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.
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).