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Address to the Japanese Society of Hepatology (Tokyo, 13th March, 1969)

Fungal Infections of the Liver

William St. Clair Symmers*

Summary

Fungal infections of the liver rarely cause specific clinical manif estations. This is because the develop- ment of hepatic lesions is, in most cases, merely an incident in the courseof a progressive haematogenous systemic , the clinical picturebeing dominated by the general effects of the septicaemic infection. In most of these cases the fungal septicaemia is itself secondary to someunderlying disease that has predisposed to invasion of the body by the fungi, which in such circumstances commonly belong to the numerous group of so-called 'opportunistic' organisms. For the same reason, fungal infections involving only the liver are exceptionally rare. Such may result from a penetrating injury by some article contaminated by fungi: an illustrative case is described. An occasional case of actinomycosis of the liver in the absence of any recognized actinomycotic focus elsewhere in the body may reflect an observational error(e. g., the overlooking of a small intestinal focus in a case here recorded); alternatively, the initial focus may have healed. Clinically or pathologically obtrusive hepatic mycosis may be secondary to recognized infection elsewhere in the body. The direct extension of actinomycosis from an infected lung through the diaphragm into the liver is an instance of how this may occur. Likewise, fungal infection may spread by the portal blood stream from a primary focus of disease in the alimentary tract: actinomycosis, again, is the most frequent example of this event, but comparable cases of hepatic candidosis and hepatic geotrichosis are included in the paper. A particular manifestation of hepatic mycosis is the occurrence of hepatic failure or hepatorenal failure from widespread infarction of the liver or of the liver and kidneys, the result of vasothrombosis due to invasion by phycomycetes, at least some of which provoke extensive thrombosis in the course of their haema- togenous dissemination. What is known of the aetiology and pathogenesis of fungal infections of the liver indicates that the principles of diagnosis and treatment are no different from those relating tofungal infections of other parts of the body.

liver may become infected by micro-organisms: portal Introduction vein, hepatic artery, common bile duct,lymphatics, Theoretically, there are six routes by which the direct extension from an infected adjoining structure , and penetrating wounds. In fact, as far as fungal * Professor of Histopathology in the University of infections are concerned, only the portal vein and he- London and Consultant Pathologist to the Charing Cross Group of Hospitals, London. patic artery are of practical importance. I know of 10:374 肝 臓10巻5号(1969)

no record of mycotic infection of the liver taking place tenderness of the liver. The cause of these symp- by the biliary or lymphatic routes. Direct extension toms remained uncertain until the development into the liver of a mycotic infection in a contiguous of sinuses discharging through the skin of the structure must be very infrequent: two instances are right hypochondrium: Actinomycesisraelii was demon- summarized below. Again, I know of no reported strated in the exudate. This was before the days case of fungal infection resulting from a penetrating of penicillin and the patient eventually died of wound of the liver: a possibly unique case of infection the effects of the long-standing infection. by this means is recorded here for the first time. Necropsy showed very extensive actinomycosis The case reports that follow illustrate these various of the liver and overlying tissues. A particularly pathways of infection of the liver by fungi. thorough search did not reveal any evidence of the infection in any other parts of the body, the A) Hepatic Mycosis Resulting from Infection rest of the abdomen and the lungs and the mouth by Way of the Portal Vein and throat being specially carefully examined. Comment. When, as in such a case as this, When a fungal infection of the liver results from hepatic infection is the sole discovered manifestation dissemination of the causative organism in the portal of actinomycosis, there are two possible explanations. blood stream it may ordinarily be assumed that the First, the initial actinomycotic focus may have source of the infection is intestinal. The intestinal been so insignificant that it escaped notice at nec- infection may be a primary mycosis, particularly ac- ropsy. Second, it is conceivable that the initial tinomycosis, or a mycosis complicating a pre-existing focus healed without detectable trace, the secondary lesion, e. g., infection of an ulcerated carcinoma or foci of infection in the liver persisting and advancing. comparable condition by Candida species or Geotrichum Case2: Fatal Hepatic ActinomycosisSecondary to candidum. It is also possible that moulds, such as a Small Focus in the Ileocaecal Region That Almost species and the various phycomycetes, might Escaped Detection. An elderly man died of cachexia also enter the body through intestinal ulcers and then complicating extensive and long-standing ac- reach the liver in the portal blood, but as far as I know tinomycosis of the liver. His case seemed in general this has not as yet been observed. somewhat similar to Case 1 (above), for the post- mortem examination at first did not reveal any i) Actinomycosis* evidence of actinomycotic lesions outside the liver Actinomycosis remains by far the least infrequent and the overlying tissues of the abdominal and fungal infection of the liver. Its occurrence in this chest wall. However, more detailed dissection organ is usually due to spread from an intestinal focus of the intestinal tract disclosed a firm mass in the by way of the portal vein. fatty tissue between the ileum and the caecum. Case 1: Fatal Hepatic Actinomycosis.without Recognized This mass, about 2 cm. across, consisted of scar ActinomycoticInfection Elsewherein the Body. A woman, tissue enclosing a series of small abscesses: histolo- aged 46, died of actinomycotic infection of the gical examination demonstrated typical colonies liver. During two years preceding her death of Actinomycesin the pus. she had a series of febrile illnesses accompanied Comment. The actinomycotic focus in the by slight jaundice and by some enlargement and ileocaecal angle may have been the source of the * In accordance with the practice endorsed by the hepatic disease, the infection spreading through Medical Mycology Committee of the British Medical the portal venous system. One can only speculate Research Council the actinomycetes are regarded for on the sequence of events that might explain this the purposes of this paper as fungi (Actinomyces spe- cies, Nocardia species, StrePtomyces species). unusual clinicopathological picture. Fungal Infections of the Liver 10:375

Hepatic Involvement, Following Fungal Colonization Staphylococcal Infections Can Be Mistaken (Possibly Chlortetracycline-Induced)of an Unsuspected for Actinoniycosis Colonic Carcinoma in a Patient under Treatment for Staphylococcal Hepatitis (Staphylococcal Bo- Myelomatosiswith CytotoxicDrugs. A man, aged 70, tryomycosis). The classic 'honeycomb' abscesses charac- had for many months been under treatment for teristic of actinomycosis of the liver are well known myelomatosis with cytotoxic drugs. He developed to generations of medical students and are tradition- an acute bacterial pneumonia: this responded to ally represented in most museums of pathological large doses of chlortetracycline. However, his anatomy. It is therefore important in practice to general condition deteriorated more rapidly as remember that staphylococcal hepatitis can simulate he recovered from the pneumonia, and his blood actinomycosis, both macroscopically and microscopically. was repeatedly found to grow Geotrichumcandidum Staphylococcal hepatitis is sometimes an outcome in pure culture. at first seemed of suppurative pylephlebitis originating in local septic to control the fungal septicaemia, but this response thrombosis of the radicles of the portal vein in the was not sustained and he died. vicinity of an appendix abscess; in other cases it re- Necropsy showed several very large abscesses sults without any associated thrombosis at the point in the liver. The geotrichum was isolated in of entry of the infection, the staphylococci then pre- pure culture from these and from multiple miliary sumably gaining access directly to the circulating blood lesions in other organs. The source of the geo- to establish a portal pyaemia. The ramifying cavi- trichal infection was considered to be a clinically ties of the subacute or chronic abscesses that charac- unsuspected primary carcinoma of the caecum, terize staphylococcal hepatitis are considerably larger the ulcerated surface of which was heavily colo- and correspondingly less numerous than those of ac- nized by the fungus. The presence of widespread tinomycosis. skeletal myelomatosis was also confirmed. It is important to remember, in relation to Comment. Presumably, the chlortetracycline the histological diagnosis of hepatic actinomycosis had so altered the normal colonic flora that the (as of actinomycosis elsewhere in the body), that geotrichum proliferated freely and was able to the peculiar aggregates of staphylococci that are the infect the carcinomatous ulcer, thence gaining characteristic feature of the lesions of so-called access to the portal blood stream and so eventually staphylococcal botryomycosis may simulate the co- to the systemic circulation. Myelomatosis may lonial grains of the actinomyces very closely. These have predisposed to infection and the administration collections of staphylococci, like colonies of the actino- of cytotoxic drugs have further lowered resistance myces in the tissues, are covered by an eosinophile to the establishment of the fungal septicaemia. mass of fibrin, globulin and other constituents, very The predominant involvement of the liver in the similar to the eosinophile 'club' zone at the surface mycotic process clearly resulted from the initial of the actinomycetic grain: it is little wonder that the invasion of the portal venous system. two organisms can easily be confused when present This is one of two instances of fatal geotrichal in such. form. It is therefore essential to study the septicaemia that I have seen. In both cases haematoxyphile core of the colony very carefully, there was a predisposing disease under treatment particularly by examining Gram-stained preparations with cytotoxic drugs, a recent history of adminis- under the oil immersion objective. tration of a broad-spectrum antibiotic, and an unsuspected cancer of the large bowel that was ii) Geotrichosis regarded as the portal of entry of the fungus . Case 3: Fatal Geotrichal Septicaemiawith Predominant The second case did not show the preponderant 10:376 肝 臓10巻5号(1969)

hepatic involvement in the mycosis that charac- B) Hepatic Mycosis Resulting from Infection terized Case 3 (above). by Way of the Hepatic Artery The liver is likely to be involved in the course of iii) Candidosis any generalized fungal infection that is disseminated The case that follows is comparable to Case 3 except through the systemic circulation. Any of the deep- that the fungus concerned was . seated fungal infections may in this way incidentally Case 4: Fatal Candida Septicaemiawith Predominant involve the liver. In such cases the mycotic lesions Hepatic Involvement, Following Fungal Colonization in the liver are unlikely to attract attention clinically- (Possibly Tetracycline-Induced) of an Unsuspected the only notable exception is the development of hepatic Colonic Carcinoma in a Patient under Corticosteroid failure (or, more typically, hepatorenal failure) as Treatment for Chronic . A man, aged 46, outcome of massive ischaemic necrosis of the liver had been under treatment for asthma with cortico- (or of the liver and kidneys) from involvement of steroids for many months when he developed a the visceral vasculature in the course of septicaemic staphylococcal infection of the urinary tract. phycomycetoses (thrombosis of infected vessels is a The urinary infection responded to treatment with particular feature of the pathology of the infections tetracycline, but his general condition did not caused by at least some of the phycomycetes). A case improve. He developed high fever and was found of phycomycotic hepatorenal failure is summarized to have Candida albicans in his blood. After a week below. First, however, attention is drawn to a pos- of this septicaemic illness, which seemed to be sible advantage of undertaking biopsy of the liver when responding slowly to treatment with amphotericin there is any question that a generalized fungal infection B, he developed symptoms of acute myocardial may be present. infarction and died a few hours later. Necropsy showed coronary atheroma, with Diagnosis of Disseminated Fungal Infections fresh thrombosis and an apical cardiac infarct. by Liver Biopsy Bronchopulmonary and cardiac changes attribut- In spite of the fact that clinical manifestations only able to chronic asthma were also present. In exceptionally result from involvement of the liver in addition, there was an ulcerated carcinoma of the course of generalized mycoses, it is pertinent to the the hepatic flexure of the colon; its surface was theme of this paper to refer briefly to the occasional thickly covered with a growth of Candida albicans. value of biopsy of the liver in indicating the presence Confluent abscesses in the liver were heavily in- of an otherwise unsuspected fungal infection. My fected by this fungus; there were a few miliary first experience of this was in the case of a patient known candida abscesses in other organs. to have Hodgkin's disease: it was thought necessary Comment. As in Case 3, the fungus presumably to examine the liver by needle biopsy in order to in- entered the body through the ulcerated surface vestigate the reason for its enlargement: there had been of the clinically unsuspected colonic cancer. Again, no grounds for suspecting any infection, yet the biopsy the history suggests the possibility that a change showed foci of . At that time ampho- in bowel flora brought about by administration tericin B had not been discovered; the patient died of a broad-spectrum antibiotic enabled the fungus some months later of cryptococcal meningoencephal- to colonize the ulcer. Corticosteroid therapy may itis. have contributed to the establishment of the fungal Since that initial experience it has seemed ap- septicaemia by its side effects on the body's mecha- propriate on four further occasions to undertake liver nisms of defence against infections. biopsy with the purpose of investigating the possibility that patients with diseases predisposing to cryptococ- Fungal Infections of the Liver 10:377

cosis (particularly Hodgkin's disease and sarcoidosis) litus. A woman, aged 50, had been a diabetic were developing the infection. A positive result was for almost 30 years when she began to be careless. obtained in one only of these four additional cases, both in watching her diet and in her use of insulin. a patient with sarcoidosis, who was then treated with As a result her diabetes had tended to go out of amphotericin B, apparently successfully. control. She was admitted to hospital for in- Needle biopsy of the liver has disclosed the presence vestigation of upper abdominal pain of fairly sud- of a disseminated mycosis in five other cases within the den onset. Her liver was found to be considerably experience of my laboratories: enlarged, there was slight jaundice and heavy pro- infection twice and infection (African teinuria, and mentally she was disoriented. The ) once, actinomycosis once and Blastomyces jaundice rapidly deepened and anuria developed. dermatitidis infection once. In each of these cases the She died in coma a few days later. patient was under investigation for symptoms sug- Necropsy showed very extensive haemorrhagic gesting some form of progressive generalized in- necrosis of the liver and of both kidneys. Histo- fection, without localizing manifestations and with logical examination confirmed the clinical sus- failure of all other laboratory and clinical investigations picion that the condition was the result of septic- to disclose the nature of the disease. It may be noted aemic , with thrombosis of invaded- in passing that all five patients were in hospitals in the visceral blood vessels and consequent infarction. British Isles, where actinomycosis is the only one of The infarcts, like the blood vessels themselves, the mycoses named that occurs naturally: the other were extensively colonized by the fungus. Cultures. four infections had been acquired while the patients proved this to be a species of Rhizopus. were in other parts of the world. Comment. Diabetes mellitus is notoriously liable Liver biopsy may also be useful occasionally in to predispose to phycomycosis. The commonest the further investigation of known cases of generalized clinicopathological form of the infection in such. mycotic infection. Thus, in my own experience it cases is, of course, orbitomeningocerebral disease, has twice provided evidence of persistent activity of in which the portal of entry is thought to be the septicaemic candidosis when there was doubt whether mucosa of the nasal sinuses, the infection ad- treatment had effectively overcome this complication vancing along the blood vessels into the orbit and of some other illness. However, as in any biopsy pro- thence to the cranial cavity. Generalized septi- cedure involving the viscera, care in the selection of caemic phycomycosis is more characteristic of cases and attention to the choice of operation (per- 'opportunistic' infection by fungi of this group cutaneous or laparotomy biopsy) are imperative: it is in cases of leukaemia and the like under treatment not an investigation to be recommended lightly. with cytotoxic drugs, corticosteroids or other resistance-lowering agents. Phycomycotic Hepatorenal Failure The following case illustrates the exceptional C) Hepatic Mycosis Resulting from Direct circumstances, already briefly noted above, in which Extension of Infection from an Adjoining Structure involvement of the liver in the course of a systemic The liver may be infected by the extension of a haematogenous mycosis results in significant clinical fungal infection from the lung across the obliterated manifestations. This occurrence reflects the predispo- pleural cavity and through the diaphragm. This sition to vasothrombosis that is a peculiarity of certain must occur only with extreme rarity, and even more phycomycetous infections. rarely than extension of such an infection in the op- Case 5: Rapidly Progressive HepatorenalFailure Due posite direction, from liver to lung. As far as I am to SepticaemicPhycomycosis Complicating Diabetes Mel- aware, spread of a mycosis from liver to lung or from 10:378 肝 臓10巻5号(1969) lung to liver has been noted only in respect of actino- Englishman had returned to live in the British mycosis. Isles at the age of 58, when he retired from a life- Case 6: Hepatic Actinomycosis Following Lobec- time of working in southern and south-eastern Asia. tomy for Pulmonary Actinomycosis and Complicating He had never lived in or visited any other parts Chronic Intestinal Amoebiasis: A Problem in Differential of the world except during repeated sea passages Diagnosis. A woman was found to have actino- from Britain to Asia through the Mediterranean mycosis of the right lung, confined to the lower and Red Seas. His fatal illness presented (12 years lobe. This was treated by lobectomy, preceded after his retirement to Britain) with a very painful, and followed by a month's course of penicillin. chronic ulcer of the lower lip. Biopsy showed A year later she was found to have a mass in the this to be a histoplasmic ulcer in which the pe- right lobe of the liver. In the interval since the culiar cyst-like tissue form of the histoplasma, thoracic operation she had suffered a recurrence characteristic of this clinicopathological form of of chronic intestinal amoebiasis, a condition that histoplasmosis of Asian origin, was conspicuous had troubled her intermittently for more than (Symmers, 1966). As usual in these cases, the ten years. In view of the absence of any evidence cultural characteristics of the organism were identi- of recurrent disease in the chest, it was thought cal with those of Histoplasma capsulatum. Treatment likeliest that the hepatic condition would prove with amphotericin B was begun in full doses. to be an amoebic pseudo-abscess. Treatment The patient's condition deteriorated very rapidly with emetine was started and the lesion in the and he died a few days later of acute adrenocortical liver was aspirated: the aspirate consisted of true failure. pus and contained colonies of Actinomycesisraelii; The necropsy showed massive enlargement of no amoebae were found. A course of penicillin both adrenals, which had been converted into in large doses was continued for five months. There caseous masses. The right adrenal could scarcely has been no further evidence of actinomycosis in be distinguished from a caseous mass that had the period of six years that has passed since then. formed in the contiguous part of the liver, involv- Comment. The findings in this case suggest ing that organ to a depth of some 5 cm. in all that the liver was invaded by the actinomyces directions. The caseous material in the liver tracking directly from the infected lung rather and to a much greater degree in the adrenals was than in the reverse direction or through the blood. heavily infected by the histoplasma. As in all the There was no evidence of the infection elsewhere other cases of histoplasmosis of Asian origin that in the body. The penicillin 'cover' provided that I have seen, the fungus in the viscera presented immediately before and after the pulmonary only the appearances that are ordinarily character- lobectomy was by any standard insufficient in istic of the tissue form of Histoplasma capsulatum, duration to justify any belief that it would eli- without the cyst-like structures that are present minate residual foci of actinomycotic infection. along with the ordinary form in the ulcerated The extension of a mycosis into the liver from an superficial lesions. There were only relatively abdominal organ must also be extraordinarily rare. few and miliary-sized foci of histoplasmosis in other In the following case this occurrence was without clini- organs. cal significance. Comment. It seems possible that the sudden Case 7: Massive Necrotizing Histoplasmosis in the onset of adrenal cortical failure in cases of this type Liver Immediately Adjoining the Necrotic Adrenal Gland of histoplasmosis may represent something akin in a Case of Fatal AdrenocorticalFailure Complicating to a Herxheimer reaction, the result of the de- Histoplasmosis of Asian Origin. A 70-years-old struction of a heavy concentration of histoplasmas Fungal Infections of the Liver 10:379

early in the course of treatment with amphotericin site of the injury. The abscess was aspirated.. B. For this reason treatment should probably Cultures of the pus grew a brown mould that be started, in these cases, at a low level of dosage was regarded as a contaminant and not further and only gradually built up to the full doses re- investigated. Further pus accumulated and the quired; facilities for detecting and countering in- abscess was explored at laparotomy and drained. cipient adrenal failure should be available. A course of amphotericin B was given. This time In the case described the hepatic involvement the abscess healed without incident and there has. was presumably due to direct spread of the infection been no recurrence during the four years that into the liver in the region where it and the infected have passed since then. Histological examination adrenal gland were in contact. The liver was of material from the lining of the abscess showed otherwise uninvolved, apart from a very few micro- a pigmented, branching fungus, morphologically scopical foci of infection. identical with the organisms in cases of cerebra/ chromomycosis (cladosporiosis). D) Hepatic Mycosis Resulting from a Pene- Comment. Chromomycotic abscesses, similar trating Wound to the lesion found in this child's liver, are familiar- The case reported here is without precedent. though rear-in the central nervous system and in Case 8: Chromomycosisof the Liver Following a subcutaneous tissue. The evidence that the fungus. Wound by a Partly Rotten Branch of a Tree. A child, responsible for the hepatic infection entered the aged 12, fell from the upper branches of a pine tissues when they were penetrated by the tree tree that he had climbed. In falling, he struck branch is wholly presumptive. It seems, however, the broken tip of a partly dead branch, which a reasonable presumption. Various 'brown moulds' penetrated his right side. He was admitted to are known to occur on wood, particularly when hospital: immediate laparotomy showed the peri- rotting, and these may well include potentially toneal cavity to contain a very large volume of pathogenic varieties that, given a suitable milieu blood that had escaped from an irregular rent in the tissues, could establish an infection. in the liver. The wound in the liver was cleaned and sutured and, with blood transfusion, the child made a quick recovery from the accident. Reference Symmers, W. St. C., Deep-seated funga) infections currently seen in the histopathologic service Ten weeks later he was readmitted to the hospi- of a medical school laboratory in Britain (Case 24), tal with a liver abscess that had developed at the Amer. J. din. Path., 46 : 514-537, 1966.