IM - CASE RECORD

Challenges in dealing with a cirrhotic patient

Diana Spinelli • Sarah Damanti • Francesca Minonzio •

Cinzia Hu • Maria Domenica Cappellini

Received: 16 September 2011 / Accepted: 1 March 2012 / Published online: 15 March 2012

� SIMI 2012

Case presentation

Dr. Spinelli We report a case of a 75-year-old woman with

Child-Pugh Class 7 B HCV cirrhosis, admitted to our

hospital for high fever (38.5 �C), chills and fatigue. These

symptoms started approximately 1 month prior, and pro-

gressively worsened. At home, she was treated with levo-

floxacin without benefit. She reported anorexia and loss of

weight of 4 kg. A recent upper-digestive endoscopy

(EGDS) showed fine caliber esophageal varices; the

ultrasonography of the abdomen revealed signs of chronic

liver disease and splenomegaly.

The patient was alert and oriented, even if a bit slack-

ened. On physical examination, she had no sign of men-

ingismus and no jaundice. Vital signs: body temperature

37.5 �C, heart rate 72 beats/min, blood pressure of

100/60 mmHg. Oxygen saturation by pulse oximetry was

95 % on room air. Body mass index (BMI): 19.9. Cranial

nerve examination was normal. She had minimal ascites

and hepatomegaly. There was edema of grade-2 in the

lower extremity bilaterally. The rest of the general body

examination was normal. Blood laboratory tests revealed a

sever iron deficiency anaemia (haemoglobin 7.6 g/dl),

increased transaminases, low pseudocholinesterase and

hypoalbuminemia. Inflammation indices were negative.

She was transfused with several red blood cells (RBC)

units, and was initially treated with ceftriaxone without

benefit. She was initially supported with a balanced hyp-

oproteinemic low-sodium oral diet. Because of worsening

deterioration of the general condition, she was also treated

with parenteral nutrition (aminoacid solution, vitamins,

glucose, electrolytes, lipids) for a total caloric contribution

of 1,320 kcal/daily.

Further investigations

Dr. Spinelli The blood culture was positive for a yeast, thus

therapy with fluconazole intravenously was promptly

started. A few days later, Cryptococcus neoformans was

identified in culture; serum cryptococcal antigen was only

1:4. HIV-serum antibody test was negative, and the blood

CD4 and CD8? T-lymphocyte counts were normal. Chest

and brain computerized tomography (CT scans) were

negative. Cerebral spinal fluid (CSF) analysis (opening

pressure of 7.5 cmH2O) revealed a clear fluid, a lympho-

cytic pleocytosis, hyperproteinorachia and hypoglycorrha-

chia. The CSF gram stain demonstrated a yeast, and culture

grew C. neoformans. CSF cryptococcal antigen was also

positive (1:128).

After 13 days of antifungal therapy, she was still febrile

and her kidney function was worsening; so, she was shifted

to a lipid formulation of amphotericin B (LFAmB).

LFAmB intravenously was dramatically reduced in the

following days because of the further impairment of liver

and kidney functions. Two weeks later, she was afebrile

but a brain CT scan revealed a small multiloculated ring

enhancing mass, in the left pulvinar suspected of being a

cryptococcosis-related lesion (Fig. 1). A second measure-

ment of serum cryptococcal antigen showed an increase in

D. Spinelli (&) � M. D. Cappellini

Department of Internal Medicine, UO Medicina Interna 1-A,

Universita degli Studi di Milano, Scuola di specializzazione in

Medicina Interna, Via F. Sforza 35, 20122 Milan, Italy

e-mail: dia.spinelli@gmail.com

S. Damanti � F. Minonzio � C. Hu

Department of Internal Medicine, UO Medicina Interna 1-A,

Universita degli Studi di Milano, Via F. Sforza 35, 20122 Milan,

Italy

123

Intern Emerg Med (2013) 8:161–164

DOI 10.1007/s11739-012-0771-3

the titre (1:128).The treatment was prolonged for 23 days,

after it had been stopped for a week because of severe

kidney damage. During this suspension period, she devel-

oped leucocytosis and a mild increase of C reactive protein;

the therapy was enforced by a broad spectrum antibiotic

followed by Linezolid to treat a multiresistant Enterococ-

cus in the urine. After the reintroduction of LFAmB,

our patient fell into a deep coma. A brain CT scan did not

show any new lesions. Because of a hyperammoniemia

(227 lmol/L) and its neurotoxical effect exacerbated by

LFAmB we suspected a development of hepatic encepha-

lopathy, so, she was managed with lactulose, branched-chain

amino acids and albumin. Despite a slow improvement of the

intellectual impairment, cryptococcal encephalitis (confirmed

by a high positive cryptococcus antigen in CSF) excluded the

complete resolution. In the following days, the patient

developed multi-systemic organ failure, anasarca (with con-

sistent ascites) and jaundice. Laboratory studies revealed

leucocytosis, hyponatremia (Na 127 mEq/L), hyperkalemia

(5.4 mEq/L), BUN 162 mg/dL, total bilirubin 26.5 mg/dL,

undetectable creatinine (for jaundice). Soon after the onset of

coma, she expired.

Diagnosis

Dr. Damanti The diagnostic gold standard for C. neofor-

mans infection is the blood culture for the growth of the

organism from any other site [1]. To obtain culture results,

usually takes 7–9 days, delaying the diagnosis.

Investigation of cryptococcal antigen in organic fluids

allows an earlier disclosure of the infection. Nevertheless,

it can be falsely negative in the early phase of the disease in

patients with cryptococcoma. An antigen titre [1:164 is

strongly associated with disseminated disease [2]. The

measurement of its sequential changes in serum and CSF is

useful for evaluating the response to the treatment [3].

Direct fluid examination with India ink, rather than Gram-

stain, is recommended [4].

Radiographic features of pulmonary cryptococcosis are

variable with solitary or a few well defined, non calcified

nodules; sometimes a lobar infiltrate, hilar or mediastinal

adenopathy and a pleural effusion.

CNS mass lesions are seen in 10 % of patients, and are

typically localized in the basicranium.

CSF analysis typically reveals a cloudy fluid, a lym-

phocitic pleocytosis with elevated protein and decreased

glucose. Opening pressure during lumbar puncture is often

elevated to values [20 cmH2O. An opening pressure

[25 cmH2O is associated with increased morbidity (dimin-

ished mental capacity, vision loss, cranial nerve palsies and

hydrocephalus).

Diagnosis of peritoneal disease, often associated with dis-

semination, relies on analysis of ascetic fluid and not imaging

studies. Ascitic fluid analysis reveals a low protein level and

moderately elevated WBC count with lymphocytosis.

Therapy

Dr. Minonzio, Dr. Hu The treatment is the same for both

C. neoformans and C. gattii with regard to CNS and dissem-

inated disease [5]: induction therapy with Amphotericin B

deoxycholate (AmBd 0.7–1.0 mg/kg per day IV) plus flu-

cytosine (100 mg/kg per day orally in four divided doses)

for at least 4 weeks, then consolidation with fluconazole

(400 mg per day) for 8 weeks. After that, use maintenance

therapy with fluconazole [200 mg (3 mg/kg) per day orally]

for 6–12 months. If patient is AmBd intolerant (e.g., renal

impairment), substitution with LFAmB (3–4 mg/kg per day

IV) is advised. If flucytosine is not given (e.g., renal insuffi-

ciency) or treatment is interrupted, consider lengthening

AmBd or LFAmB induction therapy for at least 2 weeks.

Primary therapy with fluconazole alone (administered

for 10–12 weeks) needs high daily dosages (1,200–2,000

mg/day), that can produce gastrointestinal toxicity.

For cerebral cyptococcomas, the induction therapy is the

same, but consolidation treatment needs a higher dosage of

fluconazole (400–800 mg/day orally) for a longer period

(6–18 months). Surgery may be required for large (3 cm

diameter), accessible lesions with mass effect [6].

Repeat CT scans, demonstrating regression of the lesions,

are needed to monitor the response to treatment.

Fig. 1 Brain CT scan reveals a small multiloculated ring enhancing

lesion, in the left pulvinar, compatible with cryptococcal localisation

162 Intern Emerg Med (2013) 8:161–164

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Because peritonitis is a rare manifestation of crypto-

coccosis, no gold standard of antifungal chemotherapy is

available for treating these patients [7].

Discussion

Dr. Damanti, Dr. Spinelli Cryptococcus neoformans is an

ubiquitous encapsulated yeast that predominately causes

significant infections in immunocompromised individuals.

In addition to HIV, immunosuppressive drugs, chronic

organ failure (renal and liver), malignancies, chronic lung

disease and diabetes mellitus can also predispose to this

infection [8]. Patients with hepatic cirrhosis are susceptible

to infections, and are more likely to have septic shock at

presentation [9]. Acute mortality is high: case fatality rate

is up to 31 % on day 14, and as high as 37 % by day 30.

The majority of deaths (68 %) occur within 30 days after

blood culture. They have a particularly high 30-day mor-

tality (82 %) compared to patients with AIDS (21 %) or

patients receiving immunosuppressive therapy (33 %) [9],

because, specific treatment is often without benefit, even if

started within 48 h of positive blood cultures, due to an

advanced degree of hepatic insufficiency.

Cryptococcus is inhaled into the respiratory tract.

Depending on the immune response, the host may be

asymptomatic or have overwhelming infection [10, 11].

The primary infection is in the lung, then, Cryptococcus

can spread to distant sites. In patients with liver disease,

predisposing factors to dissemination are impaired phago-

cytic function, reduced complement levels, lower opsonin

activity, defects in chemotaxis, malnutrition, portal-sys-

temic shunt (that bypass Kuppfer cell scavenging), the need

for invasive procedures, (which predispose to direct inoc-

ulation), use of antibacterial agents (which favour fungus-

overgrowth), GI bleeding with translocation of pathogens

into the blood, and direct inoculation of the organism with

continuous paracentesis [7].

The clinical presentation of disseminated disease is

variable depending on the organ involved. The central

nervous system (CNS) is the most frequently involved site

because the CSF has low complement activity, and is a

favourable growth medium for Cryptococcus. Meningo-

encephalitis is predominant in HIV-positive patients, while

HIV-negative subjects generally present with CNS mass

lesions. Symptoms are usually subacute: headache and

fever; sometimes seizures, confusion, dementia and bizarre

behaviour. Cerebral edema is rare. It leads to elevated

intracranial pressure that can cause blurred vision, diplopia,

confusion, hearing loss and severe headache. Cryptococco-

mas usually present with focal signs [12]. In patients with

hepatic cirrhosis, symptoms of meningitis may be attributed

to hepatic encephalopathy. Peritoneal involvement by

C. neoformans is an uncommon indicator of dissemination

usually related to chronic liver disease. Clinical presentation

of spontaneous cryptococcal peritonitis may be similar to

that of spontaneous bacterial peritonitis, so it is often

misdiagnosed.

Conclusions

Prof. Cappellini The advanced liver failure, disseminated

fungal infection and delayed diagnosis may contribute to a

high mortality rates. The absence of characteristic local and

systemic signs and symptoms of cryptococcosis (mismatch

CNS involvement by C. neoformans with hepatic enceph-

alopathy [13]; fever as the only indicator of peritoneal

involvement), the lack of clinical awareness of this entity

in combination with a slow growth of the organism in

diagnostic cultures cause a delay in antifungal treatment,

and under-utilisation of specific diagnostic testing. All

these factors in association with the underlying advanced

liver dysfunction and systemic dissemination contributed

to the very poor outcome of our patient [14].

This case serves to remind the clinician that all cirrhotic

patients with fever of unknown origin should be investi-

gated for possible C. neoformans infection [15].

Conflict of interest None.

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