Primary Hepatic Histoplasmosis with Dissemination Presenting as Chronic Liver Disease in an Immunocompetent Individual

https://meditropics.com/primary-hepatic-histoplasmosis-with-dissemination-presenting-as-chronic-liver-disease-in-an-immunocompetent-individual/

 

 *Vishesh Goel, **Ramesh Aggarwal, ***L.H. Ghotekar,

*Post-graduate Resident, **Professor, ***Director professor & Head , Department Of Medicine ,LHMC New Delhi

 

Abstract

We present a case of a 60 year old gentleman with no features of immunosuppression presenting with a one month history of fever, pain abdomen, nausea and decrease in appetite. Patient initially had features suggestive of chronic liver disease with splenomegaly and ascites. Ascitic fluid analysis revealed an exudative etiology and was started on anti-tubercular therapy in view of granulomas and necrotic lymph nodes on CT scan. Patient later developed respiratory symptoms and coupled with non-resolving symptoms, prompted us to perform a diagnostic liver biopsy, which revealed characteristic histoplasma capsulatum granulomas, confirming the diagnosis of disseminated histoplasmosis with a primary hepatic lesion. Patient was started on anti-fungal therapy and rapid improvement of symptoms was observed.

 

Introduction

Histoplasmosis is fungal infection seen generally in the immunocompromised. It is associated with not only primary lung involvement, but also disseminated disease involving multiple organs. Here we present a case of an immunocompetent individual with primary hepatic histoplasmosis with dissemination presenting as chronic liver disease.

 

Case Presentation

A 60 year old gentleman, resident of Badaun, Uttar Pradesh, India presented to the outpatient department with a 1 month history of documented, high grade fever (documented ~ 103°F – 104°F), pain in right upper abdomen, nausea and decreased appetite. On examination, patient was vitally stable, febrile and had hepatomegaly and splenomegaly without any shifting dullness. Patient had an outside report suggestive of cholelithiasis without any surrounding gallbladder wall edema or thickening. Liver function tests revealed an increase in alkaline phosphatase (ALP) levels, with direct hyperbilirubinemia (R-Factor – 0.2 suggestive of cholestatic pattern). GGT was also raised. Patient was evaluated in view of possible choledocholithiasis with cholangitis with a background of gallstone disease and review ultrasound was performed to look for dilated biliary radicles and possibly common bile duct stone. Inpatient ultrasound revealed cholelithiasis, hepatomegaly with coarsened hepatic echotexture, splenomegaly and mild ascites. Patient was then planned for MRCP for further evaluation of obstructive jaundice. Blood and urine cultures performed multiple times were negative and broad spectrum antibiotics were added in view of negative cultures. Chest x-ray was negative. Meanwhile, fibroscan performed revealed a liver stiffness of 14.5 kilopascals suggestive of severe fibrosis (F3). On review of history, there was no obvious implicating factor indicative of etiology of chronic liver disease. Viral markers performed were all negative along with a negative autoimmune hepatitis profile. There was no other cause for immunodeficiency identified. Diagnostic ascitic fluid paracentesis performed revealed a low SAAG high protein fluid with highly increased cell numbers, consisting of both neutrophils and lymphocytes. A possibility of malignancy and tuberculosis were kept on a background of chronic liver disease. SPA doppler performed was indicative of hepatopetal flow. Serum alpha-fetoprotein levels were not raised. Malignant cytology performed on ascitic fluid did not reveal any atypical cells. CBNAAT for ascitic fluid was negative. Patient developed shortness of breath during admission on day 6. On examination a decrease in air entry was present in the left infrascapular area. Repeat chest x-ray revealed a left sided pleural effusion. Patient was started on low flow oxygen therapy and diagnostic pleural fluid analysis was done which was exudative. Cytology of the pleural fluid was similar to ascitic fluid with highly increased cell count and a mix of neutrophils and lymphocytes. Pleural fluid CBNAAT and malignant cytology were unrevealing. An urgent CT scan of chest and abdomen was performed which revealed paraseptal emphysematous changes in bilateral upper lobes with scattered calcified granulomas in upper lung fields. Calcified and non-calcified mediastinal and abdominal lymph nodes with internal necrosis were also observed. Furthermore, the surface and contour of liver appeared normal. Anti – tubercular therapy was added empirically in view of the very high prevalence of the disease in India but fever spikes were consistently present with no improvement in shortness of breath. ACE levels performed were raised. MRCP performed revealed no evidence of obstruction. In view of persistently raised ALP levels, with non-diagnostic MRCP and no improvement in patient condition, liver biopsy was performed. Liver biopsy showed fibrous expansion of portal tract with moderate to marked mononuclear cell inflammatory infiltrate comprising of lymphocytes, plasma cells and occasional eosinophils. Bile ducts were reduced in number and epithelioid cell granulomas were noted. Special staining done revealed Histoplasma capsulatum in the giant cell and foamy histiocytes. A diagnosis of subacute disseminated histoplasmosis involving liver, spleen and lung was made and patient was started on liposomal amphotericin B at 3mg/kg followed by tablet itraconazole 200mg twice daily. Fever resolved after two days of starting anti-fungal therapy and shortness of breath improved. Patient was then discharged and advised to continue antifungal therapy for 12 weeks with regular outpatient follow-up.

 

Discussion

Histoplasma capsulatum is a dimorphic fungus. Inhalation of spores lead to acquisition of infection in primarily leading to pulmonary infection. Histoplasma is an endemic organism found in mid-western and south-eastern parts of the United States, South America, Africa, Eastern Asia and Australia1. In India, a review of cases by Vikram et al. revealed that from 1994 to 2017, 144 cases were reported from various parts of India including West Bengal, the Gangetic belt, western parts of India and a few states in the south and north2.

 

Histoplasmosis can present as an asymptomatic form, primary lung involvement or disseminated histoplasmosis. Disseminated histoplasmosis is defined as histoplasmosis present in more than one more location. As such, the disseminated form is indeed the rarest form of histoplasmosis3. Wheat et al. in their study found that an immunocompromised state and age more than or equal to 54 years are risk factors for disseminated forms of histoplasmosis4. However, in a study conducted over 15 years in mayo clinic, Assi et al. attributed risk factors for histoplasma fungemia to total leukocyte count <3000/mm3 and immunocompromised state. Interestingly, increased age was not found to be associated with increased risk for histoplasmosis5. In our case, the patient was elderly, and no other risk factor attributable was found.

 

There was no evidence of immunocompromise in our patient. In general, immunocompetent individuals present with asymptomatic or mildly symptomatic disease and can be a mimic for many other systemic diseases, especially granulomatous diseases. Coupled with the remarkable endemicity of tuberculosis in a place like India, a very high index of suspicion is important and in this respect, determining the epidemiological risk of exposure becomes paramount6. Cases of disseminated histoplasmosis in an immunocompetent individual such as ours is extremely rare, and case reports have been identified which link the occurrence of the disease to either exposure to large amounts of spores or to a highly virulent strain7,8.

 

The most common symptoms of disseminated histoplasmosis include fever (89.1%), respiratory complaints (38.1%), weight loss (37.4%) and signs include splenomegaly (72%), hepatomegaly (68.1%) and lymphadenopathy (41.2%)9. In most cases however, there is an initial infection of the lung alveoli, with further dissemination into various organs10. In our case, the progression of symptomatology of the patient suggests that there was a primary hepatic involvement followed by pulmonary involvement. Primary hepatic histoplasmosis is an extremely rare entity, with only a handful a cases reported11. As stated previously, histoplasmosis can mimic many diseases and our case seemed to mimic chronic liver disease at initial presentation; it is an uncommon presentation12. Ultrasound analysis provided by the radiologist suggested to us the diagnosis of cirrhosis, though it is operator dependent. In a study, it was found that out of the 990 patients without compensated cirrhosis that were analysed using ultrasound, 29 (2.9%) were positive for ultrasound-identified cirrhosis i.e. false positive results13. FIbroscan has time and again been proved to be better at “ruling out” cirrhosis than “ruling in” cirrhosis (Negative predictive value-96%, positive predictive value-74%)14. Serum ACE levels have been found to be increased in around 25% of cases with histoplasmosis, implying to the need to consider histoplasmosis as a differential other than sarcoidosis15. Lastly, MRCP is generally able to detect granulomatous causes of obstruction, which was not true in our case.

 

Conclusion

To conclude, we present a case of disseminated histoplasmosis in an immunocompetent individual with a primary hepatic lesion. It is an extremely rare presentation and requires a very high degree of suspicion, especially in India where tuberculosis, another granulomatous infection, is very common. It should always be suspected in cases where evidence of tuberculosis is not available, or prolonged treatment with anti-tubercular therapy in cases of empirically started drugs do not yield any clinical improvement. It should also be suspected in cases of suspected chronic liver disease patients who present with an exudative ascitic fluid and no evidence of malignancy or tuberculosis on cytology.

 

Bibliography

  1. Diaz JH. Environmental and Wilderness-Related Risk Factors for Histoplasmosis: More Than Bats in Caves. Wilderness Environ Med. 2018;29:531–40.
  2. Mahajan VK, Raina RK, Singh S, Rashpa RS, Sood A, Chauhan PS, et al. Case report: Histoplasmosis in Himachal Pradesh (India): An emerging endemic focus. American Journal of Tropical Medicine and Hygiene [Internet]. 2017 [cited 2024 Jun 6];97:1749–56. Available from: https://www.researchgate.net/publication/320038465_Histoplasmosis_in_Himachal_Pradesh_India_An_Emerging_Endemic_Focus
  3. de D, Nath UK. Disseminated Histoplasmosis in Immunocompetent Individuals- not a so Rare Entity, in India. Mediterr J Hematol Infect Dis [Internet]. 2015 [cited 2024 Jun 5];7. Available from: https://pubmed.ncbi.nlm.nih.gov/25960856/
  4. Wheat LJ, Slama TG, Norton JA, Kohler RB, Eitzen HE, French ML, et al. Risk factors for disseminated or fatal histoplasmosis. Analysis of a large urban outbreak. Ann Intern Med [Internet]. 1982 [cited 2024 Jun 6];96:159–63. Available from: https://pubmed.ncbi.nlm.nih.gov/7059062/
  5. Assi MA, Sandid MS, Baddour LM, Roberts GD, Walker RC. Risk factor analysis of Histoplasma capsulatum fungemia. Med Mycol [Internet]. 2010 [cited 2024 Jun 6];48:85–9. Available from: https://dx.doi.org/10.3109/13693780902755299
  6. Staffolani S, Buonfrate D, Angheben A, Gobbi F, Giorli G, Guerriero M, et al. Acute histoplasmosis in immunocompetent travelers: a systematic review of literature. BMC Infect Dis [Internet]. 2018 [cited 2024 Jun 6];18. Available from: /pmc/articles/PMC6299618/
  7. Ling Q, Zhu W, Lu Q, Jin T, Ding S. Disseminated histoplasmosis in an immunocompetent patient from an endemic area: A case report. Medicine [Internet]. 2018 [cited 2024 Jun 6];97. Available from: /pmc/articles/PMC6086525/
  8. Klein M, Khan M, Salinas JL, Sanchez R. Disseminated pulmonary histoplasmosis in immunocompetent patients: a common epidemiological exposure. BMJ Case Reports CP [Internet]. 2019 [cited 2024 Jun 6];12:e227994. Available from: https://casereports.bmj.com/content/12/3/e227994
  9. Lamps LW, Molina CP, West AB, Haggitt RC, Scott MA. The Pathologic Spectrum of Gastrointestinal and Hepatic Histoplasmosis. Am J Clin Pathol. 2000;113:64–72.
  10. Wheat J, Sarosi G, McKinsey D, Hamill R, Bradsher R, Johnson P, et al. Practice Guidelines for the Management of Patients with Histoplasmosis. Clinical Infectious Diseases. 2000;30:688–95.
  11. Sayeed M, Benzamin M, Nahar L, Rana M, Aishy AS. Hepatic Histoplasmosis: An Update. J Clin Transl Hepatol [Internet]. 2022 [cited 2024 Jun 6];10:726. Available from: /pmc/articles/PMC9396312/
  12. Extrapulmonary Hepatic Histoplasmosis Presenting as Chronic… : Official journal of the American College of Gastroenterology | ACG [Internet]. [cited 2024 Jun 6]. Available from: https://journals.lww.com/ajg/fulltext/2018/10001/extrapulmonary_hepatic_histoplasmosis_presenting.2251.aspx
  13. Yen YH, Kuo FY, Chen CH, Hu TH, Lu SN, Wang JH, et al. Ultrasound is highly specific in diagnosing compensated cirrhosis in chronic hepatitis C patients in real world clinical practice. Medicine [Internet]. 2019 [cited 2024 Jun 6];98:e16270. Available from: /pmc/articles/PMC6635248/
  14. Interpretation of FibroScan TE & CAP.
  15. Ryder KW, Jay SJ, Kiblawi SO, Hull MT. Serum angiotensin converting enzyme activity in patients with histoplasmosis. JAMA. 1983;249:1888–9.