α-Ketoglutaramate: an overlooked metabolite of glutamine and a biomarker for hepatic encephalopathy and inborn errors of the urea cycle.

Glutamine metabolism is generally regarded as proceeding via glutaminase-catalyzed hydrolysis to glutamate and ammonia, followed by conversion of glutamate to α-ketoglutarate catalyzed by glutamate dehydrogenase or by a glutamate-linked aminotransferase (transaminase). However, another pathway exists for the conversion of glutamine to α-ketoglutarate that is often overlooked, but is widely distributed in nature. This pathway, referred to as the glutaminase II pathway, consists of a glutamine transaminase coupled to ω-amidase. Transamination of glutamine results in formation of the corresponding α-keto acid, namely, α-ketoglutaramate (KGM). KGM is hydrolyzed by ω-amidase to α-ketoglutarate and ammonia. The net glutaminase II reaction is: L - Glutamine + α - keto acid + H2O → α - ketoglutarate + L - amino acid + ammonia. In this mini-review the biochemical importance of the glutaminase II pathway is summarized, with emphasis on the key component KGM. Forty years ago it was noted that the concentration of KGM is increased in the cerebrospinal fluid (CSF) of patients with hepatic encephalopathy (HE) and that the level of KGM in the CSF correlates well with the degree of encephalopathy. In more recent work, we have shown that KGM is markedly elevated in the urine of patients with inborn errors of the urea cycle. It is suggested that KGM may be a useful biomarker for many hyperammonemic diseases including hepatic encephalopathy, inborn errors of the urea cycle, citrin deficiency and lysinuric protein intolerance.

Non-traumatic pseudocyst of Glisson capsule complicating a ventriculoperitoneal shunt.

BACKGROUND: Cerebrospinal fluid pseudocysts in the peritoneal cavity following ventriculoperitoneal shunt are relatively uncommon. In these complications, perforation of solid organs is unusual. CASE DESCRIPTION: A case of subcapsular hepatic pseudocyst is described. A 48-year-old man treated by ventriculoperitoneal shunt presented with abdominal pain. Laboratory examinations revealed hepatic cytolysis. The CT-scan of the abdomen demonstrated a small ovoid non-enhanced cystic collection in the subcapsular area of hepatic segment V. Percutaneous hepatic fine-needle aspiration of the cyst guided by abdominal ultrasonography showed no abnormal findings. Peritoneal reimplantation at a different site was performed. The clinicopathological features of this entity are described and treatments are discussed. CONCLUSION: Reinsertion of the catheter at a different abdominal site is effective in non-infections cases. In contrast, a temporary external drainage with adequate antibiotic treatment followed by shunt reinsertion is necessary to treat a documented infection of CSF collections.

CSF liver pseudocyst as a complication of a ventriculoperitoneal shunt.

We have a 30-year-old female patient suffering from secondary hydrocephalus. She has had a ventriculoperitoneal shunt (VPS) implanted following a rupture and a successful clipping of the aneurysm of the anterior communicating artery (ACoA). Three weeks after implanting of the VPS, respiratory and abdominal difficulties with febrility appeared. We diagnosed cerebrospinal fluid liver pseudocyst using ultrasound (US) and computer tomography scan (CT). Given that we found bacteria in the cerebrospinal fluid (CSF), we converted VPS into an external ventricular drain (EVD). After that, we conducted a US-guided punction and drainage of the CSF liver pseudocyst. The subsequent CT of abdomen showed a regression of the cystic form. The patient died following the septic condition with multiple organ failures (MOF) a month after the cerebrospinal fluid liver pseudocyst diagnosis.The perforation of parenhimatose abdominal organs with distal part of VPS is a rare complication which is most likely a consequence of a shunt infection and of an immunological reaction that took place during the process of localizing an infection.

High resolution proton nuclear magnetic resonance studies of human cerebrospinal fluid.

One- and two-dimensional (correlated shift spectroscopy) high resolution proton n.m.r. spectra of human cerebrospinal fluid (CSF) are reported. The merits of water suppression by freeze drying or irradiation, and spectral simplification by spin-echo methods, are discussed. Well-resolved resonances for a range of low molecular weight metabolites such as lactate, 3-D-hydroxybutyrate, alanine, acetate, citrate, glucose, valine and formate were observed. Resonances for glutamine were observed only from freeze dried samples. Concentrations determined by n.m.r. were in reasonable agreement with those from conventional methods. The n.m.r. spectra of CSF were related to the clinical conditions of the subjects. No resonances for citrate were present in spectra of CSF from subjects (three infants) with bacterial meningitis; high lactate and lowered glucose levels were observed. Strong resonances for glucose and glycine were observed for mildly diabetic subjects. Both the aromatic and the aliphatic regions of the CSF spectra from subjects suffering from liver failure contained distinctive features characteristic for hepatic coma: Intense resonances for lactate, alanine, valine, methionine, tyrosine, phenylalanine and histidine. In some cases guanine was also present, which does not appear to have been reported previously. The two-dimensional spectrum suggested the presence of abnormally high levels of a number of endogenous metabolites. Such assignments were not possible using one-dimensional spectra alone because of signal overlap.

[Cyclic adenosine monophosphate in the cerebrospinal fluid of patients with liver disease (author's transl)]. / Adenosín monofosfórico cíclico en líquido cefalorraquídeo de enfermos hepáticos.

The concentration of adenosine 3':5'-cyclic monophosphate in the spinal fluid of ten patients with liver dysfunction was analyzed. Ages of the patients ranged from 31 to 75 years. The state of consciousness varied between normality and stupor. After a liver biopsy the diagnoses were as follows: cirrhosis in six cases, porphyria cutanea tarda in one case, hepatic metastases in two cases and Wilson's disease in one case. Mean values in these patients (22.91 +/- 4.18 pM/ml) have been significantly greater (p less than 0.0005) than those in ten control individuals (15.55n control individuals (15.44 +/- 3.66 pM/ml). Values corresponding to two patients in coma were still higher (52.62 and 36.50 pM/ml respectively). A previous lumbar puncture carried out in one of these patients when he was conscious showed a figure of 23 pM/ml. These results suggest a progressive rise of cyclic adenosine monophosphate in the spinal fluid in relation to clinical impairment, and may indicate a similar behaviour for this nucleotide to that of tryptophan, as reported by other authors. These findings point toward the role of the alteration of neurotransmitters in the pathogenesis of hepatic coma.

Total devascularization of the Liver: an experimental model of acute liver failure.

An experimental model of clinical liver failure, using total devascularization of the liver is described in the pit. The survival time was 1495 +/- 75 (SEM) minutes. Clinically the pigs showed a uniform course. They became lethargic after eight to ten hours and following a period of increasing drowsiness they became comatose. The immediate cause of death was cardio-vasculary collaps. The ammonium ion concentration in the blood increased to 696 +/- 57 umol/l and in cerebrospinal fluid to 664 +/- 57 umol/l. Cerebrospinal fluid glucose concentration was significantly decreased.

Total and partial anoxia of the liver. An attempt to create protracted liver failure in the pit.

In an attempt to produce severe, but non-lethal experimental liver failure, pig livers were exposed to partial or total anoxia for various periods. The experiments were divided into 5 groups. Group I with total anoxia for 30 minutes, group II for 50 minutes, group III for 60 minutes, and group IV for 75 minutes. In group V a subtotal devascularization was performed. In group I (3 animals) and II (3 animals) all survived the period of observation (one week). In group III (4 animals) half of the animals, and in group IV (3 animals) all died within 24 hours. In group V (10 animals) five of 10 animals died with a mean survival time of 22 hours and a half. The animals surviving the period observation did show changes in the routine liver tests, but none of them showed clinical signs of liver insufficiency. This indicates that the differences between lethal and clinically insignificant liver damage is very small. It is concluded that the pig lever can tolerate 50 minutes of total anoxia and recover almost completely after one week, and that a period of anoxia or subtotal devascularization does not create protacted liver failure.

Alpha-ketoglutaramate: increased concentrations in the cerebrospinal fluid of patients in hepatic coma.

alpha-Ketoglutaramate, a deaminated metabolite of glutamine not previously identified in biological tissues, was measured in the cerebrospinal fluid of human subjects and found to be increased three- to tenfold in patients with hepatic coma. When perfused into the cerebral lateral ventricles of rats, alpha-ketoglutaramate (10 mM) depressed the animals' nocturnal locomotor activity, and at higher doses induced circling behavior and myoclonus. The concentration of alpha-ketoglutaramate in cerebrospinal fluid appears to be a reliable diagnostic indicator of hepatic coma, and its accumulation may contribute to the pathogenesis of this disease.