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Granulomatous hepatitis of unknown etiology
Granulomatous
Hepatitis
Unknown
of
Etiology*
An Etiologic and Functional Evaluation JAMES
C. GUCKIAN,
M.D.
and JOHN
Galveston,
E. PERRY,
M.D.
Texas
The diagnosis in patients with granulomatous hepatitis can usually be obtained if the proper approach and criteria, such as previously outlined, are utilized. Liver destruction and fibrosis can usually be halted if specific therapy for infectious causes is instituted. Corticosteroid therapy seems to be indicated in patients with sarcoidosis with documented severe or progressive hepatitis, that is, the presence of jaundice, hypoalbuminemia, ascites, markedly elevated alkaline phosphatase levels and portal hypertension. Granulomatous disease may be associated with agammaglobulinemia, autoimmune disease, hematopoietic malignancies and carcinomas. Whether there is a statistically significant correlation between these diseases is not known.
D
specimen
sence mon
in
IAGNOSIS
a
of identifiable problem,
alence
patient
shows
whose
granulomas
organisms
as reflected
of granulomas
is not
liver in
biopsies
ab-
an uncom-
by a 4 per cent
in liver
examination performed on each. All medications were continued, including antituberculous drugs. unless there were specific contraindications. A complete hemogram and platelet count, serum glutamic oxaloacetic transaminase (SGOT)? serum glutamic pyruvic transaminase (SGPT), serum alkaline phosphatase, bilirubin, prothrombin time, serum protein electrophoresis, Venereal Disease Research Laboratory (VDRL) and quantitative Kolmer tests were performed. The retention of bromosulphathalein, forty-five minutes after intravenous injection, was determined. The presence of Brucella and Pasteurella agglutinins and syphilitic reagin was determined, and complement fixing antibodies1 to Blastomyces, Histoplasma, Coccidioides and Coxiella burnetti were surveyed. These studies were accomplished on all patients. Serum from selected patients was assayed for complement fixing antibodies to lymphopathia venereum, treponemal antibodies using fluorescent technics (FTA), treponemal immobilizing antibodies @PI) * and latex agglutinins to Trichinella. Hepatic tissue was obtained by the Menghini needle biopsy technic. A portion of the tissue was fixed in 10 per cent formalin for histopathologic study and for Ziehl-Neelsen and Gomori methenamine silver stains. The remainder was macerated in 2 ml. sterile normal saline solution, plated and incubated
biopsy the
prev-
performed
and 3 to 10 per cent prev[Z-5]. Recently, we studied retrospectively sixty-three patients with granulomas in the liver. Of these sixty-three patients thirteen had granulomas due to undetermined etiology. Seven of these thirteen patients were available for further investigation. The purposes of this study were twofold. Patients were studied, prospectively, to determine the etiology of the granulomatous disease. In this manner, the diagnostic criteria and diagnostic approach previously described [ 7 ] were evaluated. Secondly, the change in liver function from the time of the initial biopsy until the subsequent biopsy was determined in these seven patients. The records of seven other patients with granulomatous hepatitis were reviewed to determine changes in the liver parameters over a number of years. at this
hospital
alence
elsewhere
[I],
METHODS Seven patients were admitted to the Clinical Study Center; a thorough history was taken and a physical
t Performed Laboratories.
by
the Texas
Department
of Health
* From the Division of Infectious Diseases, Department of Internal Medicine, University of Texas-Medical Branch, Galveston, Texas. This study was supported by the Jeane B. Kempner Scholarship Fund and U.S. Public Health Service Grant FR-73. Manuscript received March 20, 1967. “01.
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207
Granulomatous
208
Hepatitis-Guckian,
Perry TABLE CLINICAL
CaSC
NO.
Patient
Sex and Age (yr.)
Diagnosis
1
Z.W.
F, 58
Q fever
2
E.D.
F, 44
Disseminated t”berc”losis
Other Diagnoses Unknown
Diabetes mellitus with neuropathy; osteoarthritis; obesity; rheumatic aortic insufficiency; “tosclerosis; adenocarcinoma of endomctrium Carcinoma of cervix; systemic lupus erythematosus; latent syphilis (late)
7 yr.
3
B.M.
F, 30
Sarcoidosis
At least 16 mo.
4
M.E.P.
F, 49
Tuberculosis
At least 1 yr.
5
J.F.
M, 43
Sarcoidosis
1 yr.
6
J.M.
M, 43
Sarcoidosis
16 mo.
7
C.E.
F, 52
Tertiary syphilis
1 yr.
Iron deficiency anemia Psoriasis; carcinoma of thyroid Bilateral peroneal palsy
Polythemia rubra “era; renal disease of unknown etiology
Duodenal ulcer; rheumatic aortic stenosis; iron deficiency anemia
* N.D. = not done.
Lowenstein-Jensen agar (37”c.), blood and Sabouraud agar (25’ and 37’c.), and in trypticase soy broth, with and without added carbon dioxide (37’c.). Bone marrow, when obtained, was processed identically. Intracutaneous skin tests with old tuberculin (OT), histoplasmin and coccidioidin were made after serum was obtained for serologic study. The criteria [7] upon which diagnoses were based were (1) presence of microbial organisms (acid-fast staining bacteria or fungi) detected by special stains of the liver or other tissues; (2) positive cultures of organisms from liver biopsy specimens, tissue or body fluids; (3) clinical and laboratory data compatible with the diagnosis of sarcoidosis, combined with the finding of noncaseating hepatic granulomas in the absence of positive histopathologic stains and cultures; (4) negative stains and cultures of tissue for organisms, but definite serologic evidence of specific disease; (5) the presence of Sternberg-Reed cells; (6) caseating granulomas of the liver or other tissues, negative stains and cultures of tissues or body fluid, but strong clinical evidence of tuberculosis. The hospital and clinic records of seven additional patients with a definitive etiologic diagnosis of their granulomatous hepatitis were reviewed retrospectively. All these patients were evaluated at least twice in this hospital. The records were reviewed for the etiology of the granulomas and, in particular, the changes in the results of liver function studies and changes in liver size with or without therapy. On
RESULTS
Case histories are included in the appendix. Table I depicts the clinical data in the prospectively studied patients. Five of the seven pa-
tients were female, and all but one was over forty years of age. All the patients had granulomas in the liver at the time of the initial biopsy, but none of the biopsies revealed organisms when stained for mycobacteria or fungi. Only one patient had granulomas in the subsequent liver biopsy specimen, but only one specimen was interpreted as normal. Three showed chronic inflammatory infiltrates and fatty metamorphosis, and one showed focal fibrosis. One patient did not undergo liver biopsy because of thrombocythemia. An etiologic diagnosis was established in all seven patients (Table I). One patient (Case 1) was thought to have had Q fever hepatitis on the basis of a complement fixing antibody titer of 1: 32. The presence of caseous necrosis in the initial biopsy specimen was atypical of this disease, but the granulomas disappeared even though she did not receive antimicrobials in the interim. Another patient (Case 2) had disseminated tuberculosis and antituberculous therapy was initiated after the latest biopsy. One patient (Case 3) had typical sarcoidosis involving the liver, spleen and lungs. In one patient (Case 4) evaluation was more difficult. This patient had been taking sodium para-aminosalicylate and isoniazid for one year at the time the biopsy was performed in 1966. Based on the presence of caseation in the initial granulomas and the histopathologic improvement in the liver after antituberculosis therapy was given, tuberculosis AMERICAN
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Perry
Hepatitis-Gwkian,
309
I
DAT.4
Liver
Biopsy
1st
Caseatinq 1960
qranulomas;
2nd
no organisms;
Noncaseating gmnulomas; nisms; 1963
no
Other
Marked fatty infiltration and minimal chronic infiltrate; no organisms or granulomas; 1966 Scattered mononuclear infiltrate; mild fatty metamorphosis; no granulomas; 1966
orga-
Noncaseating granulomas; no organisms; 1965 C&eating granulomas; no organisms; 1965 Noncasearing granulomas; no “rganismr; 1965
Normal;
Noncasenting nisms, 1965
granulomas;
no
orga-
Not performed
Noncaseating nisms; 1965
granulomas;
no
orga-
Mild fatty infiltration, and chronic inflammatory infiltrate; no granulomas; 1966
Focal
1966
fibrosis;
Noncaseating nisms ; 1966
no granulomas; granulomas;
1966 no
orga-
TABLE LABORATORY
Eosinophils
Serum Bilirubin
(%)
(mg.%)
(%)
Bone marrow--sterile
N.D.”
Sicrilc
Skin-erythema induratum sterile; lymph node-granulomas with acid-fast staining bacteria observed, sterile; Kidneynecrotizing arteriolith and glomeruliris Bone marrowsterile
Sterile
Sterile
N.D.
Sterile
None
Sterile
Sterile
Bone marrow--sterile; abdominal lymph node, noncaseating granulomas, no organisms, sterile Lymph node-hyperplasia; skin and muscle-normal; bone marrow-sterile, compatible with myeloproliferative disorder None
Sterile
Sterile
Sterile
N.D.*
N.D.*
Sterile
had lesions of lupus erythematosus in the kidney and erythema induratum in the skin. In this patient the diagnosis of tuberculosis was established by lymph node biopsy. The laboratory data and changes in liver function are shown in Table II. None of the patients had an elevated serum bilirubin level at any time in the course of their disease. Only three patients had an elevated serum alkaline phosphatase level (Cases 2, 5, and 6). One patient (Case 2) had tuberculosis, and two others (Cases 5 and 6) had sarcoidosis. The serum alkaline phosphatase in both the latter patients decreased significantly while they were receiving glucocorticoids. The SGOT was minimally elevated in several patients, but never exceeded 60 units per 100 ml. The gamma globulin concentration, as determined by paper electrophoresis, was elevated in five patients. The patient
was the most likely diagnosis. Two patients (Cases 5 and 6) were quite similar. Both were thought to have sarcoidosis, and both were treated with isoniazid and glucocorticoids with dramatic improvement. One patient (Case 7) had syphilis and was treated with erythromycin in 1965, after the first biopsy was performed. Results of her serologic tests for syphilis reverted to normal, and the granulomas disappeared from the liver. None of the patients had evidence of portal hypertension. Various diseases were associated with the primary granulomatous disease (Table I) : rheumatic valvular disease, carcinomas, systemic lupus erythematosus, renal disease and polycythemia rubra Vera. Cultures of the liver were unrewarding in all instances. However, biopsies of other tissues were occasionally helpful. One patient (Case 2)
Hematocrit
.%-““I Alkaline Phosphatase (Sigma units) ___
II DATA
Serum Albumin SGOT/SGPT _
Case NO.
Patient
1st
2nd
1st
2nd
1st
2nd
1st
2nd
1st
1 2 3 4 5 6 7
Z.W. ED. B.M. M.E.P. J.F. J.M. C.E.
42 33 29 42 28 31 27
45 40 32 43 40 60 26
1 8 2 2 3 0 5
3 4 4 0 3 1 0
0.7 0.6 0.4 0.5 0.5 0.1 0.3
0.5 0.6 0.5 0.6 1.1 0.7 0.6
4.0 1.5 3.3 5.5 14.0 2.0
3.1 3.9 1.2 1.7 2.6 8.1 2.8
55/40 19/16 16/9 58/40 14;15 8/11
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Biopsies
Serum GZ”“ma Globulin
Bro”lsillfalein Retention (45 min.)
(gm. % ) -~
(gm.%) ~_
2nd
1st
2nd
1st
2nd
1st
2nd
ll/ll llj14 5/4 46/9 16/14 52/23 44/16
3.0 2.2 4.5 2.0 2.0 3.7
3.5 3.7 3.5 3.5 3.0 3.6 3.5
._, 3.5 1.8 0.8 1.4 1.4 1.1
0.9 3.2 2.2 0.6 0.7 1.2 0.6
__. 32 _.. 5 10 7 8
17 49 5 3 14 17 9
210
Granulomatous
Hepatitis-Guckian,
with the highest concentration (Case 2) had both tuberculosis and lupus erythematosus. The elevation was almost solely due to IgA. The other patient with tuberculosis had normal gamma globulin levels. The three patients with sarcoidosis (Cases 3, 5 and 6) had elevated gamma globulin levels. In one patient (Case 5) the gamma globulin IeveI decreased during prednisone therapy. In another (Case 7) the gamma globulin level returned to normal after treatment with erythromycin. Bromsulfalein retention was elevated in five of the seven patients. Retention increased in the patient with untreated tuberculosis and in two of the patients with sarcoidosis. The retention was normal in one patient with sarcoidosis and one with tuberculosis. In the patient with syphilis bromsulfalein retention was unchanged. Serologic studies were valuable in ruling out certain diseases but the diagnosis was established in only two patients on this basis. One patient (Case 1) had a positive complement fixation test for Q fever, 1: 32, and one (Case 6) had positive fluorescent treponemal and treponemal immobilizing antibody studies. In one patient (Case 2) FTA and TPI studies yielded positive results, but mycobacteria were demonstrated in a lymph node. The skin tests were negative initially in all three patients with sarcoidosis. While taking glucocorticoids, the old tuberculin skin test converted in one patient, and the histoplasmin converted in another. In general, the skin tests were of no diagnostic value. One patient who had tuberculosis had a negative reaction to the old tuberculin skin test. The seven patients who were reviewed retrospectively had been followed at this hospital because of granulomatous hepatitis for two to eleven years. One had tuberculosis with severe involvement of the liver. While taking streptomycin, para-aminosalicylate and isoniazid, the serum alkaline phosphatase and SGOT decreased, and the serum albumin increased. The serum bilirubin and the bromsulfalein retention remained normal, but the enlarged liver did not change. The initial liver biopsy specimen showed caseating granulomas with acid-fast organisms identified by Ziehl-Neelsen stains, and the culture yielded Mycobacterium tuberculosis. Eighteen months after chemotherapy was begun, noncaseating granulomas were still present in the liver, but no organisms were found by either stain or culture.
Perry
Six patients had sarcoidosis, but none had severe liver involvement. One patient received no glucocorticoids, and during the five years of observation the bromsulfalein retention, alkaline phosphatase and liver size decreased. The serum albumin increased, but the gamma globulin concentration remained the same. Five patients with sarcoid involvement of the liver were treated with glucocorticoids. The liver size decreased in three and in one it remained unchanged. One patient’s liver was not enlarged. Two patients underwent liver biopsies after glucocorticoid therapy was initiated. One had no granulomas while taking prednisone, and the other had granulomas in the liver nine years after cortisone therapy was discontinued. Only one of the five patients had an elevated serum bilirubin level, and it was unaffected by the administration of steroids. Two patients with an elevated alkaline phosphatase level showed decreases in this enzyme with steroid therapy. In another patient the alkaline phosphatase increased during prednisone therapy. The serum albumin increased in three patients, and the gamma globulin concentration decreased in three patients. COMMENTS
An approach to the diagnosis of patients with granulomatous hepatitis has been outlined elsewhere [I]. This approach was evaluated in the present study in seven patients with previously undiagnosed granulomatous disease of the liver. In all seven, diagnoses were reached using this comprehensive approach and strict diagnostic criteria. Follow-up studies of patients with undiagnosed hepatic granulomas are scarce. Klatskin [6] found that in three of fifty-five patients with granulomatous hepatitis of unknown etiology, tuberculosis developed within three years. The etiologic factors in the remainder were unknown. He postulated that these patients had either sarcoidosis or granulomas due to underlying primary liver disease. It appears that in the majority of patients with granulomatous hepatitis, destruction of liver parenchyma and/or fibrosis progresses very slowly. Specific therapy of infectious causes usually halts this process. Brucellosis, however, may progress to cirrhosis [7,8] if untreated, and even after appropriate antimicrobial therapy [S]. Sarcoidosis usually causes minimal liver disease. However, cirrhosis, portal hypertension AMERICAN
JOURNAL
OF
MEDICINE
Granulomatous
Hepatitis-Chd-ian,
ancl,‘or liver failure can occur when the liver is se\:erely involved [6$7.3]. In two of Klatskin’s patients [S] who had granulomas of unknown etiology localized in the liver, cirrhosis and portal hypertension developed. These patients probably had sarcoidosis. There is still debate whether glucocorticoids affect the ultimate outcome of sarcoidosis of the Ii\-er. One report describes a patient, not treated with steroids, who had progressive functional li\rer impairment and died of cirrhosis in five years [ TO]. There is, however, evidence that steroids may not mitigate the progressive fibrosis [9,7 I]. Other workers have found no increase in fibrosis and disappearance of granulomas while their patients were receiving steroids [ 72,13,16]. One of our patients had a normal liver biopsy while not receiving steroids, one had no granulomas while taking prednisone, one still had granulomas in the liver after one year of prednisone therapy and one had granulomas in the liver while not treated with steroids. There is little doubt that corticosteroids can alleviate the constitutional symptoms of sarcoidosis [ 74-761 and decrease the serum alkaline phosphatase [ 72,1.?, 151, as was demonstrated in We also present evidence that our patients. serum albumin may increase and gamma globulin concentration and liver size decrease during glucocorticoid therapy. However, the liver size may not change [9,12]. Serum bilirubin and brornsulfalein retention may also decrease while the patient is receiving steroids [ 1 l- 13,151. Klatskin [6] favors the use of steroids in such patients with progressive liver disease if the diagnosis of sarcoidosis is relatively certain. One of the recently stated criteria for steroid therapy in sarcoidosis was the presence of liver dysfunction [ / 71. We are of the opinion that the mere presence of liver dysfunction is not justification for steroid therapy, but we agree with Klatskin in that if progressive or more than minimal liver disease is present, steroid therapy is indicated. The association of various diseases with the primary granulomatous disease deserves comment. Carcinomas, rheumatic valvular disease, renal disease, systemic lupus erythematosus and pal!-cythemia rubra vera were discovered in the seven patients studied prospectively. Of the sixty-three patients whose records were previously reviewed [I], two had rheumatic valvular disease, one systemic lupus erythematosus, one polycythemia rubra Vera, one chronic myelocytic leukemia and one adenocarcinoma of the
VOL..
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Perry
pancreas. Sarcoidosis associated with systemic lupus erythematosus has been reported previously [ IK]. Immunologic aberrations and hypersensitivity-like states in leprosy have been documented [IO]. Active extrapulmonary tuberculosis has also been associated with constrictive arteritis of the Takayasu type [20]. Granulomas of rmknown cause in lymph nodes, liver and spleen have been described in patients with congenital and acquired agallunaglobulinemia [21-271. At least one case of sarcoidosis [28] and two cases of probable tuberculosis [2,?,24] associated with agammaglobulinemia have been reported. Collagen or autoimmune-like diseases, hepatosplenomegaly, lymphoreticular neoplasms and renal lesions are also known to occur in these patients. It has been postulated that the granulomas were the result of repeated infections, or that the agammaglobulinemia was due to disseminated lymphoreticular granulomatous disease. There certainly seems to be more than a chance relationship between granulomatous diseases, abnormal immune globulins, autoimmune diseases, and various malignancies. Perhaps the excessive antigenic stimulus which produces the granulomatous disease and hypergammaglobulinemia causes aberrant immunologic responses or even exhaustion of immunologically competent cells, failure to reject “self” antibody clones and neoplastic cell lines, and consequent autoimmune disease and malignancy. APPENDIX
A fifty-six year old Negro woman (Z.W., 68668-M) was hospitalized in 1960 for adenocarcinoma of the endometrium. She was treated with radium inserts, followed by panhysterectomy. She had had rheumatic fever at age seventeen. Physical examination revealed left cardiac ventricular hypertrophy, a murmur of aortic insufficiency and hepatomegaly. At the time of hysterectomy an open liver biopsy was performed and revealed caseating granulomas without identifiable organisms. In 1962 she was found to have diabetes. When admitted in July 1966 she denied fever, weight loss, chills or anorexia but did complain of tiring easily. She was afebrile and the lungs were normal. Her heart was enlarged with left ventricular preponderance. There was a grade 2/6 early short ejection murmur and a grade 3 decrescendo diastolic murmur was heard in the right CASE
1.
second and left third intercostal spaces, respectively. The liver was felt 4 cm. below the costal margin. The spleen was not palpable. The hemoglobin and white blood cell count were within normal limits. The urinalysis showed 2-t
212
Granulomatous
Hepatitis-Guckiun,
glucosuria. Tularemia agglutinins were found at a 1: 160 dilution. A Coxiella burnetti complement Bxation test was reactive 1: 32. Serum protein electrophoresis showed a completely normal pattern and the reactions to all skin tests were negative. On April 25, 1966, a liver biopsy specimen was obtained with the Menghini needle. The final diagnoses were (1) rheumatic heart disease with aortic insufficiency, (2) diabetes mellitus with neuropathy and (3) arteriosclerotic cardiovascular disease. CASE 2. A forty-four year old Negro woman (E.D., 30701-M) complained of epigastric pain, fatty food intolerance, fever, chills and weight loss in 1956. Two large lymph nodes were felt in the left axilla. She did not return to the clinic, and no studies were performed. She had pneumonia in 1959, followed by the onset of generalized migratory arthritis and the appearance of small, hot, tender nodules on the legs and arms. Examination at that time showed these subcutaneous nodules and slight swelling of the right ankle. The serologic test for syphilis was reactive. In 1962 a chest roentgenogram showed an infiltrate in the right perihilar area and possibly in the apex of the left lung. Lupus erythematosus preparations were negative. A liver biopsy specimen, obtained in January 1963, showed granulomatous hepatitis without necrosis or organisms. A culture of this specimen for Mycobacteria was negative. The large left axillary nodes were again felt; there was no hepatosplenomegaly. The reaction to an old tuberculin skin test, 1: 10,000, was markedly positive. Cultures of the urine and sputum for Mycobacteria were negative as were sputum cultures for fungi. A Wertheim hysterectomy was performed in February 1963 for carcinoma of the cervix in situ. She was never treated with antituberculous therapy. In April 1963 the symptoms of joint involvement and subcutanequs nodules recurred. She had had intermittent fever, rigors and night sweats one to three times per week since 1959. In 1965 she had supraorbital pain, blurring of the vision, conjunctival injection and photophobia. Physical examination in September 1966 showed her to be afebrile. There were 1.5 cm. indurated, tender nodules on the anterior and posterior areas of the legs, several of which were crusted. The left conjunctiva was injected and the pupils reacted very sluggishly to light and accomodation. In the left axilla there were three lymph nodes, 1 to 1.5 cm. in diameter, which were nontender, firm and slightly matted. The heart and lungs were normaal. The abdomen was protuberant, but no organomegaly was palpable. A complete blood count was normal. A rheumatoid factor latex agglutination test was negative, but the reaction to the serologic test for syphilis was weakly positive, the Kolmer was not reactive, but the FTA
Perry
was reactive. Heterophil and cold agglutinin tests yielded normal results. A liver biopsy specimen was obtained with a Menghini needle. Biopsy of the lesions on the leg was consistent with erythema induraturn, but acid-fast bacteria could not be identified. Biopsy of the left axillary lymph node showed partial replacement with granulomatous inflammation but without true caseous necrosis. Ziehl-Neelsen stains were positive for acid-fast bacilli, but cultures for Mycobacteria were sterile. A kidney biopsy specimen obtained with a Menghini needle showed necrotizing arteriolitis and focal glomerulitis. Immunoelectrophoresis revealed that the IgG and IgM levels were normal, and the IgA level accounted for the marked hypergammaglobulinemia. Sputum smears and cultures for acid-fast bacilli were negative. Two lupus erythematosus preparations were strongly positive. The administration of isoniazid, sodium para-aminosalicylate and prednisone was started on June 7, 1966. The final diagnoses were (1) chronic disseminated tuberculosis, (2) systemic lupus erythematosus, (3) erythema induratum, (4) episcleritis and (5) late latent syphilis. CASE 3. A thirty year old Negro woman (B.M., 34570-P) was first seen at this hospital in March 1965, when she was three months pregnant. The chest roentgenogram revealed infiltrates compatible with sarcoidosis, and splenomegaly was present. Reactions to skin tests were negative, but a liver biopsy showed noncaseating granulomatous inflammation. It was thought that she probably indeed had sarcoidosis and she was discharged without therapy. She returned in August 1965 and was delivered of a stillborn infant. She was asymptomatic when she was admitted in September 1966. She was normotensive and afebrile. No adenopathy was palpable. The liver was felt at the right costal margin, but the spleen was enlarged 8 cm. below the costal margin. The chest roentgenogram showed diffuse nodular thickening of the interstitial tissues throughout both lungs, and there was slight increased prominence of the left hilum. The serum uric acid level was 5.8 mg. per cent. On August 16, 1966, a liver biopsy was performed using the Menghini needle. The old tuberculin and fungal skin tests were negative. The fmal diagnoses were (1) sarcoidosis, and (2) iron deficiency anemia, probably due to multiparity. CASE 4. A forty-nine year old white woman (M.E.P., 9973-J) was seen at this hospital in 1953 with psoriasis, which subsequently resolved. She was not seen again until 1963 when she underwent a total thyroidectomy for follicular adenocarcinoma. In early 1965 an exploratory laparotomy and hysterosalpingo-oophorectomy were performed. At the time of surgery nodules were noticed on the surface of the liver, and a biopsy specimen from one of these showed AMERICAN
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Granulomatous
Hepatitis-Gudin~~,
caseating granulomas without identifiable organisms. No other abnormalities were noted. The patient was given isoniazid and sodium para-aminosalicylate. Ihere was no history of pulmonary tuberculosis, and all cultures for Mycobacteria were negative. The liver was palpable 4 cm. below the costal margin at that time. The reaction to all skin tests was negative and liver function tests were within normal limits. In September 1966 gastrointestinal intolerance to para-aminosalicylate developed. Isoniazid and paraaminosalicylate therapy was discontinued for two weeks and then restarted; however, vomiting recurred on two occasions prior to her admission in October 1966. The patient was afebrile and normotensive. The chest was mildly emphysematous but no rales or wheezes were audible. The liver and spleen were not palpable. The chest roentgenogram showed no abnormalities, and a film of the upper gastrointestinal tract showed no abnormality except for a diverticulum-like structure adjacent to the duodenal loop. A liver biopsy specimen was obtained with the Menghini needle on August 24, 1966. Skin tests were again negative at forty-eight and seventy-two hours. The patient was given Neopasalate@, which she tolerated well, and isoniazid. The final diagnoses were (1) tuberculous hepatitis, inactive, (2) endogenous depression and (3) duodenal diverticulum. A forty-three year old white man (J.F., CASE 5. 43248-P) was decribed in some detail previously [ 71. In January 1966 he complained of excessive fatigue, and the liver was palpable 6 cm. below the costal margin. In June 1966 weakness, most pronounced in his legs, was noted and he especially had difficulty in dorsiflexing his right foot. Isoniazid, which he had been taking, was discontinued in July 1966. His blood pressure was 128/84 mm. Hg, pulse 120 per minute, respirations 22 per minute and temperature 101.4”F. upon admission in November 1966. He was a plethoric man with several ecchymotic areas over the ulnar surfaces of the arms. The skin was hot and moist. The chest was normal, and the lungs were clear. The liver was palpable 4 cm. below the costal margin, but there was no tenderness or ascitic fluid. There was pain with movement of the left arm, especially with elevation and rotation. The neurologic examination showed bilateral peroneal nerve palsies. The complete blood count, urinalysis, blood urea nitrogen, fasting blood sugar and uric acid were normal. Roentgenograms of the chest and of the left shoulder were within normal limits. Skin tests resulted in a positive reaction to old tuberculin (1: loo), but negative reaction to coccidioidin and histoplasmin. On October 13, 1966, a Menghini needle liver biopsy was performed. The patient remained febrile, and because of this, VOL.
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the dosage of preclnisone was increased to 15 mg. daily. After this he remained afebrile. 1 lie linal ciiagnoses were (1) sarcoidosis, (2) peroneal nl’r\-e palsy, bilateral, (3) tendonitis. bronchitis.
left shoulder
and 14) chronic
In this forty-three year old Negro man CASE 6. (J.M., 44625-P) progressive pedal edema, orthopnea and dyspnea developed in December 1964. He underwent an exploratory laparotomy in another hospital, and a splenectomy was performed. He had hypoalbuminemia, pleural effusions, ascites and an elevated serum alkaline phosphatase level. A liver biopsy was said to have been normal. He continued to have edema, ascites, weakness and malaise. In May 1965, physical examination revealed ascites and pleural effujions, but no adenopathy. l‘he liver was palpable 7 cm. below the costal margin, and pedal edema was present. A gamut of laboratory and x-ray studies failed to reveal a diagnosis. An inferior vena cavagram was normal. A liver biopsy specimen showed noncaseating granulomas without identifiable organisms. The reaction to old tuberculin and fungal skin tests was negative. Cultures of pleural fluid, peritoneal fluid and sputum for mycobacteria and fungi were negative. The ascitic fluid showed 1,536 leukocytes per cu. mm., 56 per cent of which were lymphocytes and 3.9 gm. per cent of protein. Serum immunoelectrophoresis was normal. Because of the patient’s deterioration, the administration of isoniazid, potassium para-aminosalicylate, streptomycin and prednisone, 40 mg. daily, was begun. His condition improved gradually, with return of appetite, weight gain and a sense of well-being. The pleural effusions and ascites disappeared. Cultures of the liver and bone marrow for Mycobacteria and fungi were sterile. In March 1966 the patient was asymptomatic but the liver was still palpable 4 cm. below the costal margin, and there was a trace of pedal edema. In June 1966 his hemoglobin was 18.2 gm. per cent, hematocrit 54 per cent and white blood cell count 12,900 per cu. mm. At the time of admission in November 1966 he was taking isoniazid, potassium, para-aminosalicylate and prednisone, 5 mg. every other day. He denied weakness, fever or anorexia. His blood pressure was 86/56 mm. Hg, pulse 84 per minute, respirations 16 per minute, temperature 97.4’F. and weight 67 kg. Nonpathologic shotty lymph nodes were palpable in the posterior cervical and anterior cervical chains. The chest, lungs and heart were within normal limits. There was bilateral gynecomastia. The liver was palpable 4 cm. below the costal margin, but there was no ascites. Skin tests with old tuberculin and coccidioiden were negative. However, the histoplasmin skin test was positive, 1 :lOO. The hemoglobin was 18.5 gm. per cent, hematocrit 58 per cent, white blood count
214
Granulomatous Hepatitis-Guckian,
25,900 per cu. mm. with 46 per cent neutrophils, 41 per cent lymphocytes, 11 per cent monocytes, 1 per cent eosinophils and 1 per cent basophils. The platelet count was 1,245,OOO per cu. mm. The blood urea nitrogen was 20 mg. per cent, and the endogenous creatinine clearance was 12 cc. per minute. The serum uric acid was 11.8 mg. per cent. The chest roentgenogram showed generalized mild opacification resembling congestion, and the skull roentgenogram was within normal limits. An intravenous pyelogram showed poor excretion of the contrast media, but no definite abnormalities were visible. A bone marrow examination disclosed hypercellularity with hyperplasia of red cell precursors, megakaryocytes and myeloid precursors and mild basophilia and eosinophilia. Blood gas studies showed a mild, persistent alveolararterial oxygen gradient. The diffusing capacity of carbon monoxide was also slightly decreased. The plasma volume and red blood cell volume were greatly increased. Lupus erythematosus preparations were negative. The leukocyte alkaline phosphatase was markedly decreased. Phlebotomies totaling 1,300 ml. were performed, and the patient was given radiophosphorus. The final diagnoses were (1) sarcoidosis, (2) polycythemia (3) renal insufficiency of unknown rubra Vera, etiology, and (4) gynecomastia due to liver disease.
CASE 7. A fifty-two year old Negro woman (C.E., 34088-P) had bleeding in the upper gastrointestinal tract on three occasions between 1959 and 1965, for which she required transfusions. In the 1940’s she was told that she was hypertensive and that she had a heart murmur. During a bleeding episode in 1963 right and left ventricular failure developed and she was digitalized. She was first seen here in February 1965 ; the physical examination revealed an aortic systolic thrill with a grade 5/6 aortic ejection murmur. Breath sounds were absent at the posterior base of the right lung, and the liver was palpable 4 cm. below the costal margin. The chest roentgenogram showed consolidation or atelectasis in the base of the right lung, and films of the gastrointestinal tract showed a deformed duodenal bulb. The old tuberculin skin test was positive. Bronchograms showed partial atelectasis of the middle and lower lobes of the right lung. Cultures of bronchial and gastric washings for Mycobacteria were negative. The serologic test for syphilis was positive, and a Kolmer test was reactive. A liver biopsy specimen obtained on April 2, 1965 showed foci of granuinflammation without identifiable orlomatous ganisms. The patient was readmitted in January 1966. A liver biopsy specimen at this time showed no granulomas, and indeed it was normal. The density in the lower lobe of the right lung was thought to represent atelectasis and pleural thickening. Liver function studies were again normal and mycobacterial cultures of gastric washings were negative. The patient was
Perry
treated with erythromycin, 2 gm. daily, for ten days. In May 1966 bleeding in the gastrointestinal tract recurred and she was given 3 units of blood. She was admitted again in November 1966. On admission, she was normotensive and afebrile; the physical findings in the lower right side of the chest were unchanged. There was left cardiac ventricular enlargement, a systolic thrill in the aortic area, and a grade 5/6 harsh early systolic ejection murmur loudest in the aortic area. The liver was palpable 4 cm. below the costal margin, but was not tender. The old tuberculin skin test was positive at a 1: 10,000 dilution, but the coccidioidin and histoplasmin skin tests were negative. The complete blood count showed a normal white cell count and normal differential and platelet count. The hemoglobin was 5.9 gm. per cent with microcytic hypochromic indices. After oral iron therapy the reticulocyte count was 9.9 per cent. A quantitative Kolmer test was nonreactive. A liver biopsy was performed with a Menghini needle on October 24, 1966. The chest roentgenogram again showed pleural scarring, and the duodenal bulb again was deformed. The administration of Pamine,@ Gelusil@ and ferrous sulfate was initiated, with good response. The final diagnoses were (1) granulomatous hepatitis due to syphilis, healed, (2) dental caries, (3) duodenal peptic ulcer disease, (4) anemia due to chronic blood loss, (5) diabetes mellitus and (6) rheumatic aortic valvular stenosis. REFERENCES 1. GUCKIAN, J. C. and PERRY,J. E. Granulomatous hepatitis. An analysis of 63 cases and review of the literature. Ann. ht. Med., 65: 1081, 1966. 2. SCHIPF, L. The clinical value of needle biopsy of the liver. Ann. Znt. Med., 34: 948, 1951. 3. EDMONDSON,H. A. Needle biopsy in differential diagnosis of acute liver disease. J.A.M.A., 191: 480, 1965. 4. RUBIN, E. Interpretation of the liver biopsy. Diagnostic criteria. Gmtroenterolou, 45: 400, 1963. 5. KLATSKIN, G. and YESNER, R. Hepatic manifestations of sarcoidosis and other granulomatous diseases. Yale J. Biol. & Med., 23: 207, 1950. 6. BUNIM,J. J., KIMBERG, D. V., THOMAS, L. B., VAN SCOTT,E. J. and KLATSKIN, G. The syndrome of sarcoidosis, psoriasis, and gout. Ann. Znt. Med., 57: 1018, 1962. 7. JOSKE, R. A. and FINCKH, E. S. Hepatic changes in human brucellosis. M. J. Austral&, 1: 266, f955. 8. MCCULLOUGFL N. B. and EISELE. C. W. Brucella hepatitis leading to cirrhosis of the liver. Arch. Znt. Med., 88: 793, 1951. 9. NELSON, S. and SCHWABE, A. D. Progressive hepatic decompensation with terminal hepatic coma in sarcoidosis. Am. J. Digest DC., 11: 495, 1966. 10. BRANSON, J. H. and PARK, J. H. Sarcoidosishepatic involvement. Presentation of a case with fatal liver involvement, including autopsy findings and review of the evidence for sarcoid involvement of the liver as found in the literature. Ann. Znt. Med., 40: 111, 1954. 11. KELLEY, M. L. and MCHARDY, R. J. An unusual AMERICAN
JOURNAL
OF
MEDICINE
Granulomatous
12.
13.
14.
15.
16.
17.
18.
19.
Hepatitis-
c,+se of fatal hepatic sarcoidosis. ,4m. J. Med., 19: 842, 1955. PORTER, G. H. Hepatic sarcoidosis-A cause of pxtal hypertension and liver failure: Review. Arch. Int. MPd., 108: 483, 1961. Mrsrn.~s, S. P., GREEN, J. R. and SCHIFF, L. Hepatic sarcoidosis with portal hypertension. Am. J. Med., 36: 470, 1964. SIL I‘ZBACH, L. E. Effects of cortisone in sarcoidosisa study of thirteen patients. Am. J. Med., 12: 139, 1952. SHULMAN, L. E., SHOENRICH, E. H. and HARVEY. A. M. The effects of adenocorticotrophic hormone (ACTH) and cortisone on sarcoidosis. Bull. Johns Hopkins Has)., 91: 371, 1952. M;ZTHER, G., DAWSON, J. and HOYLE, C. Liver biopsy in sarcoidosis. Quart. J. Med., 24: 331, 1955. Committee on Therapy. The use of corticosteroids in the treatment of sarcoidosis. A statement of the committee on therapy. Am. Rev. Resp. Dis., 82: 753, 1960. MAYOCK, R. L., BERTRAND, P., MORRISON, C. E. and SCOTT, J. H. Manifestations of sarcoidosis. Analysis of 145 patients with a review of nine series selected from the literature. Am. J. Med., 35: 67, 1963. MATTHEWS, L. J. and TRAUTMAN, J. R. Clinical and serological profiles in leprosy. Lamet, 2: 915, 1965.
VOL.
44,
FEBRUARY
1968
20.
21.
22.
23.
24.
25.
26.
215
GucX-icr~,PETTY
CL .4. and SWTH, S. R. Extrapulmonary tuberculosis with erythema nodosum and occlusi\ c arterial disease. Canad. .W. .4. J., 95 : L7i, 1960. ZINNEMAN, H. H. and HALL, LIT. 1 I. .\cquired agammaglobulinrmia. Report of 3 cask. ./.9..1f.r1. 156: 1390, 1954. PRASAD, .I. S., REINEK, E. and bV..x~soi\l.C. .J. S~IIdrome of hypogammaglobulinemia, splenomrgaly, and hypersplenism. Blood, 12: 926, 1957. ROHN, R. .J., BEHNKE, K. 1-I. and BOND, W. II. .4r:quired agammaglobulinemia with hypersplrnism-A case report. Am. J. ‘21. kSc., 229: 406, 1955. ZINNEMAN, H. H. and HALL, \Y. I-I. Steatorrhea and probable tuberculosis with acquired hypogammaglobulinemia. Am. Reu. Tuberc., 74: 773, 1956. PEARCE, K. M. and PERINPANAYAGAM,M. S. Congenital idiopathic hypogammaglobulinemia. Arch. Dis. Childhood, 32: 422, 1957. ZELMAN, S. and LEWIN, H. :\dult agammaglobulin-
TIIIPFAULT,
emia associated with multiple congenital anomalies. Am. J. Med., 25: 150, 1958. ’ 27. GREEN, I., LITWIN,S., :\DLERSBERG, Ii. and RUBIN,
I. Hypogammaglobulinemia ment of lymphosarcoma. Arch. 1966. 28. BROWSKY, D. and L~JNN, Y. 0. hypogammaglobulinemia. Am. 1965.
with late developZnt. Med., 118: 592, I,. Sarcoidosis
with J. *cf. SC., 250: 11,
Hepatitis
Unknown
of
Etiology*
An Etiologic and Functional Evaluation JAMES
C. GUCKIAN,
M.D.
and JOHN
Galveston,
E. PERRY,
M.D.
Texas
The diagnosis in patients with granulomatous hepatitis can usually be obtained if the proper approach and criteria, such as previously outlined, are utilized. Liver destruction and fibrosis can usually be halted if specific therapy for infectious causes is instituted. Corticosteroid therapy seems to be indicated in patients with sarcoidosis with documented severe or progressive hepatitis, that is, the presence of jaundice, hypoalbuminemia, ascites, markedly elevated alkaline phosphatase levels and portal hypertension. Granulomatous disease may be associated with agammaglobulinemia, autoimmune disease, hematopoietic malignancies and carcinomas. Whether there is a statistically significant correlation between these diseases is not known.
D
specimen
sence mon
in
IAGNOSIS
a
of identifiable problem,
alence
patient
shows
whose
granulomas
organisms
as reflected
of granulomas
is not
liver in
biopsies
ab-
an uncom-
by a 4 per cent
in liver
examination performed on each. All medications were continued, including antituberculous drugs. unless there were specific contraindications. A complete hemogram and platelet count, serum glutamic oxaloacetic transaminase (SGOT)? serum glutamic pyruvic transaminase (SGPT), serum alkaline phosphatase, bilirubin, prothrombin time, serum protein electrophoresis, Venereal Disease Research Laboratory (VDRL) and quantitative Kolmer tests were performed. The retention of bromosulphathalein, forty-five minutes after intravenous injection, was determined. The presence of Brucella and Pasteurella agglutinins and syphilitic reagin was determined, and complement fixing antibodies1 to Blastomyces, Histoplasma, Coccidioides and Coxiella burnetti were surveyed. These studies were accomplished on all patients. Serum from selected patients was assayed for complement fixing antibodies to lymphopathia venereum, treponemal antibodies using fluorescent technics (FTA), treponemal immobilizing antibodies @PI) * and latex agglutinins to Trichinella. Hepatic tissue was obtained by the Menghini needle biopsy technic. A portion of the tissue was fixed in 10 per cent formalin for histopathologic study and for Ziehl-Neelsen and Gomori methenamine silver stains. The remainder was macerated in 2 ml. sterile normal saline solution, plated and incubated
biopsy the
prev-
performed
and 3 to 10 per cent prev[Z-5]. Recently, we studied retrospectively sixty-three patients with granulomas in the liver. Of these sixty-three patients thirteen had granulomas due to undetermined etiology. Seven of these thirteen patients were available for further investigation. The purposes of this study were twofold. Patients were studied, prospectively, to determine the etiology of the granulomatous disease. In this manner, the diagnostic criteria and diagnostic approach previously described [ 7 ] were evaluated. Secondly, the change in liver function from the time of the initial biopsy until the subsequent biopsy was determined in these seven patients. The records of seven other patients with granulomatous hepatitis were reviewed to determine changes in the liver parameters over a number of years. at this
hospital
alence
elsewhere
[I],
METHODS Seven patients were admitted to the Clinical Study Center; a thorough history was taken and a physical
t Performed Laboratories.
by
the Texas
Department
of Health
* From the Division of Infectious Diseases, Department of Internal Medicine, University of Texas-Medical Branch, Galveston, Texas. This study was supported by the Jeane B. Kempner Scholarship Fund and U.S. Public Health Service Grant FR-73. Manuscript received March 20, 1967. “01.
44.
FEBRUARY
1968
207
Granulomatous
208
Hepatitis-Guckian,
Perry TABLE CLINICAL
CaSC
NO.
Patient
Sex and Age (yr.)
Diagnosis
1
Z.W.
F, 58
Q fever
2
E.D.
F, 44
Disseminated t”berc”losis
Other Diagnoses Unknown
Diabetes mellitus with neuropathy; osteoarthritis; obesity; rheumatic aortic insufficiency; “tosclerosis; adenocarcinoma of endomctrium Carcinoma of cervix; systemic lupus erythematosus; latent syphilis (late)
7 yr.
3
B.M.
F, 30
Sarcoidosis
At least 16 mo.
4
M.E.P.
F, 49
Tuberculosis
At least 1 yr.
5
J.F.
M, 43
Sarcoidosis
1 yr.
6
J.M.
M, 43
Sarcoidosis
16 mo.
7
C.E.
F, 52
Tertiary syphilis
1 yr.
Iron deficiency anemia Psoriasis; carcinoma of thyroid Bilateral peroneal palsy
Polythemia rubra “era; renal disease of unknown etiology
Duodenal ulcer; rheumatic aortic stenosis; iron deficiency anemia
* N.D. = not done.
Lowenstein-Jensen agar (37”c.), blood and Sabouraud agar (25’ and 37’c.), and in trypticase soy broth, with and without added carbon dioxide (37’c.). Bone marrow, when obtained, was processed identically. Intracutaneous skin tests with old tuberculin (OT), histoplasmin and coccidioidin were made after serum was obtained for serologic study. The criteria [7] upon which diagnoses were based were (1) presence of microbial organisms (acid-fast staining bacteria or fungi) detected by special stains of the liver or other tissues; (2) positive cultures of organisms from liver biopsy specimens, tissue or body fluids; (3) clinical and laboratory data compatible with the diagnosis of sarcoidosis, combined with the finding of noncaseating hepatic granulomas in the absence of positive histopathologic stains and cultures; (4) negative stains and cultures of tissue for organisms, but definite serologic evidence of specific disease; (5) the presence of Sternberg-Reed cells; (6) caseating granulomas of the liver or other tissues, negative stains and cultures of tissues or body fluid, but strong clinical evidence of tuberculosis. The hospital and clinic records of seven additional patients with a definitive etiologic diagnosis of their granulomatous hepatitis were reviewed retrospectively. All these patients were evaluated at least twice in this hospital. The records were reviewed for the etiology of the granulomas and, in particular, the changes in the results of liver function studies and changes in liver size with or without therapy. On
RESULTS
Case histories are included in the appendix. Table I depicts the clinical data in the prospectively studied patients. Five of the seven pa-
tients were female, and all but one was over forty years of age. All the patients had granulomas in the liver at the time of the initial biopsy, but none of the biopsies revealed organisms when stained for mycobacteria or fungi. Only one patient had granulomas in the subsequent liver biopsy specimen, but only one specimen was interpreted as normal. Three showed chronic inflammatory infiltrates and fatty metamorphosis, and one showed focal fibrosis. One patient did not undergo liver biopsy because of thrombocythemia. An etiologic diagnosis was established in all seven patients (Table I). One patient (Case 1) was thought to have had Q fever hepatitis on the basis of a complement fixing antibody titer of 1: 32. The presence of caseous necrosis in the initial biopsy specimen was atypical of this disease, but the granulomas disappeared even though she did not receive antimicrobials in the interim. Another patient (Case 2) had disseminated tuberculosis and antituberculous therapy was initiated after the latest biopsy. One patient (Case 3) had typical sarcoidosis involving the liver, spleen and lungs. In one patient (Case 4) evaluation was more difficult. This patient had been taking sodium para-aminosalicylate and isoniazid for one year at the time the biopsy was performed in 1966. Based on the presence of caseation in the initial granulomas and the histopathologic improvement in the liver after antituberculosis therapy was given, tuberculosis AMERICAN
JOURNAL
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Granulomatous
Perry
Hepatitis-Gwkian,
309
I
DAT.4
Liver
Biopsy
1st
Caseatinq 1960
qranulomas;
2nd
no organisms;
Noncaseating gmnulomas; nisms; 1963
no
Other
Marked fatty infiltration and minimal chronic infiltrate; no organisms or granulomas; 1966 Scattered mononuclear infiltrate; mild fatty metamorphosis; no granulomas; 1966
orga-
Noncaseating granulomas; no organisms; 1965 C&eating granulomas; no organisms; 1965 Noncasearing granulomas; no “rganismr; 1965
Normal;
Noncasenting nisms, 1965
granulomas;
no
orga-
Not performed
Noncaseating nisms; 1965
granulomas;
no
orga-
Mild fatty infiltration, and chronic inflammatory infiltrate; no granulomas; 1966
Focal
1966
fibrosis;
Noncaseating nisms ; 1966
no granulomas; granulomas;
1966 no
orga-
TABLE LABORATORY
Eosinophils
Serum Bilirubin
(%)
(mg.%)
(%)
Bone marrow--sterile
N.D.”
Sicrilc
Skin-erythema induratum sterile; lymph node-granulomas with acid-fast staining bacteria observed, sterile; Kidneynecrotizing arteriolith and glomeruliris Bone marrowsterile
Sterile
Sterile
N.D.
Sterile
None
Sterile
Sterile
Bone marrow--sterile; abdominal lymph node, noncaseating granulomas, no organisms, sterile Lymph node-hyperplasia; skin and muscle-normal; bone marrow-sterile, compatible with myeloproliferative disorder None
Sterile
Sterile
Sterile
N.D.*
N.D.*
Sterile
had lesions of lupus erythematosus in the kidney and erythema induratum in the skin. In this patient the diagnosis of tuberculosis was established by lymph node biopsy. The laboratory data and changes in liver function are shown in Table II. None of the patients had an elevated serum bilirubin level at any time in the course of their disease. Only three patients had an elevated serum alkaline phosphatase level (Cases 2, 5, and 6). One patient (Case 2) had tuberculosis, and two others (Cases 5 and 6) had sarcoidosis. The serum alkaline phosphatase in both the latter patients decreased significantly while they were receiving glucocorticoids. The SGOT was minimally elevated in several patients, but never exceeded 60 units per 100 ml. The gamma globulin concentration, as determined by paper electrophoresis, was elevated in five patients. The patient
was the most likely diagnosis. Two patients (Cases 5 and 6) were quite similar. Both were thought to have sarcoidosis, and both were treated with isoniazid and glucocorticoids with dramatic improvement. One patient (Case 7) had syphilis and was treated with erythromycin in 1965, after the first biopsy was performed. Results of her serologic tests for syphilis reverted to normal, and the granulomas disappeared from the liver. None of the patients had evidence of portal hypertension. Various diseases were associated with the primary granulomatous disease (Table I) : rheumatic valvular disease, carcinomas, systemic lupus erythematosus, renal disease and polycythemia rubra Vera. Cultures of the liver were unrewarding in all instances. However, biopsies of other tissues were occasionally helpful. One patient (Case 2)
Hematocrit
.%-““I Alkaline Phosphatase (Sigma units) ___
II DATA
Serum Albumin SGOT/SGPT _
Case NO.
Patient
1st
2nd
1st
2nd
1st
2nd
1st
2nd
1st
1 2 3 4 5 6 7
Z.W. ED. B.M. M.E.P. J.F. J.M. C.E.
42 33 29 42 28 31 27
45 40 32 43 40 60 26
1 8 2 2 3 0 5
3 4 4 0 3 1 0
0.7 0.6 0.4 0.5 0.5 0.1 0.3
0.5 0.6 0.5 0.6 1.1 0.7 0.6
4.0 1.5 3.3 5.5 14.0 2.0
3.1 3.9 1.2 1.7 2.6 8.1 2.8
55/40 19/16 16/9 58/40 14;15 8/11
VOL.
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FEBRUARY
1968
Biopsies
Serum GZ”“ma Globulin
Bro”lsillfalein Retention (45 min.)
(gm. % ) -~
(gm.%) ~_
2nd
1st
2nd
1st
2nd
1st
2nd
ll/ll llj14 5/4 46/9 16/14 52/23 44/16
3.0 2.2 4.5 2.0 2.0 3.7
3.5 3.7 3.5 3.5 3.0 3.6 3.5
._, 3.5 1.8 0.8 1.4 1.4 1.1
0.9 3.2 2.2 0.6 0.7 1.2 0.6
__. 32 _.. 5 10 7 8
17 49 5 3 14 17 9
210
Granulomatous
Hepatitis-Guckian,
with the highest concentration (Case 2) had both tuberculosis and lupus erythematosus. The elevation was almost solely due to IgA. The other patient with tuberculosis had normal gamma globulin levels. The three patients with sarcoidosis (Cases 3, 5 and 6) had elevated gamma globulin levels. In one patient (Case 5) the gamma globulin IeveI decreased during prednisone therapy. In another (Case 7) the gamma globulin level returned to normal after treatment with erythromycin. Bromsulfalein retention was elevated in five of the seven patients. Retention increased in the patient with untreated tuberculosis and in two of the patients with sarcoidosis. The retention was normal in one patient with sarcoidosis and one with tuberculosis. In the patient with syphilis bromsulfalein retention was unchanged. Serologic studies were valuable in ruling out certain diseases but the diagnosis was established in only two patients on this basis. One patient (Case 1) had a positive complement fixation test for Q fever, 1: 32, and one (Case 6) had positive fluorescent treponemal and treponemal immobilizing antibody studies. In one patient (Case 2) FTA and TPI studies yielded positive results, but mycobacteria were demonstrated in a lymph node. The skin tests were negative initially in all three patients with sarcoidosis. While taking glucocorticoids, the old tuberculin skin test converted in one patient, and the histoplasmin converted in another. In general, the skin tests were of no diagnostic value. One patient who had tuberculosis had a negative reaction to the old tuberculin skin test. The seven patients who were reviewed retrospectively had been followed at this hospital because of granulomatous hepatitis for two to eleven years. One had tuberculosis with severe involvement of the liver. While taking streptomycin, para-aminosalicylate and isoniazid, the serum alkaline phosphatase and SGOT decreased, and the serum albumin increased. The serum bilirubin and the bromsulfalein retention remained normal, but the enlarged liver did not change. The initial liver biopsy specimen showed caseating granulomas with acid-fast organisms identified by Ziehl-Neelsen stains, and the culture yielded Mycobacterium tuberculosis. Eighteen months after chemotherapy was begun, noncaseating granulomas were still present in the liver, but no organisms were found by either stain or culture.
Perry
Six patients had sarcoidosis, but none had severe liver involvement. One patient received no glucocorticoids, and during the five years of observation the bromsulfalein retention, alkaline phosphatase and liver size decreased. The serum albumin increased, but the gamma globulin concentration remained the same. Five patients with sarcoid involvement of the liver were treated with glucocorticoids. The liver size decreased in three and in one it remained unchanged. One patient’s liver was not enlarged. Two patients underwent liver biopsies after glucocorticoid therapy was initiated. One had no granulomas while taking prednisone, and the other had granulomas in the liver nine years after cortisone therapy was discontinued. Only one of the five patients had an elevated serum bilirubin level, and it was unaffected by the administration of steroids. Two patients with an elevated alkaline phosphatase level showed decreases in this enzyme with steroid therapy. In another patient the alkaline phosphatase increased during prednisone therapy. The serum albumin increased in three patients, and the gamma globulin concentration decreased in three patients. COMMENTS
An approach to the diagnosis of patients with granulomatous hepatitis has been outlined elsewhere [I]. This approach was evaluated in the present study in seven patients with previously undiagnosed granulomatous disease of the liver. In all seven, diagnoses were reached using this comprehensive approach and strict diagnostic criteria. Follow-up studies of patients with undiagnosed hepatic granulomas are scarce. Klatskin [6] found that in three of fifty-five patients with granulomatous hepatitis of unknown etiology, tuberculosis developed within three years. The etiologic factors in the remainder were unknown. He postulated that these patients had either sarcoidosis or granulomas due to underlying primary liver disease. It appears that in the majority of patients with granulomatous hepatitis, destruction of liver parenchyma and/or fibrosis progresses very slowly. Specific therapy of infectious causes usually halts this process. Brucellosis, however, may progress to cirrhosis [7,8] if untreated, and even after appropriate antimicrobial therapy [S]. Sarcoidosis usually causes minimal liver disease. However, cirrhosis, portal hypertension AMERICAN
JOURNAL
OF
MEDICINE
Granulomatous
Hepatitis-Chd-ian,
ancl,‘or liver failure can occur when the liver is se\:erely involved [6$7.3]. In two of Klatskin’s patients [S] who had granulomas of unknown etiology localized in the liver, cirrhosis and portal hypertension developed. These patients probably had sarcoidosis. There is still debate whether glucocorticoids affect the ultimate outcome of sarcoidosis of the Ii\-er. One report describes a patient, not treated with steroids, who had progressive functional li\rer impairment and died of cirrhosis in five years [ TO]. There is, however, evidence that steroids may not mitigate the progressive fibrosis [9,7 I]. Other workers have found no increase in fibrosis and disappearance of granulomas while their patients were receiving steroids [ 72,13,16]. One of our patients had a normal liver biopsy while not receiving steroids, one had no granulomas while taking prednisone, one still had granulomas in the liver after one year of prednisone therapy and one had granulomas in the liver while not treated with steroids. There is little doubt that corticosteroids can alleviate the constitutional symptoms of sarcoidosis [ 74-761 and decrease the serum alkaline phosphatase [ 72,1.?, 151, as was demonstrated in We also present evidence that our patients. serum albumin may increase and gamma globulin concentration and liver size decrease during glucocorticoid therapy. However, the liver size may not change [9,12]. Serum bilirubin and brornsulfalein retention may also decrease while the patient is receiving steroids [ 1 l- 13,151. Klatskin [6] favors the use of steroids in such patients with progressive liver disease if the diagnosis of sarcoidosis is relatively certain. One of the recently stated criteria for steroid therapy in sarcoidosis was the presence of liver dysfunction [ / 71. We are of the opinion that the mere presence of liver dysfunction is not justification for steroid therapy, but we agree with Klatskin in that if progressive or more than minimal liver disease is present, steroid therapy is indicated. The association of various diseases with the primary granulomatous disease deserves comment. Carcinomas, rheumatic valvular disease, renal disease, systemic lupus erythematosus and pal!-cythemia rubra vera were discovered in the seven patients studied prospectively. Of the sixty-three patients whose records were previously reviewed [I], two had rheumatic valvular disease, one systemic lupus erythematosus, one polycythemia rubra Vera, one chronic myelocytic leukemia and one adenocarcinoma of the
VOL..
44,
FEBRUARY
1968
Perry
pancreas. Sarcoidosis associated with systemic lupus erythematosus has been reported previously [ IK]. Immunologic aberrations and hypersensitivity-like states in leprosy have been documented [IO]. Active extrapulmonary tuberculosis has also been associated with constrictive arteritis of the Takayasu type [20]. Granulomas of rmknown cause in lymph nodes, liver and spleen have been described in patients with congenital and acquired agallunaglobulinemia [21-271. At least one case of sarcoidosis [28] and two cases of probable tuberculosis [2,?,24] associated with agammaglobulinemia have been reported. Collagen or autoimmune-like diseases, hepatosplenomegaly, lymphoreticular neoplasms and renal lesions are also known to occur in these patients. It has been postulated that the granulomas were the result of repeated infections, or that the agammaglobulinemia was due to disseminated lymphoreticular granulomatous disease. There certainly seems to be more than a chance relationship between granulomatous diseases, abnormal immune globulins, autoimmune diseases, and various malignancies. Perhaps the excessive antigenic stimulus which produces the granulomatous disease and hypergammaglobulinemia causes aberrant immunologic responses or even exhaustion of immunologically competent cells, failure to reject “self” antibody clones and neoplastic cell lines, and consequent autoimmune disease and malignancy. APPENDIX
A fifty-six year old Negro woman (Z.W., 68668-M) was hospitalized in 1960 for adenocarcinoma of the endometrium. She was treated with radium inserts, followed by panhysterectomy. She had had rheumatic fever at age seventeen. Physical examination revealed left cardiac ventricular hypertrophy, a murmur of aortic insufficiency and hepatomegaly. At the time of hysterectomy an open liver biopsy was performed and revealed caseating granulomas without identifiable organisms. In 1962 she was found to have diabetes. When admitted in July 1966 she denied fever, weight loss, chills or anorexia but did complain of tiring easily. She was afebrile and the lungs were normal. Her heart was enlarged with left ventricular preponderance. There was a grade 2/6 early short ejection murmur and a grade 3 decrescendo diastolic murmur was heard in the right CASE
1.
second and left third intercostal spaces, respectively. The liver was felt 4 cm. below the costal margin. The spleen was not palpable. The hemoglobin and white blood cell count were within normal limits. The urinalysis showed 2-t
212
Granulomatous
Hepatitis-Guckiun,
glucosuria. Tularemia agglutinins were found at a 1: 160 dilution. A Coxiella burnetti complement Bxation test was reactive 1: 32. Serum protein electrophoresis showed a completely normal pattern and the reactions to all skin tests were negative. On April 25, 1966, a liver biopsy specimen was obtained with the Menghini needle. The final diagnoses were (1) rheumatic heart disease with aortic insufficiency, (2) diabetes mellitus with neuropathy and (3) arteriosclerotic cardiovascular disease. CASE 2. A forty-four year old Negro woman (E.D., 30701-M) complained of epigastric pain, fatty food intolerance, fever, chills and weight loss in 1956. Two large lymph nodes were felt in the left axilla. She did not return to the clinic, and no studies were performed. She had pneumonia in 1959, followed by the onset of generalized migratory arthritis and the appearance of small, hot, tender nodules on the legs and arms. Examination at that time showed these subcutaneous nodules and slight swelling of the right ankle. The serologic test for syphilis was reactive. In 1962 a chest roentgenogram showed an infiltrate in the right perihilar area and possibly in the apex of the left lung. Lupus erythematosus preparations were negative. A liver biopsy specimen, obtained in January 1963, showed granulomatous hepatitis without necrosis or organisms. A culture of this specimen for Mycobacteria was negative. The large left axillary nodes were again felt; there was no hepatosplenomegaly. The reaction to an old tuberculin skin test, 1: 10,000, was markedly positive. Cultures of the urine and sputum for Mycobacteria were negative as were sputum cultures for fungi. A Wertheim hysterectomy was performed in February 1963 for carcinoma of the cervix in situ. She was never treated with antituberculous therapy. In April 1963 the symptoms of joint involvement and subcutanequs nodules recurred. She had had intermittent fever, rigors and night sweats one to three times per week since 1959. In 1965 she had supraorbital pain, blurring of the vision, conjunctival injection and photophobia. Physical examination in September 1966 showed her to be afebrile. There were 1.5 cm. indurated, tender nodules on the anterior and posterior areas of the legs, several of which were crusted. The left conjunctiva was injected and the pupils reacted very sluggishly to light and accomodation. In the left axilla there were three lymph nodes, 1 to 1.5 cm. in diameter, which were nontender, firm and slightly matted. The heart and lungs were normaal. The abdomen was protuberant, but no organomegaly was palpable. A complete blood count was normal. A rheumatoid factor latex agglutination test was negative, but the reaction to the serologic test for syphilis was weakly positive, the Kolmer was not reactive, but the FTA
Perry
was reactive. Heterophil and cold agglutinin tests yielded normal results. A liver biopsy specimen was obtained with a Menghini needle. Biopsy of the lesions on the leg was consistent with erythema induraturn, but acid-fast bacteria could not be identified. Biopsy of the left axillary lymph node showed partial replacement with granulomatous inflammation but without true caseous necrosis. Ziehl-Neelsen stains were positive for acid-fast bacilli, but cultures for Mycobacteria were sterile. A kidney biopsy specimen obtained with a Menghini needle showed necrotizing arteriolitis and focal glomerulitis. Immunoelectrophoresis revealed that the IgG and IgM levels were normal, and the IgA level accounted for the marked hypergammaglobulinemia. Sputum smears and cultures for acid-fast bacilli were negative. Two lupus erythematosus preparations were strongly positive. The administration of isoniazid, sodium para-aminosalicylate and prednisone was started on June 7, 1966. The final diagnoses were (1) chronic disseminated tuberculosis, (2) systemic lupus erythematosus, (3) erythema induratum, (4) episcleritis and (5) late latent syphilis. CASE 3. A thirty year old Negro woman (B.M., 34570-P) was first seen at this hospital in March 1965, when she was three months pregnant. The chest roentgenogram revealed infiltrates compatible with sarcoidosis, and splenomegaly was present. Reactions to skin tests were negative, but a liver biopsy showed noncaseating granulomatous inflammation. It was thought that she probably indeed had sarcoidosis and she was discharged without therapy. She returned in August 1965 and was delivered of a stillborn infant. She was asymptomatic when she was admitted in September 1966. She was normotensive and afebrile. No adenopathy was palpable. The liver was felt at the right costal margin, but the spleen was enlarged 8 cm. below the costal margin. The chest roentgenogram showed diffuse nodular thickening of the interstitial tissues throughout both lungs, and there was slight increased prominence of the left hilum. The serum uric acid level was 5.8 mg. per cent. On August 16, 1966, a liver biopsy was performed using the Menghini needle. The old tuberculin and fungal skin tests were negative. The fmal diagnoses were (1) sarcoidosis, and (2) iron deficiency anemia, probably due to multiparity. CASE 4. A forty-nine year old white woman (M.E.P., 9973-J) was seen at this hospital in 1953 with psoriasis, which subsequently resolved. She was not seen again until 1963 when she underwent a total thyroidectomy for follicular adenocarcinoma. In early 1965 an exploratory laparotomy and hysterosalpingo-oophorectomy were performed. At the time of surgery nodules were noticed on the surface of the liver, and a biopsy specimen from one of these showed AMERICAN
JOURNAL
OF
MEDICINE
Granulomatous
Hepatitis-Gudin~~,
caseating granulomas without identifiable organisms. No other abnormalities were noted. The patient was given isoniazid and sodium para-aminosalicylate. Ihere was no history of pulmonary tuberculosis, and all cultures for Mycobacteria were negative. The liver was palpable 4 cm. below the costal margin at that time. The reaction to all skin tests was negative and liver function tests were within normal limits. In September 1966 gastrointestinal intolerance to para-aminosalicylate developed. Isoniazid and paraaminosalicylate therapy was discontinued for two weeks and then restarted; however, vomiting recurred on two occasions prior to her admission in October 1966. The patient was afebrile and normotensive. The chest was mildly emphysematous but no rales or wheezes were audible. The liver and spleen were not palpable. The chest roentgenogram showed no abnormalities, and a film of the upper gastrointestinal tract showed no abnormality except for a diverticulum-like structure adjacent to the duodenal loop. A liver biopsy specimen was obtained with the Menghini needle on August 24, 1966. Skin tests were again negative at forty-eight and seventy-two hours. The patient was given Neopasalate@, which she tolerated well, and isoniazid. The final diagnoses were (1) tuberculous hepatitis, inactive, (2) endogenous depression and (3) duodenal diverticulum. A forty-three year old white man (J.F., CASE 5. 43248-P) was decribed in some detail previously [ 71. In January 1966 he complained of excessive fatigue, and the liver was palpable 6 cm. below the costal margin. In June 1966 weakness, most pronounced in his legs, was noted and he especially had difficulty in dorsiflexing his right foot. Isoniazid, which he had been taking, was discontinued in July 1966. His blood pressure was 128/84 mm. Hg, pulse 120 per minute, respirations 22 per minute and temperature 101.4”F. upon admission in November 1966. He was a plethoric man with several ecchymotic areas over the ulnar surfaces of the arms. The skin was hot and moist. The chest was normal, and the lungs were clear. The liver was palpable 4 cm. below the costal margin, but there was no tenderness or ascitic fluid. There was pain with movement of the left arm, especially with elevation and rotation. The neurologic examination showed bilateral peroneal nerve palsies. The complete blood count, urinalysis, blood urea nitrogen, fasting blood sugar and uric acid were normal. Roentgenograms of the chest and of the left shoulder were within normal limits. Skin tests resulted in a positive reaction to old tuberculin (1: loo), but negative reaction to coccidioidin and histoplasmin. On October 13, 1966, a Menghini needle liver biopsy was performed. The patient remained febrile, and because of this, VOL.
44.
FEBRUARY
1968
213
Pry?
the dosage of preclnisone was increased to 15 mg. daily. After this he remained afebrile. 1 lie linal ciiagnoses were (1) sarcoidosis, (2) peroneal nl’r\-e palsy, bilateral, (3) tendonitis. bronchitis.
left shoulder
and 14) chronic
In this forty-three year old Negro man CASE 6. (J.M., 44625-P) progressive pedal edema, orthopnea and dyspnea developed in December 1964. He underwent an exploratory laparotomy in another hospital, and a splenectomy was performed. He had hypoalbuminemia, pleural effusions, ascites and an elevated serum alkaline phosphatase level. A liver biopsy was said to have been normal. He continued to have edema, ascites, weakness and malaise. In May 1965, physical examination revealed ascites and pleural effujions, but no adenopathy. l‘he liver was palpable 7 cm. below the costal margin, and pedal edema was present. A gamut of laboratory and x-ray studies failed to reveal a diagnosis. An inferior vena cavagram was normal. A liver biopsy specimen showed noncaseating granulomas without identifiable organisms. The reaction to old tuberculin and fungal skin tests was negative. Cultures of pleural fluid, peritoneal fluid and sputum for mycobacteria and fungi were negative. The ascitic fluid showed 1,536 leukocytes per cu. mm., 56 per cent of which were lymphocytes and 3.9 gm. per cent of protein. Serum immunoelectrophoresis was normal. Because of the patient’s deterioration, the administration of isoniazid, potassium para-aminosalicylate, streptomycin and prednisone, 40 mg. daily, was begun. His condition improved gradually, with return of appetite, weight gain and a sense of well-being. The pleural effusions and ascites disappeared. Cultures of the liver and bone marrow for Mycobacteria and fungi were sterile. In March 1966 the patient was asymptomatic but the liver was still palpable 4 cm. below the costal margin, and there was a trace of pedal edema. In June 1966 his hemoglobin was 18.2 gm. per cent, hematocrit 54 per cent and white blood cell count 12,900 per cu. mm. At the time of admission in November 1966 he was taking isoniazid, potassium, para-aminosalicylate and prednisone, 5 mg. every other day. He denied weakness, fever or anorexia. His blood pressure was 86/56 mm. Hg, pulse 84 per minute, respirations 16 per minute, temperature 97.4’F. and weight 67 kg. Nonpathologic shotty lymph nodes were palpable in the posterior cervical and anterior cervical chains. The chest, lungs and heart were within normal limits. There was bilateral gynecomastia. The liver was palpable 4 cm. below the costal margin, but there was no ascites. Skin tests with old tuberculin and coccidioiden were negative. However, the histoplasmin skin test was positive, 1 :lOO. The hemoglobin was 18.5 gm. per cent, hematocrit 58 per cent, white blood count
214
Granulomatous Hepatitis-Guckian,
25,900 per cu. mm. with 46 per cent neutrophils, 41 per cent lymphocytes, 11 per cent monocytes, 1 per cent eosinophils and 1 per cent basophils. The platelet count was 1,245,OOO per cu. mm. The blood urea nitrogen was 20 mg. per cent, and the endogenous creatinine clearance was 12 cc. per minute. The serum uric acid was 11.8 mg. per cent. The chest roentgenogram showed generalized mild opacification resembling congestion, and the skull roentgenogram was within normal limits. An intravenous pyelogram showed poor excretion of the contrast media, but no definite abnormalities were visible. A bone marrow examination disclosed hypercellularity with hyperplasia of red cell precursors, megakaryocytes and myeloid precursors and mild basophilia and eosinophilia. Blood gas studies showed a mild, persistent alveolararterial oxygen gradient. The diffusing capacity of carbon monoxide was also slightly decreased. The plasma volume and red blood cell volume were greatly increased. Lupus erythematosus preparations were negative. The leukocyte alkaline phosphatase was markedly decreased. Phlebotomies totaling 1,300 ml. were performed, and the patient was given radiophosphorus. The final diagnoses were (1) sarcoidosis, (2) polycythemia (3) renal insufficiency of unknown rubra Vera, etiology, and (4) gynecomastia due to liver disease.
CASE 7. A fifty-two year old Negro woman (C.E., 34088-P) had bleeding in the upper gastrointestinal tract on three occasions between 1959 and 1965, for which she required transfusions. In the 1940’s she was told that she was hypertensive and that she had a heart murmur. During a bleeding episode in 1963 right and left ventricular failure developed and she was digitalized. She was first seen here in February 1965 ; the physical examination revealed an aortic systolic thrill with a grade 5/6 aortic ejection murmur. Breath sounds were absent at the posterior base of the right lung, and the liver was palpable 4 cm. below the costal margin. The chest roentgenogram showed consolidation or atelectasis in the base of the right lung, and films of the gastrointestinal tract showed a deformed duodenal bulb. The old tuberculin skin test was positive. Bronchograms showed partial atelectasis of the middle and lower lobes of the right lung. Cultures of bronchial and gastric washings for Mycobacteria were negative. The serologic test for syphilis was positive, and a Kolmer test was reactive. A liver biopsy specimen obtained on April 2, 1965 showed foci of granuinflammation without identifiable orlomatous ganisms. The patient was readmitted in January 1966. A liver biopsy specimen at this time showed no granulomas, and indeed it was normal. The density in the lower lobe of the right lung was thought to represent atelectasis and pleural thickening. Liver function studies were again normal and mycobacterial cultures of gastric washings were negative. The patient was
Perry
treated with erythromycin, 2 gm. daily, for ten days. In May 1966 bleeding in the gastrointestinal tract recurred and she was given 3 units of blood. She was admitted again in November 1966. On admission, she was normotensive and afebrile; the physical findings in the lower right side of the chest were unchanged. There was left cardiac ventricular enlargement, a systolic thrill in the aortic area, and a grade 5/6 harsh early systolic ejection murmur loudest in the aortic area. The liver was palpable 4 cm. below the costal margin, but was not tender. The old tuberculin skin test was positive at a 1: 10,000 dilution, but the coccidioidin and histoplasmin skin tests were negative. The complete blood count showed a normal white cell count and normal differential and platelet count. The hemoglobin was 5.9 gm. per cent with microcytic hypochromic indices. After oral iron therapy the reticulocyte count was 9.9 per cent. A quantitative Kolmer test was nonreactive. A liver biopsy was performed with a Menghini needle on October 24, 1966. The chest roentgenogram again showed pleural scarring, and the duodenal bulb again was deformed. The administration of Pamine,@ Gelusil@ and ferrous sulfate was initiated, with good response. The final diagnoses were (1) granulomatous hepatitis due to syphilis, healed, (2) dental caries, (3) duodenal peptic ulcer disease, (4) anemia due to chronic blood loss, (5) diabetes mellitus and (6) rheumatic aortic valvular stenosis. REFERENCES 1. GUCKIAN, J. C. and PERRY,J. E. Granulomatous hepatitis. An analysis of 63 cases and review of the literature. Ann. ht. Med., 65: 1081, 1966. 2. SCHIPF, L. The clinical value of needle biopsy of the liver. Ann. Znt. Med., 34: 948, 1951. 3. EDMONDSON,H. A. Needle biopsy in differential diagnosis of acute liver disease. J.A.M.A., 191: 480, 1965. 4. RUBIN, E. Interpretation of the liver biopsy. Diagnostic criteria. Gmtroenterolou, 45: 400, 1963. 5. KLATSKIN, G. and YESNER, R. Hepatic manifestations of sarcoidosis and other granulomatous diseases. Yale J. Biol. & Med., 23: 207, 1950. 6. BUNIM,J. J., KIMBERG, D. V., THOMAS, L. B., VAN SCOTT,E. J. and KLATSKIN, G. The syndrome of sarcoidosis, psoriasis, and gout. Ann. Znt. Med., 57: 1018, 1962. 7. JOSKE, R. A. and FINCKH, E. S. Hepatic changes in human brucellosis. M. J. Austral&, 1: 266, f955. 8. MCCULLOUGFL N. B. and EISELE. C. W. Brucella hepatitis leading to cirrhosis of the liver. Arch. Znt. Med., 88: 793, 1951. 9. NELSON, S. and SCHWABE, A. D. Progressive hepatic decompensation with terminal hepatic coma in sarcoidosis. Am. J. Digest DC., 11: 495, 1966. 10. BRANSON, J. H. and PARK, J. H. Sarcoidosishepatic involvement. Presentation of a case with fatal liver involvement, including autopsy findings and review of the evidence for sarcoid involvement of the liver as found in the literature. Ann. Znt. Med., 40: 111, 1954. 11. KELLEY, M. L. and MCHARDY, R. J. An unusual AMERICAN
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19.
Hepatitis-
c,+se of fatal hepatic sarcoidosis. ,4m. J. Med., 19: 842, 1955. PORTER, G. H. Hepatic sarcoidosis-A cause of pxtal hypertension and liver failure: Review. Arch. Int. MPd., 108: 483, 1961. Mrsrn.~s, S. P., GREEN, J. R. and SCHIFF, L. Hepatic sarcoidosis with portal hypertension. Am. J. Med., 36: 470, 1964. SIL I‘ZBACH, L. E. Effects of cortisone in sarcoidosisa study of thirteen patients. Am. J. Med., 12: 139, 1952. SHULMAN, L. E., SHOENRICH, E. H. and HARVEY. A. M. The effects of adenocorticotrophic hormone (ACTH) and cortisone on sarcoidosis. Bull. Johns Hopkins Has)., 91: 371, 1952. M;ZTHER, G., DAWSON, J. and HOYLE, C. Liver biopsy in sarcoidosis. Quart. J. Med., 24: 331, 1955. Committee on Therapy. The use of corticosteroids in the treatment of sarcoidosis. A statement of the committee on therapy. Am. Rev. Resp. Dis., 82: 753, 1960. MAYOCK, R. L., BERTRAND, P., MORRISON, C. E. and SCOTT, J. H. Manifestations of sarcoidosis. Analysis of 145 patients with a review of nine series selected from the literature. Am. J. Med., 35: 67, 1963. MATTHEWS, L. J. and TRAUTMAN, J. R. Clinical and serological profiles in leprosy. Lamet, 2: 915, 1965.
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CL .4. and SWTH, S. R. Extrapulmonary tuberculosis with erythema nodosum and occlusi\ c arterial disease. Canad. .W. .4. J., 95 : L7i, 1960. ZINNEMAN, H. H. and HALL, LIT. 1 I. .\cquired agammaglobulinrmia. Report of 3 cask. ./.9..1f.r1. 156: 1390, 1954. PRASAD, .I. S., REINEK, E. and bV..x~soi\l.C. .J. S~IIdrome of hypogammaglobulinemia, splenomrgaly, and hypersplenism. Blood, 12: 926, 1957. ROHN, R. .J., BEHNKE, K. 1-I. and BOND, W. II. .4r:quired agammaglobulinemia with hypersplrnism-A case report. Am. J. ‘21. kSc., 229: 406, 1955. ZINNEMAN, H. H. and HALL, \Y. I-I. Steatorrhea and probable tuberculosis with acquired hypogammaglobulinemia. Am. Reu. Tuberc., 74: 773, 1956. PEARCE, K. M. and PERINPANAYAGAM,M. S. Congenital idiopathic hypogammaglobulinemia. Arch. Dis. Childhood, 32: 422, 1957. ZELMAN, S. and LEWIN, H. :\dult agammaglobulin-
TIIIPFAULT,
emia associated with multiple congenital anomalies. Am. J. Med., 25: 150, 1958. ’ 27. GREEN, I., LITWIN,S., :\DLERSBERG, Ii. and RUBIN,
I. Hypogammaglobulinemia ment of lymphosarcoma. Arch. 1966. 28. BROWSKY, D. and L~JNN, Y. 0. hypogammaglobulinemia. Am. 1965.
with late developZnt. Med., 118: 592, I,. Sarcoidosis
with J. *cf. SC., 250: 11,