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Keywords:

  • encephalopathy;
  • hyperammonaemia;
  • noncirrhotic;
  • urea-cycle defects

Abstract

  1. Top of page
  2. Abstract
  3. Literature search
  4. Pathophysiology of noncirrhotic hyperammonaemic encephalopathy
  5. Aetiology and underlying mechanisms of noncirrhotic hyperammonaemic encephalopathy ()
  6. Management of hyperammonaemia
  7. Acknowledgements
  8. References

Adult hyperammonaemia is associated with severe liver disease in 90% of cases. In the remainder, noncirrhotic causes should be considered. Measurements of serum ammonia level must be part of the basic work-up in all patients presenting with encephalopathy of unknown origin, even when liver function is normal. Clinician awareness of noncirrhotic hyperammonaemic encephalopathy can contribute to early diagnosis and the initiation of sometimes life-saving treatment. This review focuses on the physiology, aetiology and underlying mechanisms of noncirrhotic hyperammonaemic encephalopathy and discusses the available treatment modalities.

Abbreviations
ASS,

arginosuccinate synthetase;

CEPS,

congenital extrahepatic portosystemic shunt;

CIPS,

congenital intrahepatic portosystemic shunt;

CPS,

carbamyl phosphate synthetase;

5-FU,

5- fluouracil;

IEM,

inborn error of metabolism;

IVC,

inferior vena cava;

NCHE,

noncirrhotic hyperammonaemic encephalopathy;

OTC,

ornithine transcarbamylase;

UTI,

urinary tract infection

Hyperammonaemia usually occurs as a consequence of severe liver disease. Hepatic encephalopathy develops in 50–70% of patients with cirrhosis, and its occurrence is a poor prognostic marker (1). In the minority of hyperammonaemic patients without severe liver disease, other unusual noncirrhotic causes should be considered, such as an occult late-onset inborn error of metabolism (IEM) and intake of certain drugs.

All patients who present with encephalopathy of unknown origin should undergo measurements of serum ammonia (NH3) as part of the basic work-up, even when liver function is normal. Early symptoms of noncirrhotic hyperammonaemic encephalopathy (NCHE) include confusion or neurological manifestations such as seizures, which may be followed by life-threatening cerebral oedema and herniation. Early recognition is important (2) because effective treatment can normalize the plasma NH3 level and lead to full recovery. This reviews focuses on the pathophysiology, aetiology and underlying mechanisms of NCHE and discusses the available treatment modalities.

Literature search

  1. Top of page
  2. Abstract
  3. Literature search
  4. Pathophysiology of noncirrhotic hyperammonaemic encephalopathy
  5. Aetiology and underlying mechanisms of noncirrhotic hyperammonaemic encephalopathy ()
  6. Management of hyperammonaemia
  7. Acknowledgements
  8. References

A MEDLINE search (1966–2010) was conducted containing the key words ‘hyperammonemia’ and ‘non-hepatic’ and ‘portosystemic shunt’ separately, with fields limited to human and English. Articles included reviews, original papers and case reports. A total of 4476 citations were reviewed for relevance to the aims of the present study.

Pathophysiology of noncirrhotic hyperammonaemic encephalopathy

  1. Top of page
  2. Abstract
  3. Literature search
  4. Pathophysiology of noncirrhotic hyperammonaemic encephalopathy
  5. Aetiology and underlying mechanisms of noncirrhotic hyperammonaemic encephalopathy ()
  6. Management of hyperammonaemia
  7. Acknowledgements
  8. References

Ammonia is toxic to cells in elevated levels and therefore must be converted to nontoxic compounds. In healthy individuals, the main route for detoxification of NH3 is the synthesis of urea in the liver via urea-cycle enzymes. A second alternative pathway, which becomes important in conditions of decreased urea synthesis in the liver or hepatic shunting, is synthesis of glutamine from NH3 and glutamate via glutamine synthetase (3). In stable, nonfed individuals, most of the NH3 in the blood comes from the intestine, where urease-producing colonic bacteria break down protein degradation-derived urea into NH3 and carbon dioxide. Another contribution of NH3, predominantly in the post-absorptive state, comes from the intestines, which utilizes glutamine as an energy source and converts it to NH3 and glutamate via the enzyme glutaminase (4, 5). In addition, the kidney becomes the predominant organ responsible for hyperammonaemia in the post-absorptive state. Glutamine is the main substrate for renal ammoniagenesis and, in normal conditions, renal NH3 metabolism is in a steady state. However, acute changes in the acid–base balance alter the renal metabolism of NH3 and can lead to a net increase in urinary NH3 excretion (acidosis) or in renal ammoniagenesis (alkalosis) (4). To prevent toxicity in healthy individuals, the NH3 in portal blood is taken up by periportal hepatocytes, metabolized to urea via the urea cycle and excreted through the kidneys. Any NH3 escaping detoxification is usually trapped by perivenous hepatocytes, where it is converted to glutamine via glutamine synthetase (5). NCHE may therefore result when NH3 production exceeds the metabolic capacity of the liver, the liver cannot handle the normal nitrogen load (as in IEMs) or the nitrogen load bypasses the liver, entering directly into the systemic circulation.

In the early stages of liver failure, increased glutamine production in renal tubular cells is responsible for renal NH3 adaptation, but with advancing stages and worsening hyperammonaemia, this capacity is overwhelmed and there is a net renal NH3 production. Other organs are then forced to further metabolize the NH3.

The muscle is a net NH3 consumer and can take up NH3 from the blood and detoxify it by glutamine synthesis. In skeletal muscle, glutamine synthetase activity is low, by virtue of the high mass, but its contribution to NH3 detoxification in hyperammonaemic states is important (4, 5).

The brain also uses glutamine synthesis for metabolizing NH3. Glutamine synthetase in the brain is mainly localized to astrocytes (80%), and the glutamine that is forming is transferred to neurons. Glutamate, an important excitatory neurotransmitter, is formed by deamination of glutamine in the presynaptic terminals. When it accumulates, it is taken up by the astrocytes and recycled back to glutamine, the ‘storage centre’ for free NH3 (6, 7), Thus, a homeostatic balance in the brain among NH3, glutamine and glutamate is crucial.

Exposure of astrocytes to high levels of ammonia results in both cell swelling (acute exposure) and Alzheimer Type II astrocytosis (chronic exposure). These findings are consistent with the notion of a major pathophysiological role for NH3 in hepatic encephalopathy (8). In cirrhosis, hyperammonaemia has a more gradual course, which may have a protective effect against intracranial hypertension because of compensatory cellular processes to decrease osmolarity. Other toxins normally removed by the liver or produced by dying hepatocytes in liver injury may also be implicated in the pathogenesis of hepatic encephalopathy: Manganese and pro-inflammatory cytokines may act synergistically with NH3 to activate mitochondrial benzodiazepine receptors, leading to increased production of neuroactive steroids. Some neuroactive steriods (allopregnanolone and tetrahydrodeoxycorticosterone) have potent neuroinhibitory properties resulting from the activation of a neuromodulatory site on the γ-aminobutyric acid (GABA) – receptor (increased GABAergical tone) in the cerebral cortex (8). New evidence suggests that pro-inflammatory cytokines, such as tumour necrosis factor-α and the interleukins (IL)-1b and IL-6, are produced not only by the liver but also by the brain in liver failure (9). NH3 and pro-inflammatory cytokines generated either by intercurrent infection or from hepatocyte necrosis in liver failure act synergistically to decrease the capacity of astrocytes to remove glutamate from the brain extracellular space. This leads to alterations in metabolism, affecting the regulatory activities of important enzymes.

Aetiology and underlying mechanisms of noncirrhotic hyperammonaemic encephalopathy (Table 1)

  1. Top of page
  2. Abstract
  3. Literature search
  4. Pathophysiology of noncirrhotic hyperammonaemic encephalopathy
  5. Aetiology and underlying mechanisms of noncirrhotic hyperammonaemic encephalopathy ()
  6. Management of hyperammonaemia
  7. Acknowledgements
  8. References
Table 1.  Aetiology of noncirrhotic hyperammonaemia
Increased ammonia production
1. Infections by urea-producing bacteria: Proteus mirablis, Klebsiella species, Escherichia coli, Morganella morganii, Providencia rettgeri, diphtheroids, Mycobacterium genavense, herpes simplex
2. Haemato-oncological disorders: multiple myeloma, chemotherapy for acute leukaemia, bone marrow transplantation, 5-fluouracil
3. Organ transplantation
4. Protein load and increased catabolism: severe exercise, seizures, starvation or trauma, total parenteral nutrition, gastrointestinal bleeding, steroid use
Decreased ammonia elimination
1. Urererosigmoidostomy
2. Portosystemic shunts; congenital intrahepatic and extrahepatic
3. Drug-induced: valproic acid, glycine, carbamazepine, ribavirin, sulphadiazine with pyrimethamine, salicylate
4. Inborn errors of metabolism: urea-cycle disorders, defects in β-oxidation of fatty acids, organic acidaemias, disorder of pyruvate metabolism

Increased ammonia production

Infection

Noncirrhotic hyperammonaemic encephalopathy can be caused by urease-producing bacteria under conditions of significant urinary stasis. Infection of the urine with these organisms causes the production of NH3 and alkalinizes the urine. At a physiological pH of 7.4, NH3 accounts for about 5–10% of the total NH3 and ammonium ions (NH4+), but this increases to 50% in an alkaline environment (10). As NH3 is electrically neutral and lipid-soluble, it can readily cross cell membranes and diffuse into the urothelial cells, where the lower pH converts it to the less permeable ammonium ion, preventing its diffusion back into the urine. The venous drainage of the bladder flows directly into the systemic circulation; hence, the NH3 bypasses the liver and is not detoxified to urea (10–14).

Most of the reported cases of infection-induced NCHE have occurred in children with congenital urinary tract abnormalities, such as prune-belly syndrome (multiple genital-urinary tract abnormalities and bilateral cryptorchidism) (11–13, 15–18), obstructive uterocele (14), or neuropathic bladder (10), which cause urinary tract dilatation, urinary stasis and a tendency towards recurrent infections. The few reported patients with hepatic encephalopathy because of urinary tract infections (UTIs) were adults with a neuropathic bladder (19). Some cases of encephalopathy were described in adults with UTIs and no recognized urinary tract anomalies (20–23). The main pathogen reported in UTI-related hyperammonaemia was Proteus mirabilis (11, 12, 14, 16, 18, 20), although other urea-splitting organisms have been implicated as well, including Klebsiella species (10, 20), Escherichia coli (12), Morganella morganii (23), Providencia rettgeri (13) and diphtheroids (17, 19). Recently, hyperammonaemia because of infection with Mycobacterium genavense, a nontuberculous mycobacterium, was described in a renal transplant recipient with lymphopenia (24). M. genavense has the ability to produce urease (25). The treatment of the UTI with antibiotics and bladder drainage successfully reduced the blood NH3 level, with prompt clinical improvement and resolution of the mental status.

Herpes simplex virus infection can also increase NH3 production in neonates, either by severe hepatitis or by hypoxia-induced protein breakdown in the setting of herpes pneumonitis (26, 27).

Haemato-oncological disorders and organ transplantation

Noncirrhotic hyperammonaemic encephalopathy in the absence of documented liver dysfunction may be a rare cause of altered sensorium in patients with progressive multiple myeloma (28–31). Talamo et al. (32) found hyperammonaemia in 3.8% of 208 patients with multiple myeloma and altered mental status but no evidence of liver dysfunction. A recent study of 27 patients with multiple myeloma and NCHE showed that most had immunoglobin-A type, aggressive or chemotherapy-resistant disease; the overall mortality rate was 44% (33). The development of hepatic encephalopathy was associated with the appearance of peripheral blood myeloma cells (34). The pathophysiology of hyperammonaemia in multiple myeloma is largely unknown. However, in vitro studies have demonstrated that more than other haematological malignant cells, myeloma cells in culture can produce excess NH3 as a result of amino acid metabolism (35). The fact that hyperammonaemia usually occurs in advanced forms of multiple myeloma suggests a direct link between malignant plasma cells and NH3 level, supporting the role of NH3 in altered sensorium in this setting. Other proposed mechanisms include the formation of a systemic-portal shunt because of plasma cell infiltration of the liver (35), the interference of plasma cells with urea metabolism and excess NH3 production that accompanies the excess protein synthesis in myeloma cells (31). Effective multiple myeloma treatment can rapidly reduce the serum NH3 level with normalization of the mental status. Escalating doses of cytotoxic agents or second-line chemotherapy might be necessary for resistant disease (28–33).

An ‘idiopathic hyperammonaemia’ complicating intensive chemotherapy has been described in patients with leukaemia. This variant is characterized by a plasma NH3 level more than twice the upper limit of normal, normal liver function tests and absence of IEMs. It frequently results in intractable coma and death. The incidence in patients undergoing chemotherapy for acute leukaemia is poorly defined because of a lack of prospective studies; however, in a large retrospective case series, the rate was 2.4% (36). The interval between the development of NCHE and the commencement of therapy ranged from a few hours to several days. Most of the patients died within 1 week after the onset of the syndrome, despite specific drug therapy and haemodialysis (36).

Idiopathic hyperammonaemia has also been infrequently described in patients following bone marrow transplantation for haematological malignancies (37–39). Davies et al. (37) conducted a large database study of 3358 patients with haematological malignancies treated by bone marrow transplantation. They identified 12 patients (0.5%) with idiopathic hyperammonaemia, of whom 10 died within a median of 3.5 days after diagnosis despite dialysis and NH3-trapping therapy. Several reports described idiopathic hyperammonaemia in heart–lung and lung transplant recipients, in whom it was apparently associated with increased post-transplant mortality (40–42), and in a child after cord blood transplantation for mucopolysaccharidosis (43).

The pathogenesis of idiopathic hyperammonaemia remains poorly understood. Some authors suggest that it may be multifactorial, involving a combination of sepsis, mucositis, gastrointestinal bleeding, protein catabolism and parenteral nutrition (44). Transient abnormalities in urea synthesis, such as an acquired reduction in hepatic glutamine synthetase activity, may also play a role (45). Alternatively, the development of the syndrome in the haemato-oncological setting may have a pharmacological basis. In patients with acute lymphocytic leukaemia, asparginase, in addition to other cytotoxic drugs, has been reported to cause hyperammonaemia by hydrolysing the amino group of aspargine and via its glutaminase activity (46); cytarabine undergoes deamination in the liver and peripheral tissues, thereby increasing NH3 production (45).

Hyperammonaemia induced by 5-fluouracil (5-FU) is a distinct entity that differs clinically and pathogenetically from idiopathic hyperammonaemia (47–49). Most cases are transient and nonfatal. Yeh and Cheng (49) reported a 5.7% incidence of hyperammonaemia in cancer patients treated with a continuous infusion of 5-FU; the median time from the initiation of treatment to the onset of encephalopathy was 19.5 h. The pathogenesis may be related to NH3 being a product of 5-FU metabolism, and possibly, to the direct inhibition of the Krebs cycle (46).

Protein load and increased catabolism

Processes that increase muscle catabolism, such as seizures, starvation or trauma (50–52), can lead to hyperammonaemia, but they induce NCHE only in patients with underlying metabolic urea-cycle disorders (11, 52–55), in whom the liver cannot handle the increased nitrogen load.

Total parenteral nutrition (TPN), which often provides more protein than the patient usually consumes enterally, has been reported to cause hyperammonaemia in three clinical settings: in infants, because of hepatic immaturity (56); in adults given TPN containing only essential amino acids (57) in whom the absence of ornithine may impair NH3 detoxification; and in susceptible patients with long-term asymptomatic urea-cycle disorders in whom TPN induces a first episode of NCHE (58, 59).

Decreased ammonia elimination

Ureterosigmoidostomy

The exact incidence of NCHE in patients after ureterosigmoidostomy is probably very low (60). In a study by Koo et al. (61), of 27 patients with bladder extrophy who underwent utererosigmoidostomy, two acquired hyperammonaemia and acidosis. NCHE has been described more commonly in patients undergoing ureterosigmoidostomy associated with acute and chronic liver failure (62–64).

There are several mechanisms underlying the development of NCHE in this setting (51, 65). Following ureterosigmoidostomy, the urine is excreted directly into the sigmoid colon, where NH3 is formed through bacterial degradation of the large quantities of nitrogenous compounds in the urine. Even in patients with normal liver function, NCHE may still occur owing to the increased production of NH3 sufficient to over-saturate hepatic excretory pathways or increased NH3 production and release into the systemic circulation by the kidneys (66). This may occur in the presence of delayed colonic transit (coprostasis), which is associated with a prolonged time of contact of the nitrogenous compounds with the bowel mucosa (67), or after the action of urea-splitting bacteria in the colon (68). The alkalinic pH of the colon and rectum is expected to sustain a high luminal ratio of NH3/NH4+, further aggravating the situation (65). Post-ureterosigmoidostomy NCHE might also be attributable to NH3 absorption in the colon through haemorrhoidal veins connected to the internal iliac veins and the systemic circulation, bypassing the portal circulation (65).

Portosystemic shunts

Portosystemic venous shunts because of portal hypertension in cirrhotic patients can lead to hyperammonaemia and hepatic encephalopathy. Noncirrhotic congenital portosystemic shunts, extrahepatic or intrahepatic, may also be responsible. They are very rare in the USA, and may be more common in Japan (69).

Congenital extrahepatic portosystemic shunts (CEPSs) may be either end to side, terminating in the inferior vena cava (IVC) because the portal vein is absent (previously designated type 1 shunts), or side to side, involving a venous communication between a patent portal vein and the IVC (type 2 shunts) (70). All congenital portacaval shunts are wholly or predominantly extrahepatic. Other CEPSs include variations of type 1 in which the portal vein is absent and either the splenic or the superior mesenteric vein communicates directly with a systemic vein, or the abnormal portal vein formed from the union of these two veins drains into a systemic vein other than the IVC. Patients with a type 1 or a type 2 shunt may be asymptomatic, but they are prone, especially those with a type 1 shunt, to two specific complications, namely, intrahepatic tumours and NCHE. The age of onset of encephalopathy is variable and related in part to the volume and duration of the shunt (71) and the presence of concomitant liver disease; the ageing brain is known to be more vulnerable to encephalopathy. Spontaneous closure of CEPSs has not been reported.

Congenital intrahepatic portosystemic shunts (CIPSs) are characterized by an abnormal intrahepatic connection between branches of the portal vein and the hepatic veins or the IVC. They may be because of congenital abnormalities in the intrahepatic vascular system, degeneration of the hepatic parenchyma and anastomosing vascularization, or they may be acquired after liver biopsy, abdominal surgery or blunt trauma (72). The most common abnormalities are a single large vessel connecting the portal vein or its right branch to the IVC or a localized peripheral shunt in which one hepatic segment has one or more communications between peripheral branches of the portal vein and hepatic veins. Other, less common findings are a portosystemic shunt through an aneurysmal dilatation of a localized peripheral shunt (#2 above) or multiple communications between peripheral portal and hepatic veins in both hepatic lobes (73). CIPSs may be completely asymptomatic and undergo spontaneous closure during the first year of life; the proportion of shunts in which this occurs is unknown. Persistent shunt patency causes hyperammonaemia and renders the patient at risk of hepatic encephalopathy, particularly in adult life (74, 75). One study found an elevated NH3 level in 18.4% of patients (76).

Persistent patent ductus venosus is another rare cause of CIPSs. Hepatic encephalopathy has been recorded in affected children as young as 3 years (73).

Noncirrhotic portal vein thrombosis is caused by inherited or acquired prothrombotic disorders in the setting of favourable local factors (77, 78). Because of the well-preserved liver function, there are very few reported cases of hepatic encephalopathy secondary to portal vein thrombosis in the absence of cirrhosis . However, minimal hepatic encephalopathy was recently noted in 35–50% of adults and children with extrahepatic portal vein thrombosis. Hyperammonia resulted in generalized low-grade cerebral oedema, cognitive decline and abnormal neuropsychological tests (78).

Liver biopsy is essential for the diagnosis of noncirrhotic portal hypertension, to exclude cirrhosis of any cause, as well as primary biliary cirrhosis, schistosomiasis and granuloma, and to assess the presence of vascular lesions, perisinusoidal fibrosis, peliosis hepatis and intrahepatic portal or hepatic venous occlusions (74). The hepatic venous pressure gradient can provide information on the site of increased vascular resistance. When arterial portography fails to depict a distinct image of the shunt, percutaneous transhepatic portography may be required; in positive cases, it will show large pooling of the contrast medium flowing from the dilated portal branch, with visualization of the hepatic vein. Portal-hepatic venous shunts can be clearly demonstrated by abdominal computed tomography, abnormal blood flow on Doppler colour ultrasonography and magnetic resonance imaging (75).

In cases of intractable NCHE, portosystemic shunts can be obliterated surgically or by interventional radiological percutaneous transhepatic techniques, such as balloon-occluded retrograde transvenous obliteration. For type 2 congenital portacaval shunts, persistent CIPSs and persistent patent ductus venosus, potential therapeutic options include surgical ligation or radiological occlusion of the shunt. For symptomatic type 1 shunts, liver transplantation is the only definitive treatment (72, 79). These procedures are fairly effective, although often associated with portal hypertension.

One study reported the use of transjugular intrahepatic portosystemic shunting to treat portal hypertension secondary to noncirrhotic perisinusoidal hepatic fibrosis complicated by NCHE (80). Others described a case of relapsing encephalopathy following small bowel transplantation, which was mainly explained by direct drainage of the graft into the IVC, creating an iatrogenic portacaval shunt (81). Bacterial overgrowth and metabolic alkalosis, contributed to the hyperammonaemia.

Drug-induced hepatic encephalopathy

Noncirrhotic hyperammonaemic encephalopathy is a well-documented complication of valproic acid treatment even in patients without primary liver disease (82–84). The reported prevalence of valproic acid-induced hyperammonaemia is 35–45% (85). It is usually asymptomatic and accompanied by mildly elevated serum liver enzyme levels. Clinically, patients may present with varying degrees of cognitive dysfunction (82–84), increased aggressiveness or worsening dementia and coma (in the elderly). Valproic acid can also induce severe hepatotoxicity with resultant hepatic hyperammonaemia and neurological symptoms (86, 87). Several cases were reported in association with a urea-cycle enzyme deficiency, mainly ornithine transcarbamylase, with an unfavourable outcome (88–91). Symptoms may begin in the first 2 weeks after therapy is initiated or several (3–5) years later (82).

Blood levels of valproic acid may be normal and do not necessarily correlate with the degree of hyperammonaemia or symptom severity (82). There is also no clear correlation between blood NH3 levels and the severity of encephalopathy, suggesting that mechanisms other than those involving NH3 contribute to the neurological dysfunction (89–92). Intake of valproic acid, a fatty acid, may induce hyperammonaemia via its metabolism in the liver, which produces toxic metabolites that inhibit the activity of carbamoyl phosphate synthetase I, the first enzymatic reaction of the urea cycle, thereby hindering the excretion of NH3. Valproic, acid also decreases the levels of carnitine by enhancing its excretion in the form of a valproic acid–carnitine complex. Carnitine deficiency diminishes mitochondrial function, with inhibition of the urea cycle in the liver (93).

Other anticonvulsants may potentiate the effects of valproic acid . Phenobarbital and phenytoin increase NH3 levels in patients taking valproic acid (94). In one study, the addition of toporimate, another urea-cycle inhibitor, to valproic acid, precipitated NCHE in previously asymptomatic patients (95).

The primary treatment for valproic acid-induced NCHE is withdrawal of the drug, which leads to complete recovery over one to several days (2). l-carnitine supplementation has been shown in case reports to improve the symptoms of valproic acid-related toxicities (71). Bohnan et al. (96) reported a decline from 90% to 53% mortality after l-carnitine treatment of valproic acid-induced NCHE.

Several other drugs can cause hyperammonaemia, probably by disrupting the urea cycle or enhancing renal NH3 release into the circulation. This includes glycine used during transurethral resection of the prostate, which stimulates NH3 production (97), in addition to carbamazepine (98), ribavirin (99), sulfadiazine with pyrimethamine (100) and high-dose salicylate (101).

Inborn errors of metabolism

The IEMs that cause hyperammonaemia include urea-cycle disorders, organic acidurias, defects in fatty acid oxidation causing carnitine deficiency, dibasic aminoaciduria and defects in pyruvate metabolism (3). The symptoms of hyperammonaemia vary with age and NH3 level. Most IEMs present early in childhood; affected neonates are usually characterized by a poor suck reflex, hypotonia, vomiting, lethargy, grunting respirations, episodes of apnoea and seizures. Older children have more insidious symptoms of failure to thrive and persistent vomiting. Alternatively, there may be episodic or fluctuating neurological symptoms that are often precipitated by increased protein intake, drugs or infections (102); they may be mild (irritability, headache, cyclic vomiting, behavioural disturbances and learning disabilities) or severe (mental retardation, seizure disorders, ataxia and coma). ‘Psychiatric’ disturbances, such as manic episodes or frank psychosis, may be seen in late-onset disease.

Although the serum NH3 level does not always correlate with the clinical symptoms, children with levels of 50–100 μm rarely manifest symptoms, whereas levels in the range of 100–200 μm are associated with anorexia, vomiting and irritability. In those with levels above 200 μm, symptoms progress to stupor and coma (102, 103).

Studies have described inherited deficiencies of each of the five enzymes of the urea cycle: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinic acid lyase and arginase (104, 105). The reported prevalence is 1:30 000 live births, although this may be an underestimation, as many patients die before diagnosis (3). Using data derived from the John Hopkins Hospital (106), one group calculated the prevalence at 1:8000 live births. All the urea-cycle disorders, except OTC deficiency, are transmitted as autosomal recessive traits.

Ornithine transcarbamylase deficiency is the most common urea-cycle disorder, with an estimated prevalence of 1:14 000. It is transmitted as an X-linked trait (106, 107). The phenotype is extremely heterogeneous, ranging from the complete absence of symptoms in hemizygous males who might become symptomatic only much later in life to acute neonatal hyperammonaemic coma (108–111). Researchers hypothesize that complete OTC deficiency is associated with neonatal disease, and partial deficiency with late-onset presentations. More than 80% of heterozygous females are asymptomatic; in the remainder, the clinical severity of the disease is similar to that in males with partial deficiencies (106). More than 340 mutations in the OTC gene have been identified, most of them specific to individual families. The reason for the wide phenotypic heterogeneity, even among patients with the same mutation and within the same family, is still unclear and seems to involve a combination of genetic and environmental factors. The clinical signs and symptoms of OTC deficiency are caused by the toxic effects of hyperammonaemia on the brain (3, 105). They include lethargy, vomiting, behavioural and neurological abnormalities, and in severe cases, coma, brain oedema and death. Biochemical abnormalities include hyperammonaemia, elevated plasma levels of glutamine, decreased level of citrulline and orotic aciduria. Individuals who have mild molecular urea-cycle disorders can lead a relatively normal life until a severe environmental stress triggers a hyperammonaemic crisis (108–115). Prompt recognition of such crises is essential for a good outcome, because early treatment can normalize the plasma NH3 level and lead to full recovery.

Carbamyl phosphate synthetase deficiency may also present in adulthood (116, 117), as may partial deficiency of one its essential activators, N-acetyl glutamine synthetase (118). ASS deficiency, also called citrullinaemia, can be present in infants (type I) or adults (type II); ‘psychiatric’ disturbances are common in type II (119).

Hyperammonaemia–hyperornithinaemia–homocitrullinuria syndrome is a rare autosomal recessive disorder resulting from abnormal transport of ornithine, a dibasic amino acid, into the mitochondria, where it is catabolized by ornithine-5-aminotransferase. This results in the accumulation of ornithine in the cytoplasm, limiting its function as a substrate for ureagenesis, although the activity of the urea-cycle enzymes is normal. Children and adults usually present with neurological deficits (including spasticity and clonus), episodic confusion, seizures and mental retardation (120, 121). The principal treatment is protein restriction and ornithine supplementation in some patients.

The diagnosis of urea-cycle disorders is based on clinical, biochemical and molecular data (Table 2). Measurements of serum NH3, acid–base balance, glucose, lactate, pyruvate, ketones, plasma amino acids and urine organic and orotic acid excretion are essential for identifying specific urea-cycle disorders and excluding other IEMs (3). Patients are rarely ketotic, and less often hypoglycaemic, and may have either metabolic acidosis or respiratory alkalosis. Hepatomegaly and moderate increase in serum aminotransferases are common during episodes of acute hyperammonaemia and tend to regress with clinical improvement (3, 104, 105, 122). When a urea-cycle disorder, as well as other IEM is suspected, a liver biopsy should be considered to measure enzyme levels in hepatocytes.

Table 2.  Laboratory evaluation of urea-cycle disorders
Enzyme deficiencyInheritanceCitrullineOrotic acidArginineArgininosuccinic acid
  1. AR, autosomal recessive; ASL, argininosuccinic acid lyase; ASS, argininosuccinate synthetase; CPS I, carbamyl phosphate synthetase I; N, normal; NAGS, N-acetyl glutamine synthetase; OTC, ornithine transcarbamylase.

NAGSAR[DOWNWARDS ARROW]N  
CPS IAR[DOWNWARDS ARROW]N[DOWNWARDS ARROW] 
OTCX-linked[DOWNWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW][DOWNWARDS ARROW] 
ASSAR[UPWARDS ARROW] [UPWARDS ARROW][UPWARDS ARROW][DOWNWARDS ARROW] – NN
ASLAR[UPWARDS ARROW][UPWARDS ARROW][DOWNWARDS ARROW] – N[UPWARDS ARROW]
ArginaseARN[UPWARDS ARROW][UPWARDS ARROW] 

As noted above, in many conditions, hyperammonaemia is precipitated in patients with these metabolic disorders by intercurrent infections, both with and without urea-splitting organisms (11, 60, 116, 119), fever (11), total parenteral nutrition (58, 59), gastrointestinal bleeding (increased load of absorbed protein from the gut) (53, 54), steroid use (52) (increased muscle catabolism), trauma (55), exposure to insect repellent (115) and intake of valproic acid (88–91) or alcohol (119). Pregnancy, especially the puerperium, is also a risk factor for NCHE in susceptible patients (114), probably owing to the metabolic stress that occurs during that period, but also possibly as a consequence of the delivery of an infant who does not bear an OTC-deficient gene and can provide ureagenetic activity prenatally for the mother. In a recent report, we described a case in which initiation of the Atkins diet, a low-carbohydrate, high-protein, high-fat diet, unmasked adult-onset OTC deficiency (115). The presence of hyperammonaemia following any of these precipitants should prompt an investigation for urea-cycle disorders.

Other IEMs that can cause hyperammonaemia are defects in the β-oxidation of fatty acids causing carnitine deficiency, organic acidaemias and pyruvate metabolism disorders (3).

Management of hyperammonaemia

  1. Top of page
  2. Abstract
  3. Literature search
  4. Pathophysiology of noncirrhotic hyperammonaemic encephalopathy
  5. Aetiology and underlying mechanisms of noncirrhotic hyperammonaemic encephalopathy ()
  6. Management of hyperammonaemia
  7. Acknowledgements
  8. References

Several treatments are appropriate for all patients with hyperammonaemia, and some are reserved for those with hyperammonaemia thought to be related to an IEM. Table 3 lists the principles governing hyperammonaemia treatment.

Table 3.  Management of hyperammonaemia
  • *

    Used only for inborn errors of metabolism.

1. Treatment of increased intracranial pressure
 Endotracheal intubation and hyperventilation
 Mannitol administration
 Induction of hypothermia
2. Limitation of endogenous ammonia production
 Lactulose
 Parenteral and enteral antibiotics (metronidazole, rifaximin)
 Protein diet
 Prophylactic use of anti-epileptic agents (e.g. phenobarbital) for limitation of muscle activity
3. Facilitate ammonia elimination*
 Haemodialysis, peritoneal dialysis, continuous arteriovenous haemofiltration
 Alternative metabolic pathways – sodium benzoate and sodium phenylacetate
 l-ornithine l-aspartate
4. Supply of urea-cycle substrates*
 Arginine hydrochloride
 l-carnitine (prevention of secondary deficiency)
5. Liver transplantation

Control of increased intracranial pressure

The mainstay of the treatment of increased intracranial pressure is mannitol, which was shown to improve mortality in patients with acutely increased blood NH3 levels (123).

Limitation of endogenous ammonia production

Nonabsorbable disaccharides are metabolized by colonic bacteria to byproducts and reduce the intestinal production/absorption of NH3 in three ways: by reducing intestinal pH, thereby favouring a low luminal ratio of NH3/NH4+ and entrapping NH3 as nondiffusible ammonium in the lumen; by a direct cathartic osmotic mechanism, which also increases faecal nitrogen excretion; and by inhibiting glutaminase activity and interfering with the uptake of glutamine by the intestinal wall and its subsequent metabolism to NH3. Nonabsorbable disaccharides are the mainstay of treatment of chronic encephalopathy, and although they are an established first-line therapy for hepatic encephalopathy, evidence supporting their efficacy is limited (124). Additionally, they do not affect mortality.

Antibiotics are an alternative treatment for hepatic encephalopathy, aimed at reducing the mass of urease producing enteric bacteria. Neomycin has been approved by the US Food and Drug Administration for use in acute hepatic encephalopathy, but it is extensively applied off-label to treat chronic encephalopathy in addition to lactulose (1). It acts as an antibiotic and also as a glutaminase inhibitor. Rifaximin, a nonabsorbable rifamycin antibiotic derivative, was found to be effective in numerous clinical trials (125, 126), and has gained acceptance as a first-line treatment or adjunct to nonabsorbable disaccharides in patients with acute or chronic encephalopathy. It lacks significant toxicity and side effects because of minimal gastrointestinal absorption.

Since renal, and not intestinal, NH3 generation, predominantly contributes to hyperammonaemia following an intestinal protein load, reducing renal ammoniagenesis is a potential therapeutic target. It can be partially achieved by introducing a predominantly protein diet with a more favourable calorie-to-nitrogen ratio, preventing gastrointestinal bleeding and eliminating glutamine (the substrate for ammoniagenesis) by increasing its excretion in urea-cycle disorders.

Enhancement of ammonia elimination from the body

If NH3 levels remain at >100 mol/L and/or the cause of the hyperammonaemia remains elusive, an IEM may be present. In these cases, useful measures to actively remove NH3, facilitate its metabolism or decrease its production, include dialysis (peritoneal dialysis, haemodialysis and continuous hemofiltration) (127–129) and pharmacological manipulation.

Conventional haemodialysis has the highest ammonium clearance rate of all dialysis methods (129), and it is accepted for use in neonates with hyperammonaemic coma and a high NH3 level (>300 μmol/l), along with sodium benzoate or sodium phenylacetate to promote the metabolism of NH3 by metabolic pathways other than the urea cycle. Sodium benzoate conjugates with glycine to form hippurate (benzoglycine), which is filtered by the kidney. Sodium phenylacetate conjugates with glutamine to form phenylacetylglutamine, which is rapidly excreted in the urine (3, 103–105, 130). Besides the side effects of nausea, vomiting and hypokalaemia, a limiting factor of benzoate therapy is the glycine availability in the body and the possible potentiation of NH3 toxicity (demonstrated only in small animals). Enns et al. (2) conducted a 25-year uncontrolled study on the yield of sodium benzoate and sodium phenylacetate in urea-cycle disorders in neonates and adults. The survival rate related to episodes of hyperammonaemia was 96%, higher than reported in patients with urea-cycle disorders who did not receive alternative-pathway therapy.

l-ornithine l-aspartate (LOLA), a stable salt of ornithine and aspartic acid, provides crucial substrates for glutamine and urea synthesis, the key pathways in deammination. It has been shown in clinical studies to reduce blood NH3 levels by increasing NH3 detoxification in the muscle. In a recent meta-analysis of randomized-controlled trials comparing LOLA with placebo, patients with overt (grade I or II) hepatic encephalopathy benefited from its use but patients with subclinical disease did not (131).

Supply of urea-cycle substrates

Urea-cycle disorders lead to a deficiency in ornithine. Arginine is the immediate precursor of ornithine, and its supplementation replenishes the urea-cycle substrates (132) and prevents protein catabolism by promoting nitrogen excretion and augmenting CPS I activity. In children with IEMs, the absence of arginine led to the rapid onset of symptomatic hyperammonaemia and its resumption corrected the hyperammonaemia (132, 133). Also, long-term follow-up of patients with the late-onset variant of argininosuccinic acid lyase deficiency showed no impairment of intellectual development and improvement in biochemical parameters during therapy with arginine supplementation (134).

l-carnitine plays a critical role in the intermediary metabolism of fatty acids and their transport across mitochondrial membranes. It might be useful specifically for the removal of accumulated toxic metabolites in IEMs (3, 135). In several cases of urea-cycle disorders with secondary carnitine deficiency, supplementation of carnitine reduced attacks of hyperammonaemia (136, 137). As stated above, it plays a unique role in the treatment of valproic acid-induced NCHE (71, 96).

Liver transplantation

Liver transplantation is an important treatment modality in urea-cycle disorders, with a reported cumulative survival rate of more than 90% at 5 years, superior to the rates of liver transplantation for other diseases (138–140). Living or deceased donor transplants have been used successfully used in patients with OTC deficiency, citrullinaemia and CPS deficiency (141).

References

  1. Top of page
  2. Abstract
  3. Literature search
  4. Pathophysiology of noncirrhotic hyperammonaemic encephalopathy
  5. Aetiology and underlying mechanisms of noncirrhotic hyperammonaemic encephalopathy ()
  6. Management of hyperammonaemia
  7. Acknowledgements
  8. References