Host and fungal factors both contribute to cryptococcosis-associated hyperammonemia (cryptammonia).

Cryptococcus neoformans and Cryptococcus gattii are both known urease producers and have the potential to cause hyperammonemia. We hypothesized that the risk of hyperammonemia is increased by renal failure, burden of cryptococcal infection, and fungal strain characteristics. We performed a retrospective review of plasma ammonia levels in patients with cryptococcal infections. Risk factors for hyperammonemia were statistically compared between patients with and without hyperammonemia (>53 µmol/L). Cryptococcal cells from three patients included in the study were recovered from our biorepository. Strain characteristics including urease activity, ammonia production, growth curves, microscopy, melanin production, and M13 molecular typing were analyzed and compared with a wild-type (WT) C. neoformans strain. We included 29 patients, of whom 37.9% had hyperammonemia, 59% had disseminated cryptococcal infection (DCI), and 41% had isolated central nervous system infection. Thirty-eight percent of patients had renal failure and 28% had liver disease. Renal failure was associated with 4.4 times (95% confidence interval [CI] 1.5, 13.0) higher risk of hyperammonemia. This risk was higher in DCIs (RR 6.2, 95% CI 1.0, 40.2) versus isolated cryptococcal meningitis (RR 2.5, 95% CI, 0.40, 16.0). Liver disease and cryptococcal titers were not associated with hyperammonemia. C. neoformans from one patient with extreme hyperammonemia demonstrated a 4- to 5-fold increase in extracellular urease activity, slow growth, enlarged cell size phenotypes, and diminished virulence factors. Hyperammonemia was strongly associated with renal failure in individuals with DCI, surpassing associations with liver failure or cryptococcal titers. However, profound hyperammonemia in one patient was attributable to high levels of urease secretion unique to that cryptococcal strain. Prospective studies are crucial to exploring the significance of this association.IMPORTANCECryptococcus produces and secretes the urease enzyme to facilitate its colonization of the host. Urease breaks down urea into ammonia, overwhelming the liver's detoxification process and leading to hyperammonemia in some hosts. This underrecognized complication exacerbates organ dysfunction alongside the infection. Our study investigated this intricate relationship, uncovering a strong association between the development of hyperammonemia and renal failure in patients with cryptococcal infections, particularly those with disseminated infections. We also explore mechanisms underlying increased urease activity, specifically in strains associated with extreme hyperammonemia. Our discoveries provide a foundation for advancing research into cryptococcal metabolism and identifying therapeutic targets to enhance patient outcomes.

Contribution of Uremia to Ureaplasma-Induced Hyperammonemia.

Lung transplant recipients (LTRs) are vulnerable to hyperammonemia syndrome (HS) in the early postoperative period, a condition typically unresponsive to nonantibiotic interventions. HS in LTRs is strongly correlated with Ureaplasma infection of the respiratory tract, although it is not well understood what makes LTRs preferentially susceptible to HS compared to other immunocompromised hosts. Ureaplasma species harbor highly active ureases, and postoperative LTRs commonly experience uremia. We hypothesized that uremia could be a potentiating comorbidity, providing increased substrate for ureaplasmal ureases. Using a novel dialyzed flow system, the ammonia-producing capacities of four isolates of Ureaplasma parvum and six isolates of Ureaplasma urealyticum in media formulations relating to normal and uremic host conditions were tested. For all isolates, growth under simulated uremic conditions resulted in increased ammonia production over 24 h, despite similar endpoint bacterial quantities. Further, transcripts of ureC (from the ureaplasmal urease gene cluster) from U. urealyticum IDRL-10763 and ATCC-27816 rose at similar rates under uremic and nonuremic conditions, with similar endpoint populations under the two conditions (despite markedly increased ammonia concentrations under uremic conditions), indicating that the difference in ammonia production by these isolates is due to increased urease activity, not expression. Lastly, uremic mice infected with an Escherichia coli strain harboring a U. urealyticum serovar 8 gene cluster exhibited higher blood ammonia levels compared to nonuremic mice infected with the same strain. Taken together, these data show that U. urealyticum and U. parvum produce more ammonia under uremic conditions compared to nonuremic conditions. This implies that uremia is a plausible contributing factor to Ureaplasma-induced HS in LTRs. IMPORTANCE Ureaplasma-induced hyperammonemia syndrome is a deadly complication affecting around 4% of lung transplant recipients and, to a lesser extent, other solid organ transplant patients. Understanding the underlying mechanisms will inform patient management, potentially decreasing mortality and morbidity. Here, it is shown that uremia is a plausible contributing factor to the pathophysiology of the condition.

Prognosis of Patients with Sepsis and Non-Hepatic Hyperammonemia: A Cohort Study.

BACKGROUND Hyperammonemia has been reported in some critically ill patients with sepsis who do not have hepatic failure. A significant proportion of patients with non-hepatic hyperammonemia have underlying sepsis, but the association between non-hepatic hyperammonemia and prognosis is unclear. MATERIAL AND METHODS Information about patients with sepsis and non-hepatic hyperammonemia was retrieved from the Medical Information Mart for Intensive Care-III database. Survival rates were analyzed using the Kaplan-Meier method. Multivariate logistic regression models were employed to identify prognostic factors. Receiver operating characteristic (ROC) curve analysis was used to measure the predictive ability of ammonia in terms of patient mortality. RESULTS A total of 265 patients with sepsis were enrolled in this study. Compared with the non-hyperammonemia group, the patients with hyperammonemia had significantly higher rates of hospital (59.8% vs. 43.0%, P=0.007), 30-day (47.7% vs. 34.8%, P=0.036), 90-day (61.7% vs. 43.7%, P=0.004), and 1-year mortality (67.3% vs. 49.4%, P=0.004). In the survival analysis, hyperammonemia was associated with these outcomes. Serum ammonia level was an independent predictor of hospital mortality. The area under the ROC curve for the ammonia levels had poor discriminative capacity. The hyperammonemia group also had significantly lower Glasgow Coma Scale scores (P=0.020) and higher incidences of delirium (15.9% vs. 8.2%, P=0.034) and encephalopathy (37.4% vs. 19.6%, P=0.001). Intestinal infection and urinary tract infection with organisms such as Escherichia coli may be risk factors for hyperammonemia in patients who have sepsis. CONCLUSIONS Higher ammonia levels are associated with poorer prognosis in patients with sepsis. Ammonia also may be associated with sepsis-associated encephalopathy. Therefore, we recommend that serum ammonia levels be measured in patients who are suspected of having sepsis.

Hyperammonemia syndrome due to Ureaplasma infection after liver-kidney transplant.

Hyperammonemia syndrome, with high levels of ammonia and neurologic dysfunction, is a syndrome with historically high mortality that may occur after solid organ transplantation. Recently, this has been associated with infection due to Ureaplasma, mostly following lung transplantation. We describe the first case of hyperammonemia syndrome due to Ureaplasma infection after liver-kidney transplantation. Our patient rapidly recovered after specific antibiotic treatment. It is important to consider these infections in the differential diagnosis for encephalopathy post-transplant, as these organisms often do not grow using routine culture methods and polymerase chain reaction testing is typically required for their detection. This is particularly critical after liver transplantation, where a number of other etiologies may be considered as a cause of hyperammonemia syndrome.

[Reduced consciousness levels caused by hyperammonaemia]. / Bewustzijnsdaling door hyperammoniëmie.

Hyperammonaemia is an important cause of lethargy. In this article, we describe a lesser-known but potential fatal cause of hyperammonaemia. A 27-year-old woman presented with lethargy caused by hyperammonaemia. She was treated with the emergency regime that is used to treat hyperammonaemia in urea cycle defects. Although this effectively lowered the ammonia levels, the clinical situation of the patient initially deteriorated and she was transferred to the Intensive Care Unit and intubated. Urine culture identified Proteus mirabilis, a urea-splitting bacterium that caused the hyperammonaemia. Prompt and adequate treatment with antibiotics and adequate drainage of urine was started and she completely recovered. Although every patient can get hyperammonaemia caused by urinary tract infection with urea-splitting bacteria, patients with structural bladder abnormalities are at greater risk. Lethargy can be the only presenting symptom. When recognized early, it is quite treatable and has a good prognosis.

'All that glitters is not gold': when hyperammonaemia is not from hepatic aetiology.

Hyperammonaemia is often caused by decompensated liver disease. However, non-hepatic causes can sometimes result in hyperammonaemia, severe enough to cause symptoms.We report a case of a 65-year-old man with a history of hypertension and bilateral peripelvic renal cyst who presented with acute confusion. Laboratory investigations revealed hyperammonaemia and normal liver function test. The abdominal ultrasound did not reveal any finding of liver disease or portal-systemic shunting but demonstrated bilateral peripelvic cysts with no hydronephrosis.Hyperammonaemia was attributed to urinary tract infection with a urea-splitting Escherichia coli bacterium.Antibiotic therapy and lactulose were administered. His neurological status rapidly normalised over the next 48 hours, concomitantly with a decrease in ammonia level. Clinician awareness of non-hepatic causes of hyperammonaemic encephalopathy like urinary tract infection can contribute to early diagnosis and timely initiation of appropriate and potentially life-saving treatment including antimicrobial therapy, alleviating urinary obstruction, if present, and lactulose.

Microbiome alterations observed in liver diseases present opportunities for potential fecal transplantation.

Many disease processes lead to chronic liver disease, however, progress has been made regarding common findings amongst these disease processes that may suggest a path forward for treatment. In particular, common alterations in the intestinal microflora of patients with different etiologies of liver disease may provide a clue as to the pathogenesis of these disorders as well a potential therapy. Data is still scant at this point, however, what is available suggests a promising opportunity for future studies to expand upon what has been demonstrated.

Engineering the gut microbiota to treat hyperammonemia.

Increasing evidence indicates that the gut microbiota can be altered to ameliorate or prevent disease states, and engineering the gut microbiota to therapeutically modulate host metabolism is an emerging goal of microbiome research. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia-associated neurotoxicity and encephalopathy in patients with liver disease. Here, we engineered murine gut microbiota to reduce urease activity. Animals were depleted of their preexisting gut microbiota and then inoculated with altered Schaedler flora (ASF), a defined consortium of 8 bacteria with minimal urease gene content. This protocol resulted in establishment of a persistent new community that promoted a long-term reduction in fecal urease activity and ammonia production. Moreover, in a murine model of hepatic injury, ASF transplantation was associated with decreased morbidity and mortality. These results provide proof of concept that inoculation of a prepared host with a defined gut microbiota can lead to durable metabolic changes with therapeutic utility.

Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans.

Hyperammonemia syndrome is a fatal complication affecting immunosuppressed patients. Frequently refractory to treatment, it is characterized by progressive elevations in serum ammonia of unknown etiology, ultimately leading to cerebral edema and death. In mammals, ammonia produced during amino acid metabolism is primarily cleared through the hepatic production of urea, which is eliminated in the kidney. Ureaplasma species, commensals of the urogenital tract, are Mollicutes dependent on urea hydrolysis to ammonia and carbon dioxide for energy production. We hypothesized that systemic infection with Ureaplasma species might pose a unique challenge to human ammonia metabolism by liberating free ammonia resulting in the hyperammonemia syndrome. We used polymerase chain reaction, specialized culture, and molecular resistance profiling to identify systemic Ureaplasma infection in lung transplant recipients with hyperammonemia syndrome, but did not detect it in any lung transplant recipients with normal ammonia concentrations. Administration of Ureaplasma-directed antimicrobials to patients with hyperammonemia syndrome resulted in biochemical and clinical resolution of the disorder. Relapse in one patient was accompanied by recurrent Ureaplasma bacteremia with antimicrobial resistance. Our results provide evidence supporting a causal relationship between Ureaplasma infection and hyperammonemia, suggesting a need to test for this organism and provide empiric antimicrobial treatment while awaiting microbiological confirmation.

Recurring hyperammonemic encephalopathy induced by bacteria usually not producing urease.

BACKGROUND: Hyperammonemic encephalopathy may occur when urease-positive bacteria in the urinary tract produce ammonium which directly enters systemic circulation. Predisposing conditions such as a neurogenic bladder can increase both urinary tract infection and urine stagnation. CASE PRESENTATION: We describe the case of a 66 years old woman with a neurogenic bladder who twice developed hyperammonemic encephalopathy following urinary tract infection. During the second episode Escherichia coli and Enterococcus faecalis have been isolated in the urine. The neurologic examination showed psychomotor slowing, weak photomotor reflex, nystagmus in the lateral gaze and asterixis. The EEG showed triphasic waves which disappeared along with clinical recovery. CONCLUSION: Escherichia coli and Enterococcus faecalis are commonly considered urease-negative bacteria. Although frequently involved in urinary tract infections, their role in causing hyperammonemic encephalopathy have not been previously reported. Moreover, despite only one case with a neurogenic bladder have been described so far, our is the first patient with reoccurring hyperammonemic encephalopathy secondary to urinary tract infections.

[Helicobacter pylori infection and liver diseases].

Recently, it has been shown that Helicobacter infections are associated not only with upper gastrointestinal tract diseases but also with extra-gastrointestinal diseases such as cardiovascular, liver or biliary diseases. The contributions of H. pylori to the development of hepatic encephalopathy and hyperammonemia were reported. Some studies demonstrated the effectiveness of H. pylori eradication therapy in hepatic encephalopathy, but these results have not been supported by other reports. H. pylori eradication therapy for the treatment of hyperammonemia and hepatic encephalopathy has not been recommended. The role of H. pylori infection in cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) is uncertain. Furthermore, the question of whether H. pylori could play a role in the development of hepatoma remains controversial. Our study demonstrated that H. pylori infection was one of the independent risk factors for the development of nonalcoholic fatty liver disease (NAFLD). Further investigation is warranted.

Urea-splitting urinary tract infection contributing to hyperammonemic encephalopathy.

BACKGROUND: We present a case of severe neurological symptoms caused by hyperammonemia, secondary to a urinary tract infection with urea-splitting bacteria. INVESTIGATIONS: Blood analysis, urinalysis, urine culture, abdominal ultrasonography, cystography, CT. DIAGNOSIS: Hyperammonemia as a result of urinary tract infection with urea-spliting bacteria. MANAGEMENT: Desobstruction of the urinary tract and bladder or pouch rinsing, antibiotics, reduction of the dietary and endogenous nitrogen load, and endogenous nitrogen breakdown. Identification, prevention and treatment of underlying causes.

Hyperammonemia in generalized Mycobacterium genavense infection after renal transplantation.

After solid organ transplantation, patients are susceptible to infection caused by uncommon pathogens due the immunosuppressive drug therapy. Here, we report the first case of disseminated Mycobacterium genavense infection in a HIV seronegative renal transplant patient. The most striking clinical feature was a decreased consciousness. Blood results revealed hyperammonemia with otherwise normal liver function. Occurrence of hyperammonemia and massive M. genavense infection has not been reported before.

[The effects of Helicobacter pylori infection on hyperammonaemia and hepatic encephalopathy in cirrhotic patients].

OBJECTIVE: To evaluate the relationship among Helicobacter pylori (Hp)infection, blood ammonia concentrations, and hepatic encephalopathy (HE) status, and to investigate the effect of Hp eradication on blood ammonia levels and hepatic encephalopathy status in cirrhotic patients. METHODS: From July 2003 to Jan 2005, cirrhotic patients in 5 regions of Zhejiang Province were enrolled. Patients were evaluated for the demographic checklists, number connection test, Hp infection, liver impairment level, blood ammonia concentrations and hepatic encephalopathy status. Patients with Hp infection were given one week therapy with omeprazole plus clarithromycin and tinidazole. (14)C urea breath test was performed and the mental symptoms and blood ammonia levels were reassessed after the eradication therapy. RESULTS: (1) 457 cirrhotics were enrolled, the overall Hp infection rate was 60.6%, and HE happened with 47.5%. Subclinical hepatic encephalopathy (SHE) were detected 55 in 47.0% of 117 cirrhotics. (2) Blood ammonia concentration in Hp (-) and Hp (+) cirrhotics was (53.8 +/- 51.4) micromol/L and (78.4 +/- 63.6) micromol/L respectively (P < 0.01), which was significantly reduced to (53.5 +/- 37.7) micromol/L after Hp eradication (P < 0.01). HE was more frequently observed in patients with Hp infection than without it (58.5% vs 30.6%, P < 0.01). HE rate were significantly dropped to 34.1% after Hp eradication (P < 0.01). (3) Hp prevalence significantly differed among cirrhotic with HE (74.4%), those with SHE (69.1%), or without HE (53.2%) (P < 0.05). The level of blood ammonia had significant difference among the cirrhotics with HE (94.5 +/- 75.6) micromol/L, those with SHE (59.9 +/- 49.2) micromol/L, or without HE (47.3 +/- 33.5) micromol/L (P < 0.05). CONCLUSIONS: Hp infection was an important factor of inducing with high blood ammonia concentration and hepatic encephalopathy in cirrhotic patients. Hp eradication may be helpful for treatment and prevention of HE.

Hepatic encephalopathy and Helicobacter pylori: a critical reappraisal.

Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis, and plasma ammonia plays a pivotal role in its pathogenesis. Ammonia disposal in cirrhotics depend on intricately balanced enzyme and transport systems, involving liver, large and small bowel, muscle, and kidney. Recently, it has been suggested that Helicobacter pylori could contribute to hyperammonemia in cirrhotics, but conflicting data are available in the literature. This is a systematic review of experimental (animals and humans), epidemiological, case-control, and prospective studies, to evaluate the arguments in favor and against the role of H. pylori in HE pathogenesis. Although H. pylori produces ammonia in the stomach, several studies have shown that both basal ammonia levels and HE prevalence did not significantly differ between cirrhotics with and without infection. Moreover, some prospective studies have documented that both blood ammonia levels and mental status in HE cirrhotics are not significantly affected by H. pylori eradication. Even if a small sub-group of cirrhotics with both a high bacterial density and more severe hepatic impairment seems to benefit by bacterial eradication, data indicate that ammonia production in the stomach by H. pylori urease appears to be inadequate to clinically affect ammonia disposal in the majority of cirrhotic patients. Further studies are warranted in this field.