Clinical Aspects of Liver Diseases
26 Mycotic infections and the liver
Page:
1 Predisposing factors 506
2 Pathogens 506
3 Diagnosis 506
4 Morphological findings 507
5 Hepatobiliary organ mycoses 507
5.1 Candidosis 507
5.2 Aspergillosis 507
5.3 Blastomycosis 507
5.4 Trichosporosis 508
5.5 Cryptococcosis 508
5.6 Coccidioidomycosis 508
5.7 Histoplasmosis 508
5.8 Torulopsosis 508
5.9 Mucormycosis 508
5.10 Protothecosis 508
5.11 Coniothyrium mycosis 509
6 Therapy 509
앫 References (1⫺65) 509
(Tables 26.1 ⫺26.2)
䉴 The clinical diagnosis of any mycosis requires proof of the pathogenic fungus and, as far as possible, additional differentiation by fungal culture. • Endogenous mycosis is a fungal infection caused by saprophytic fungi ⫺ nor- mal inhabitants of the gastrointestinal tract ⫺ especially as secondary mycosis following other immunocom- promising diseases. • Exogenous mycosis is caused by primary pathogenic fungi: it may be localized or gener- alized, and it may show a preference for certain tissues or systems. • Systemic mycosis shows widespread dis- semination, predominantly affecting particular organs and tissues; it may originate from endogenous or exoge- nous mycosis. • Thus, a mycotic disease of the liver and biliary tract is always systemic.
1 Predisposing factors
Hepatic or biliary mycosis is only likely to occur with a deficiency of the endogenic defence response. However, in isolated cases, discussion has also centred on locally impaired defence mechanisms (e. g. after ERCP
(17), choledocholithiasis, papillotomy) which cause or ex- acerbate an existing mycotic focus. There have been sev- eral cases without any noticeable immunosuppression (e. g. aspergillosis and candidosis). The occurrence of systemic and organ mycosis is causally related to many factors or events leading to a reduced immune response, especially the clearance function of the hepatic RES.
Saprophytic fungi thus become opportunistic patho- gens, which, like exogenous primary pathogenic fungi, gain the upper hand over the body’s defence system. (s.
tab. 26.1)
2 Pathogens
Hepatobiliary organ mycosis may be caused by several fungal species, whereby the Candida species by far out- number the others. With the exception of Candida sp.
and Mucor sp., all hepatotoxic fungi have an airborne route of infection. (s. tab. 26.2)
3 Diagnosis
Even though hepatobiliary mycosis is a rare occurrence in terms of numbers, the possibility of mycotic infection should always be considered in the presence of predis- posing factors or respective events. • Signs of such a complication include additional complaints (e.g. loss of appetite, increasing malaise, tenderness in the right epi- gastrium) or clinical symptoms (e.g. fever of unknown origin ⫺ especially in non-response to antibiotics ⫺ hepato(spleno)megaly) and laboratory parameters (e.g.
increase in transaminases, alkaline phosphatase, serum bilirubin, ESR, CRP, decrease in ChE). (s. tab. 27.4)
1. Medicaments
⫺ immunosuppressants
⫺ glucocorticoids
⫺ cytostatics
⫺ antibiotics
2. Immunological diseases
⫺ e.g. AIDS, collagenosis 3. Haematological diseases
⫺ e.g. leukaemia, aplastic anaemia 4. Malignant diseases
5. Organ transplantation 6. Severe hepatic dysfunction 7. Serious acute diseases
⫺ e.g. pancreatitis, endocarditis, peritonitis 8. Chronic renal diseases
⫺ e.g. glomerulonephritis, dialysis 9. Intensive care
⫺ e.g. artificial respiration, parenteral feeding 10. Infectious diseases
⫺ e.g. salmonellosis, tuberculosis 11. Diabetes mellitus
12. Burns
13. Major surgery
14. Prepartal and postpartal complications 15. Chronic alcoholism
16. Malnutrition 17. Ileus
18. Tooth extraction 19. ERCP, papillotomy
Tab. 26.1: Predisposing factors for organ mycosis, including the liver and biliary tract
Ultrasound and CT only reveal hepato(spleno)megaly or suggest multiple foci similar to small abscesses, possibly in the form of a “snowstorm” ⫺ and occasionally bili- ary congestion as a result of obstruction due to fungal masses.
(1, 2, 13, 15, 25, 26, 28, 29)• MRI is a better diag- nostic tool (85 ⫺100%) ⫺ equally reliable information was also obtained with MRI when monitoring the treat- ment and follow-up of hepatolienal mycoses.
(7)These hints of hepatolienal mycosis can be confirmed
by liver biopsy or fine needle biopsy.
(9, 18, 20, 51, 52)In
this respect, however, only a small area is examined by
the puncture technique, with the result that negative his-
tological findings are not always representative of the
liver as a whole. Diagnostic reliability is, of course, in-
creased by taking 2 or 3 biopsy samples from the two
lobes of liver during laparoscopy. (s. pp 157, 161) • Con-
clusive proof of mycosis is obtained by (1.) microscopic
examination, (2.) serological tests or immunoassays, and
(3.) fungal culture.
Mycotic infections and the liver
1. Candida species
⫺ C. albicans, C. glabrata
(22), C. krusei C. parapsilosis, C. tropicalis
2. Aspergillus species
⫺ A. flavus, A. fumigatus, A. niger 3. Blastomyces species
⫺ B. brasiliensis, B. dermatitidis 4. Trichosporon species
⫺ T. beigelii, T. capitatum 5. Cryptococcus neoformans 6. Coccidioides immitis
Paracoccidioides brasiliensis 7. Histoplasma capsulatum 8. Torulopsis glabrata 9. Mucor indicus
10. Prototheca wickerhamii Prototheca zopfii 11. Coniothyrium fuckelii
Tab. 26.2: Fungal species causing hepatobiliary organ mycosis in the presence of predisposing factors
4 Morphological findings
Systemic organ mycosis is characterized by different manifestations in the area of the liver or biliary tract.
The manifestations vary depending on the type of mycosis, and indeed some of them have only been seen in certain mycosis forms. The following morphological findings have been reported:
1. Granulomas
Granulomatous suppurative or caseating foci 2. Microabscesses and small abscesses
3. Cholangitis 4. Hepatitis
⫺ portal, often eosinophilic cellular infiltration
⫺ focal inflammatory lesions
⫺ single-cell necrosis 5. Mesenchymal reactions
6. Splendore-Hoeppli phenomenon (s. p. 397, 497) 7. Biliary obstruction by fungal conglomerates
5 Hepatobiliary organ mycoses
5.1 Candidosis
䉴 Some of the facultative pathogenic Candida species are extremely common pathogens responsible for mycosis of the hepatobiliary sys- tem. (s. tab. 26.2) This candida mycosis, also called thrush or monili- asis, is a typicalopportunistic mycosis, generally known about more than 140 years ago as the “disease of the sick”. The human intestinal tract serves as a reservoir for pathogens in the body. As a rule, thrush initially manifests in the area of the oral and pharyngeal mucosa.
Depending on the degree of impairment of the body’s own defence mechanisms, the candida infection can disseminate further into the tracheobronchial system and gastrointestinal tract, where it pene- trates the intestinal wall and, via the vascular system, affects other organs (liver, lungs, spleen, bone marrow, eyes, CNS, endocardium)
as well; it may also spread systematically, possibly as septicaemic candidosis. (11)
In most cases, the liver and spleen are concurrently and similarly affected, especially in the form of microab- scesses ( ⫽ hepatolienal candidosis). A greater risk of candidosis exists for patients with severe hepatic dys- function, in particular cirrhosis or acute liver failure
(5, 19, 32), after marrow or liver transplantation
(3, 6, 8)and with leukaemia or carcinoma.
(1, 4, 31)Fever of un- known origin and non-response to antibiotics are sug- gestive of systemic candidosis. Alkaline phosphatase is always elevated.
(14, 21, 24, 25)• Morphological findings include granulomas
(12, 20, 21, 30), hepatitis-like lesions
(18)
, microabscesses
(1, 2, 4, 28), cholangitis
(16), biliary obstruction by fungal conglomerates
(10, 22, 23)and peri- hepatic adhesions.
(12)• Sonography shows multiple small abscesses (> 5 mm in diameter), which are usually detectable as hypoechoic areas and target zones; how- ever, aetiological clarification is not possible. “Wheels within wheels” is considered to be more characteristic:
a round, hypoechoic (fibrosis-related) focus shows an inner hyperechoic (inflammation-related) zone, which, in turn, exhibits an inner hypoechoic (caseation-related) area.
(26)Sonographic clues to candidosis of the (gen- erally enlarged) liver and spleen
(9, 13, 15, 24⫺28)are fur- ther underpinned by computer tomography and MRI, using gadolinium as a contrast medium. Cytological or histological clarification and cultural or serological tests as well as DNA analysis (PCR) are now indicated.
Lethality is 40 ⫺50%.
5.2 Aspergillosis
䉴 Environmental reservoirs for the Aspergillus species (s. tab. 26.2) include damp cellars and old stone walls, soil in flowerpots (thus possibly in hospital rooms!) and mouldy food. The aflatoxins of the mould Aspergillus flavus (e. g. in mouldy nuts) are deemed to have a high carcinogenic potential.
The aspergillus spores enter the body through airborne transmission, nearly always via the respiratory tract.
Under normal conditions (good defence response, no excessively high germ count), aspergillus is eliminated.
In cases of reduced body-own defence (s. tab. 26.1), the mucosa is affected more severely, and after vascular invasion, generalized aspergillosis also occurs. The lungs are mainly affected in the form of bronchopulmonary aspergillosis, aspergilloma or aspergillus pneumonia.
Generalization may likewise affect other organs, such as the liver and spleen. Focal lesions can be detected by imaging techniques.
(35, 37)Disseminated aspergillosis has also been reported in acute liver failure.
(36, 38)Following liver transplantation, aspergillosis is a feared and relatively frequent complication (6 ⫺10% of cases).
(3, 8, 33, 34, 37)
5.3 Blastomycosis
Blastomyces species cause South American (B. bra-
siliensis) and North American (B. dermatitidis) blasto-
mycosis (s. tab. 26.2), the budding forms of which are also found in body tissue. The pathogens are mainly transmitted via the respiratory tract, which explains why bronchopulmonary infections clearly predominate. Yet, multiple organ involvement, particularly with Blasto- myces dermatitidis, is also known.
A case report of blastomycosis of the hepatobiliary sys- tem describes the following conditions:
(39)development of chronic cholangitis in the area of the left hepatic duct with encroachment of the mycotic inflammation to the left lobe of liver in cases of predisposing and/or pre- existing choledocholithiasis; histological evidence of liver granulomas and periportal fibrosis; marked increase in alkaline phosphatase and γ-GT.
(40)5.4 Trichosporosis
Systemic infection induced by the Trichosporon species (s. tab. 26.2) may lead to sepsis and, in the liver, to marked hepatitis-like findings, granulomas and micro- absesses. Laboratory tests revealed an increase in trans- aminases, alkaline phosphatase and bilirubin. Diagnosis was confirmed by liver biopsy and fungal culture.
(41, 42)5.5 Cryptococcosis
Mycosis caused by Cryptococcus neoformans, also termed European blastomycosis, is airborne and reaches the organism via the respiratory tract. The source of infection is mostly bird excrement, especially pigeon droppings. The pathogen consists of large round yeast cells, 10 µm in diameter, surrounded by gelatinous cap- sules. It can be selectively demonstrated by mucicarmine staining or Chinese ink.
In generalized cryptococcosis, hepatitis-like findings, simulating a surgical emergency
(47)or causing peritoni- tis
(44)and cholangitis
(43), were reported; in a further case, the clinical picture of primary sclerosing cholan- gitis was imitated.
(45)Cryptococcosis is mainly found in AIDS patients. Both acute liver failure and liver cir- rhosis have also been provoked by cryptococcosis.
(46, 48)Proof is obtained by histological and microscopic examination as well as by fungal culture, and, if neces- sary, by serological tests.
5.6 Coccidioidomycosis
The mycelial fungus Coccidioides immitis, affecting both humans and animals, is rarely encountered in Europe, whereas endemic areas are known in America. • In this context, coccidioidomycosis (Paracoccidioides brasili- ensis) should also be mentioned.
In disseminated coccidioidomycosis
(A. Posada, 1894), lung involvement is predominant; however, in 45 ⫺60%
of cases, autopsy findings showed the liver to be affected as well. The principal manifestations are granulomas
and small abscess-like foci. Clinical findings generally include fever, hepatomegaly and eosinophilia as well as an increase in transaminases and occasionally in serum bilirubin. Liver biopsy provided the diagnosis in almost all cases.
(49⫺54)5.7 Histoplasmosis
䉴 Disseminated infection with Histoplasma capsulatum is a form of mycosis frequently found in North and South America, but rarely in Europe. It affects both animals and humans. Henhouses and caves inhabited by bats are ideal breeding grounds. Infection is usually by inhalation of dust, which is why the lungs are primarily affected. In body tissue, the pathogen is demonstrable as yeast cells, 3⫺5 µm in diameter, mainly localized intracellularly. As a rule, pulmonary infection runs a mild course with a good healing tendency.
Lymphogenous dissemination from the primary pulmon- ary focus, however, leads to serious generalized disease in the form of chronic, slowly progressive reticuloendo- theliosis with fever, lymphadenopathy and splenomegaly.
With liver involvement (organ mycosis), there is evidence of hepatomegaly with many epithelioid cell granulomas, some with central necrosis. These granulomas may subse- quently become fibrous and even calcify. The fungus can be demonstrated in the RES cells and in the granulomas by PAS staining or silver impregnation. Histoplasmosis can remain latent in the body for decades before being reactivated.
(55⫺58)5.8 Torulopsosis
Of the approximately 36 Torulopsis species known so far, T. glabrata, also classified as a Candida species, is a human pathogen. Dissemination leads to colonization of the fungus in many organs and the development of liver abscesses. Severe hepatobiliary torulopsosis was also diagnosed in one patient with diabetes and bile duct stricture, secondary to chronic pancreatitis.
(59)5.9 Mucormycosis
Mucormycosis of the liver is a rare condition. In one reported case, widespread dissemination of Mucor indi- cus, resulting from isolated ileocoecal mucormycosis with markedly reduced body-own defence, led to liver infection with multiple abscesses. A serious clinical pic- ture with fever, hepatomegaly and icterus developed.
The multiple abscesses could be identified by CT and the fungal infection confirmed by microscopic examina- tion or cultures of biopsy specimens.
(60⫺62)5.10 Protothecosis
Of the many Prototheca species, only P. wickerhamii and P. zopfii cause disease in humans. Infection only occurs when the body’s defence system is seriously impaired.
Liver involvement is rare. In one noteworthy case, a
Mycotic infections and the liver
severe feverish hepatobiliary disease simulating scleros- ing cholangitis, as demonstrated by ERC, was reported.
Liver biopsy showed portal infiltration with eosino- philic cells and granulomas as well as fibrosis.
(63, 64)5.11 Coniothyrium mycosis
Liver infection with Coniothyrium fuckelii in a female patient with leukaemia was reported for the first time in 1987.
(65)The acute clinical picture consisting of fever, arthralgia and myalgia, nightly sweats, increased inflam- matory parameters and enhanced alkaline phosphatase could be identified, after extensive examination, as a fungal infection of the liver. Histology revealed focal, partly granulomatous inflammatory lesions, from which C. fuckelii was demonstrated by culture.
6 Therapy
The fungistatic therapy, which has been used so far, includes (liposomal) amphotericin B, also in combin- ation with 5-fluorocytosine, fluconazole, ketoconazole and itraconazole.
The possibility of mycosis should be considered in all those patients with liver disease and reduced body- own defence who are experiencing growing malaise and fever!
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