reactingâ€•pigment. Con centrations of glutamic-oxaloacetic trans aminase (SGOT) and glutamic-pyruvic transaminase (SGPT) in serum were 200 and 232 Frankel units respectively.

COURSE: Treatment consisted of bed rest,

and penicillin was given for the streptococ cal pharyngitis. She was discharged on Oc tober 22, somewhat improved but still slightly icteric. At home she was main tained on strict bed rest. In November ar thralgia of the knees and ankles recurred with fever, tachycardia, and an elevated sedimentation rate. Beta-hemolytic strepto cocci were again recovered from the throat culture. These findings were interpreted as â€œ¿recurrent rheumatic fever.â€• Treatment with aspirin and penicillin resulted in sub sidence of the joint complaints. However the scleral icterus, first noted in October, persisted. By December she had improved enough to be allowed limited activity. However, shortly thereafter, she again de veloped low-grade fever, tachycardia and

Fic. 2. The patient's hands, showing minimal spindling of the proximal interphalangeal joints.

increased fatigability. She was therefore hospitalized on January 30, i961, with the diagnosis of recurrent hepatitis.

Second Hospitalization

PHYSICAL FINDINGS: Physical examination on her second admission revealed a thin, slightly pale 12 10/12 year old white female with a definite ictenic hue to the skin and sclerae (Fig. 1). The temperature was 100.4Â°F (38.0Â°C); pulse, 96/minute; blood pressure, 130/70 mm Hg; and weight 49 kg. Several spider angiomata were found over the forearms, and the venous pattern over the lower chest and upper abdomen was prominent. Examination of the heart again revealed the grade 2 systolic murmur along the lower left sternal border. The liver mar gin was palpable 3 cm below the right costal margin and the spleen 2 cm below the left costal margin. Both organs were firm and nontender. There was a suggestion of fusiform swellings of the proximal inter phalangeal joints of the hands, with mini mal atrophy of the dorsal interosseal mus cles, and slight ulnar deviation of the hands (Fig. 2). The breasts and genitalia revealed normal female pubertal changes. The onset of menarche and menstrual history were within normal limits.

LABORATORY FINDINGS: The significant

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Fic. 1. Patient P. B. before treatment, showing a normal state of nutrition and normal pubertal

changes of the breasts.

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ARTICLES 193

laboratory findings at this time were a hemoglobin concentration of 10.2 gm/iÂ® ml; leukocyte count of 9,800/mm3; and a sedimentation rate of 29 mm/hour, uncor rected (i2 mm/hour, corrected). The biliru bin concentration in serum was 3.4 mg/iOO ml, of which 2.2 mg was â€œ¿direct-reactingâ€• pigment. Concentrations of SGOT and SGPT were 440 and 320 units respectively. An LE cell clot test revealed a few typical LE cells. The total protein concentration was 11.45 gm/iÂ® ml of serum; paper elec trophoresis of the serum revealed the fol lowing concentrations per 100 ml: albumin, 2.i3 gm; alpha 1-globulin, 0.23 gm; alpha globulin, 0.45 gm; beta-globulin, 0.94 gm; and gamma-globulin, 7.7 gm (Fig. 3). Meas urements of plasma and serum prothrombin times and thromboplastin generation were within normal limits.

Needle biopsy of the liver (Fig. 4), per formed transthoracically on February 8, dis closed a moderate increase in the fibrous tissue of the periportal tracts, with distinct infiltration of these tracts and adjacent liver cell lobules by plasma cells and neutro philic leukocytes. In some areas the plasma cell infiltrates appeared rather closely packed. Although the preformed small bile ducts in the fibrous tracts were not in creased, there was some proliferation of liver cells forming solid bile ducts within them. The liver cells showed vacuolar de generation with retention of bile pigment, but it could not be determined from the biopsy material whether or not the vacuoles contained lipid. Between the liver cells, many of which appeared enlarged, were scattered leukocytic infiltrates. These latter findings were similar to the cellular infiltra tions seen in the more acute forms of hepa titis. Entirely unusual, however, was the conspicuous accumulation of plasma cells in the periportal tracts. It appeared from the small amount of biopsy material that the changes described were indicative of an early cirrhosis of the perilobular type.

COURSE: The clinical diagnosis at this time was early cirrhosis of the type de scribed by Bearn et al.1 with minimal hepa

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Alpha-i2.05 0.23 Aipha-2 3.@0 0.45 3.ta S.20 O.@4

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Fic. 3. Paper electrophoretic pattern of the pa tient's serum (January 31, 1961), before treatment, showing the markedly elevated gamma-globulin

concentration.

tic dysfunction. The child was subsequently discharged on February 9. One week after discharge, therapy with prednisone, 10 mg four times daily, was instituted. With im provement, this dosage was subsequently reduced to 5 mg three times daily on an in terrupted schedule of 4 days on medication and 3 days off medication.

On this regimen the icterus faded, the arthralgia disappeared, the appetite im proved, and there was a gain in weight. She gradually resumed normal activity at home.

Third Hospitalization

On June i2, i96i, she was admitted to the hospital a third time for further evalua tion. She appeared better nourished than on her previous admissions, with a weight of 51.3 kg. She exhibited only a trace of scleral icterus. The liver was palpable 1 cm below the right costal margin, and the spleen could no longer be palpated. The previ ously noted cardiac murmur was no longer heard.

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194 PLASMA-CELL HEPATITIS

reactingâ€• pigment. Concentrations of SGOT and SCPT were 168 and 186 units respec tively. The protein concentration in serum was 10.6 gm/iÂ® ml; paper electrophoresis of the serum revealed the following concen trations per 100 ml: albumin, 3.62 gm; alpha 1-globulin, 0.24 gm; alpha 2-globulin, 0.54 gm; beta-globulin, 0.93 gm; and gamma-globulin, 5.27 gm. A second liver l)iopsy at this time showed essentially the same pathologic changes as the first.

IMMUNOLOGIC STUDIES OF THE SERUM: In

order to further delineate the patient's globulins, ultracentrifugal studies of the serum were performed by Dr. Sidney Shtil man. These studies revealed that the pa tient's gamma-globulin was made up en tirely of 7S-globulins. Rheumatoid factor was not found in her serum.

Immunofluorescent studies were carried out in the laboratory of Dr. E. H. Beutner by means of the indirect staining technique

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Fic. 4. Initial needle biopsy of the liver. A) Medium-power view showing vacuolar

degeneration of the liver cells and fibrosis of the periportal tracts with plasma cell

infiltration (H&E, 200x). B) High-power view showing the plasma-cell infiltration in greater detail (400x).

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Subsequently more emphasis was placed on the possible role of auto-immune factors in the causation of this disease.7 Mackay

et al.2,3 have assigned the term â€œ¿lupoid

hepatitisâ€• to describe the illness of a group of patients with clinical and laboratory fea tures similar to those of â€œ¿plasma-cellhepa titisâ€•but who in addition exhibited positive LE cell phenomena. They believed these cases represented a form of auto-immune hepatitis secondary to an altered anti genicity of liver cells mediated through viral and possible nutritional damage to the liver. More recently Page and Good4 have suggested a similar concept for the patho genesis of this entity. Bartholomew et aL8 have used the finding of LE cells in their seven cases to designate this syndrome as a manifestation of disseminated lupus ery thematosus. However in all of their cases the chronic hepatitis developed only after the clinical diagnosis of disseminated lupus erythematosus had been present for varying lengths of time.

The concept of auto-immune liver dis ease can be found in the literature as early as 1944. Eaton et al.@ described a comple merit-fixing antibody against human liver in the serum of patients with acute hepa titis. Gajdusek'0 more recently has de scribed an increase in serum antibodies to various liver constituents in patients with chronic hepatitis, lupus erythematosus and acute glomerulonephritis. The nature of the antigen(s) involved in these reactions is un known.

immunonuorescent staining patterns, which may be similar to those observed with the serum of the patient described in this study, were recently reported by Paro netto et al.h1 This type of bile canaliculi and nuclear staining pattern on liver sec tions has also been observed with sera of patients with post-hepatitic cirrhosis; in one case, staining of the bile canaliculi occurred in the total absence of nuclear antibodies (unpublished observations, E. H. Beutner). Observations on the serum of the patient reported herein indicated that the antigen associated with the staining of bile canalic uli is not soluble in saline solution, is pres

ARTICLES 195

of Coons,6 using patient's serum and cryo stat cut sections of monkey liver. As seen in Figure 5B, strong immunofluoreseent stain ing of nuclei was demonstrable on monkey liver sections at serum dilutions of 1: iO. This staining reaction may be compared with the negative reaction (Figure 5A) ob tained under identical conditions with a normal human serum. At serum dilutions of 1:30, not only immunofluorescent staining of nuclei but also distinct staining of bile canaliculi and diffuse cytoplasmic staining occurred. In Figure 5C, some bile canaliculi are encircled. In view of the fact that the latter staining reaction had not been de scribed in the literature previously, further immunofluorescent studies seemed indi cated. On monkey-muscle sections cyto plasm stained diffusely, while nuclei stained intensely as expected. Absorption of the patient's serum with monkey-liver extracts failed to remove the staining activity, while absorption with liver, lung and brain sedi ments completely removed both nuclear and bile canaliculi staining activity of the serum. Thus 1) the cytoplasmic antigen(s) is (are) present in the insoluble component of tissue and 2) it is doubtful if antibodies staining bile canaliculi are organ specific. Staining patterns identical to those ob served on monkey-liver sections were ob served also on rabbit-liver sections. Thus the bile canaliculi staining antibodies are not species specffic.

COMMENT

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ent in the insoluble components of liver and other monkey organs tested, and is present in rabbit liver. It should be pointed out that the auto-antibody nature of this

immunoflorescent staining reaction has not been proven. Thus the significance of the bile canaliculi staining reaction to the dis ease process remains unknown. While the

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Fic. 5. Fluorescence photomicrographs of cryostat sections of monkey liver after treatment with serum, followed by fluorescein-labeled goat anti-human immune globulin antiserum (500x). A) Negative reac tion obtained with normal human serum. B) Strong immunofluorescent staining of nuclei demonstrable with patients serum at a dilution of 1:10. C) Immunofluorescent staining of nuclei, bile canaliculi

(circled), and diffuse cytoplasmic staining with patient's serum at a dilution of 1:30.

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ARTICLES i97

serum and cryostat cut sections of monkey liver have revealed staining of liver nuclei, bile canaliculi and a diffuse cytoplasmic staining. The findings in this case are pre sented with a brief discussion of some of the current theories on pathogenesis.

REFERENCES

1. Beam, A. G., Kunkel, H. C., and Slater, R. J.: The problem of chronic liver disease in young women. Amer. J. Med., 21:3, 1956. 2. Mackay, I. R., Taft, L. I., and Cowling, D. C.:

Lupoid hepatitis. Lancet, 2:1323, 1958. 3. Mackay, I. R., Taft, L. I., and Cowling, D. C.:

Lupoid hepatitis and the hepatic lesions of systemic lupus erythematosus. Lancet, 1:65, 1959.

4. Page, A. R., and Good, R. A.: Plasma-cell hepatitis, with special attention to steroid therapy. Amer. J. Dis. Child., 99:288, 1960. 5. Wilcox, R. C., and Lsselbacher, K. J.: Chronic

liver disease in young people. Amer. J. Med., 30:185, 1961.

6. Coons, A. H., and Kaplan, M. H.: Localiza tion of antigen in tissue cells: II. Improve ments in a method for the detection of an tigen by means of fluorescent antibody. J. Exp. Med., 91:1, 1950.

7. Goldgraber, M. B., and Kirsner, J. B.: The hy persensitive state and the liver: a critical review. Amer. J. Med. Sci., 241:109, 1961. 8. Bartholomew, L. C., et al.: Hepatitis and cir

rhosis in women with positive clot tests for lupus erythematosus. New Engl. J. Med., 259:947, 1958.

9. Eaton, M. D., Murphy, W. D., and Hanford, V. L.: Heterogenic antibodies in acute hepa titis. J. Exp. Med., 79:539, 1944. 10. Gajdusek, D. C.: An â€œ¿autoimmuneâ€•reaction

against human tissue antigens in certain acute and chronic diseases: I. Serologic in vestigations. Arch. Intern. Med., 101:9, 1958.

11. Paronetto, F., Schaffner, F., and Popper, H.: Immunocytochemical reaction of serum of patients with hepatic diseases with hepatic structures. Proc. Soc. Exp. Biol. Med., 106: 216, 1961.

Acknowledgment

We are indebted to Dr. E. H. Beutner who performed the immunofluorescent studies and who gave a great deal of help and advice in the fin munologic aspects of this case, to Dr. Sidney Shul man who performed the ultracentrifugal studies, and to Dr. E. Witebsky for his many helpful sug gestions and his critical comments.

nature of nuclear antibodies is understood more fully, their role in the pathogenesis of diseases with which they are associated also remains unknown.

This patient appeared to have this syn drome with features of chronic hepatitis with plasma cell infiltration, hypergamma globulinemia, and a weakly positive LE cell phenomenon. It is of interest that there was no history of exposure to infectious hepatitis nor any evidence of amenorrhea. Although Bearn et al.' reported arthralgia in 42% (11 of 26) of their series, only three patients showed definite changes of chronic rheumatoid arthritis. The patient reported herein showed early joint deformities, with spindling of the proximal interphalangeal joints of the hands.

Most authors agree that steroids are the drugs of choice in the treatment of â€œ¿plasma

cell 4 Page and Good4 noted

especially good results in patients with very high levels of gamma-globulin. Our patient, thus far, has shown a good clinical response to steroids and has been given maintenance therapy with prednisone, 5 mg three times daily, on an interrupted dosage schedule. Even with considerable subjective and clinical improvement, the change in the laboratory findings has been less strik ing. Although the decrease in SGOT, SGPT and gamma-globulin following treatment is encouraging, the static histologic picture of the liver seen in the second biopsy indicates little change in the basic disease process in the liver. Perhaps there is a need for an increase in the dosage of steroid.

SUMMARY

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1962;29;191

Pediatrics

Thomas S. Bumbalo, Joseph A. Bellanti and Kornel L. Terplan