CASE REPORTS ACUTE GRANULOMATOUS HEPATITIS DUE TO HISTOPLASMOSIS

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1 GASTROENTEROLOGY 1970 by The Williams & Wilkins Co. Vol. 68, No.3 Printed in U.S;A. CASE REPORTS ACUTE GRANULOMATOUS HEPATITIS DUE TO HISTOPLASMOSIS FRANK L. LANZA, M.D., ROBERT S. NELSON, M.D., AND B. N. SOMAYAJI, M.R.e.p. University of Texas, M. D. Anderson Hospital and Tumor Institute, Houston, Texas A 54-year-old man presenting with fever, hepatomegaly, and weight loss was found to have acute histoplasmosis, apparently involving only the liver. The diagnosis was established by culture of liver biopsy material and elevated complement fixation titers which declined in the convalescent phase of the patient's illness. Histological examination showed only granulomatous hepatitis. The patient recovered uneventfully without the use of systemic antifungal drugs. He did receive corticosteroids for a brief period. The patient now has been followed for 3 years and remains well. A recent liver biopsy showed only minimal periportal lymphocytic infiltration. A review of the literature fails to reveal a similar case. An analogy is drawn between this case and the acute self-limited pulmonary form of histoplasmosis. Culture of liver biopsy material showing granulomatous hepatitis is recommended in all cases where the etiology is not clear from other evidence. Granulomatous hepatitis occurs as a part of many diseases. When histoplasmosis is the etiological agent, liver involvement is most often part of a systemic dissemination usually originating in the lungs or mucous membranes of the upper respiratory tract. An unusual case of histoplasmosis is reported, in which the diagnosis was established by culture of liver biopsy material without evident disease elsewhere in the body. Case Report This 54-year-old white male was admitted to The University of Texas M. D. Anderson Hospital and Tumor Institute on June 6, 1966, with a presumptive diagnosis of tumor of the liver. He had been well until 2 months prior to admission when he developed febrile episodes in the midafternoon associated with shaking Received August 11, Accepted September 29,1969. Address requests for reprints to: Dr. Frank L. Lanza, University of Texas, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner, Houston, Texas chills and accompanied by anorexia and a 20-lb weight loss. Approximately 1 month prior to being seen, he noted nausea, postprandial vomiting, and weakness. He denied having abdominal pain, diarrhea, rectal bleeding, acholic stools, dark urine, or obvious jaundice. The past history was entirely negative for major illnesses and the family history was noncontributory. The patient smoked two packages of cigarettes per day and denied alcohol intake. Physical examination revealed a slightly plethoric, chronically ill appearing white male. The vital signs were within normal limits. No icterus was noted in the skin or sclera and the fundi were normal. There were no lesions in the mouth or pharynx. The lungs were clear and the breath sounds were of good quality. There was no cardiomegaly, murmur, or arrhythmia. There was no cyanosis, clubbing, or edema of the extremities and the peripheral pulses were strong. Abdominal palpation revealed a diffusely enlarged liver 4 fingerbreadths below the right costal margin which was moderately tender. There was no friction rub. No distinct nodules were palpated but there seemed to be a large mass present in the right lobe. There was no splenomegaly and no other abdominal findings.

2 March 1970 CASE REPORTS 393 TABLE 1. Summary of liver function studies Study 6/7/66 6/22/66a 6/27/66 7/6/66 8/9/66 9/8/66 12/13/66 6/13/67 6/15/68 7/15/ Bromsulphalein (%) Alkaline phosphatase (Bessey-Lowry units) Serum glutamic oxaloacetic transaminase (U) transaminase (U) Serum glutamic pyruvic a Steroids begun on 6/17/66. Rectal examination was negative. No abnormalities were noted on the neurological examination and careful palpation revealed no significant adenopathy in any area. The hemoglobin was 17.8 g with a hematocrit of 49%, and the white count was 7330 with 59% polymorphonuclear leukocytes, 25% lymphocytes, 10% monocytes, 5% eosinophils, and 1 % basophils. Urinalysis was within normal limits. The Venereal Disease Research Laboratory test was nonreactive. Liver function studies (table 1) revealed a serum bilirubin of 0.9 mg per 100 ml. The total proteins were 7.6 g per 100 ml, 5.8 g of which were albumin. The thymol turbidity was 0.2 U and the alkaline phosphatase was 18.8 Bessey-Lowry units. Serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase were 117 and 46 U, respectively. Bromsulphalein retention was 28% after 45 min. Urinary urobilinogen was present in normal concentration. Fasting glucose was 99 mg per 100 ml and the urea nitrogen was 14 mg per 100 ml. Stools were negative on three occasions for blood, ova, and parasites. Cephalin flocculation was negative at 24 hr and 1+ at 48 hr. An upper gastrointestinal series, barium enema, oral cholecystogram, chest roentgenogram, and intravenous pyelogram all were within normal limits. A liver scan performed with Au'98 showed diffuse enlargement, the lower border extending 8 cm below the right costal margin. The uptake was slightly patchy throughout and there were several areas of decreased uptake suggesting small space-occupying lesions. The scan was felt to be compatible with either diffuse parenchymal disease or multiple small metastases. Transthoracic and transabdominal liver biopsies were done with the Nelson modification of the Vim-Silverman needle.' The transabdominal biopsy was obtained from the mass-like lesion in the right lobe. Both of these revealed granulomatous in- flammation and were felt to be suggestive of tuberculosis, but acid-fast stains were negative. Multiple cuts of the biopsy specimen were made and special stains with periodic acid Schiff, Giemsa, and Gomori methenamine silver were negative for histoplasmosis. and other fungi. The pathologist suggested sarcoidosis and brucellosis in the differential diagnosis (fig. 1). Because of these findings, another liver biopsy was obtained and the specimen was cultured for fungi, yeast, ordinary pathogens, and Brucella. Direct smears also were made from the material and no fungi were seen, although on two of the slides occasional blastospores were seen on the direct smear. No acid-fast organisms were seen on several direct smears and no bacteria were grown from the specimen. Serum agglutination studies for all species of Brucella were negative, as were those for tularemia, paratyphoid A and B, and Proteus OX-19. Thypoid 0 and H were reactive in dilutions of 1: 40 and 1: 160, respectively, on the slide test. Fungal agglutination studies were sent to the Texas State Health Laboratory, using Communicable Disease Center antigens. The histoplasmosis histoplasmin complement fixation was nonreactive, but the yeast phase was positive, 1: 116 dilution. Coccidioidomycosis and blastomycosis were nonreactive and reactive in 1: 32 dilutions, respectively. Sputums were collected for acid-fast bacillus, fungus, and yeast cultures and all of these were negative, as were direct smears. A K veim test was not done. Culture of the liver biopsy material was reported as growing organisms of Histoplasma capsulatum. Another fungal agglutination study was obtained 10 days after the intial one and the yeast phase of histoplasmosis had decreased to 1: 16 dilutions. The patient's hospital course was initially one of gradually accelerating deterioration.

per day). On this regimen, the patient improved dramatically, both clinically and in liver function studies.

3 394 CASE REPORTS Vol. 58, No.3 FIG. 1. Initial biopsy done during acute phase of disease revealing typical hepatic granuloma. After the second liver biopsy and before the reporting of the fungal agglutinations and biopsy material culture, the patient was begun on fairly large doses of corticosteroids (40 mg of prednisone per day). On this regimen, the patient improved dramatically, both clinically and in liver function studies. When the diagnosis of histoplasmosis became apparent, consideration was given to systemic therapy with amphotericin; however, because of the rapidly improving clinical situation, it was deferred. The corticosteroids were tapered off slowly and the patient was dismissed from the hospital. When seen 2 months after discharge, he continued to show improvement. Six months after discharge, he had gained 15 lb, looked quite robust, and was asymptomatic; all liver function studies had returned to normal. One year after dismissal from the hospital, liver function studies still were normal and he was readmitted to the hospital for liver biopsy. The sections showed only chronic inflammatory cells in the portal fields but no granulomata (fig. 2). There was no evidence of hepatic necrosis or fatty metamorphosis. The patient now has been followed for 3 years with normal liver functions and no evidence of disease. Chest films and flat plate film of the abdomen, made 3 years after his acute illness, revealed no evidence of hepatic calcification, but two discrete calcifications were seen in the spleen. Discussion The identification of histoplasma organisms in culture material from liver biopsy and the elevated complement fixation titers for histoplasmosis leave little doubt as to the etiology of this patient's granulomatous hepatitis. Unfortunately, the organism was not seen in the biopsy material and a diagnosis of sarcoidosis was not unwarranted. The patient's clinical deterioration, which was reversed abruptly by the administration of corticosteroids, supported the initial diagnosis of sarcoidosis. The difficulty in differentiating between sarcoidosis and histoplasmosis histologically has been the subject of several reports. 2-4 Histoplasmosis has been found in reviewed autopsy material of patients dying from what was thought to be widespread sarcoidosis.4 In view of the diagnosis of histoplasmosis, this patient's response to the administration of corticosteroids was quite enigmatic. Even more interesting was the patient's continued recovery during the period of

March 1970 CASE REPORTS 395 FIG. 2. Follow-up biopsy done 6 months later showing only mild periportal lymphocytic infiltration. decreasing dosage and final discontinuance of prednisone.

The entity of granulomatous hepatitis has been reviewed extensively.

4 March 1970 CASE REPORTS 395 FIG. 2. Follow-up biopsy done 6 months later showing only mild periportal lymphocytic infiltration. decreasing dosage and final discontinuance of prednisone. Consideration was given to the administration of amphotericin; however, because of the known toxicity of this agent and the patient's rapid improvement, its use was deferred. The entity of granulomatous hepatitis has been reviewed extensively.5-7 The majority of such patients are found to have sarcoidosis or tuberculosis,s although numerous other etiologies have been described.5-7 Histoplasmosis is a well recognized but not common cause of hepatic granulomatous disease. Reports of the diagnosis of disseminated histoplasmosis by culture of liver biopsy tissue are rare.lo The liver often is involved in the course of systemic disease, but the diagnosis usually is made by pathological examination and culture of tissue from a primary lesion in the upper respiratory tract or from the bone marrow.h- 13 This is true even when the disease presents primarily with gastrointestinal manifestations.14 The present patient is unique in that there appeared to be no involvement other than the liver. The lungs were clear and there was no primary lesion in the upper respiratory passages. An analogy may be drawn between this patient and those with the more usual forms of primary pulmonary histoplasmosis. This condition presents with three distinct clinical typesl3 : (1) an acute pulmonary infection with rapid systemic dissemination and death; (2) a chronic pulmonary type with cavity formation but no dissemination; (3) a benign acute pulmonary type which often is no more than a severe flu syndrome leaving the residual speckled calcifications so often seen in routine roentgenograms of the chest. Similar calcifications have been found in the liver and spleen of asymptomatic individuals living in an endemic area for histoplasmosis who have no history of a severe antecedent disease.15 Evidence also has been found that a transitory fungemic state can occur in minimally symptomatic individuals.16 It would appear, therefore, that this case could represent an acute granulomatous hepatitis due to H. capsulalum analogous to a benign acute pulmonary histoplasmosis. The patient's response to steroids would indicate that the

5 396 CASE REPORTS Vol. 68, No.3 majority of the symptomatology and liver function abnormalities were due to hypersensitivity to the histoplasma organisms. A review of the literature failed to reveal a similar case where Histoplasma organisms were cultured from biopsy tissue when the liver seemed to be the only involved organ, indicating that either this situation is exceedingly rare or is not being diagnosed, especially in endemic areas. The latter is suspected to be the case. The large percentage of patients having hepatosplenic calcifications in endemic areas would seem to support this contention.15 It would appear advisable to culture biopsy material in all patients with granulomatous hepatitis either from the initial or subsequent biopsy specimens with special attention to the identification of H. cap8ulatum. As with the benign acute pulmonary type, the majority of the patients with this condition probably would recover without any treatment. Amphotericin probably should not be used unless multisystem involvement is obvious or cavitary lesions occur. Although the excellent clinical response in the reported patient is hardly conclusive, steroids may be valuable in the individual who presents with liver involvement as a sole manifestation of disease. REFERENCES 1. Nelson, R. S Modification of the Voegtlin liver biopsy needle for transthoracic approach. Gastroenterology 21: Klatskin, G., and R. Yesner Hepatic manifestations of sarcoidosis and other granulomatous diseases. Yale J. BioI. Med. 23: Israel, H. L., E. Delamater, M. Sones, W. D. Willis, and A. Mirmelstein Chronic disseminated histoplasmosis. An investigation of its relationship to sarcoidosis. Amer. J. Med. 12: Pinkerton, H., and L. Iverson Histoplasmosis, 3 fatal cases with disseminated sarcoid-like lesions. Arch. Intern. M ed. (Chicago) 90: Wagoner, G. P., A. T. Anton, E. A. Gall, and L. Schiff Needle biopsy of the liver. VIII. Experiences with hepatic granulomas. Gastroenterology 25: Bunim, J. J., D. V. Kimberg, L. B. Thomas, E. J. Van Scott, and G. Klatskin The syndrome of sarcoidosis, psoriasis, and gout. Ann. Intern. M ed. 57: Guckian, J. A., and J. E. Perry Granulomatous hepatitis. An analysis of 63 cases and review of the literature. Ann. Intern. M ed. 65: Edmondson, H. A Needle biopsy in differential diagnosis of acute liver disease. J. A. M. A. 191: Frank, B. B., and E. C. Raffensperger Hepatic granulomata. Report of a case with jaundice improving on anti-tuberculosis therapy and review of the literature. Arch. Intern. Med. (Chicago) 115: Partridge, B. M., and A. R. Tanser Disseminated histoplasmosis and its treatment. P08tgrad. Med. J. 42: Bennett, D. E Histoplasmosis of the oral cavity and larynx. A clinicopathologic study. Arch. Intern. Med. (Chicago) 120: Parsons, R. J., and C. J. D. Zarafonetis Histoplasmosis in man. Report of seven cases and a review of seventy-one cases. Arch. Intern. Med. (Chicago) 75: Rubin, H., M. L. Furcolow, J. L. Yates, and C. A. Brasher The course and prognosis of histoplasmosis. Amer. J. M ed. 27: Sturim, H. S., N. T. Kouchoukos, and R. C. Ahlvin Gastrointestinal manifestations of disseminated histoplasmosis. Amer. J. Surg.110: Okudaira, M., M. Straub, and J. Schwarz Etiology of discrete splenic and hepatic calcifications in an endemic area of histoplasmosis. Amer. J. Path. 39: Rohn, R. J., and W. N. Bond The value of routine bone marrow culture for histoplasma capsulatum in pediatric hematology. Blood 8:

Fungal Diseases of the Respiratory System

Fungal Diseases of the Respiratory System Histoplasmosis(cave disease) Dr. Hala Al Daghistani Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum. Histoplasma capsulatum, is usually