Metabolic encephalopathy functional

A. Assessment. Agitation, delirium, or psychosis may be caused by a variety of drugs and toxins (Table 1-14). In addition, such symptoms may result from a functional thought disorder or metabolic encephalopathy caused by medical... 

However, encephalopathies with a metabohc basis tend to be the most problanatic for infants or children, with functional outcomes dependent upon timely and pradent interventions. Three varieties of metabolic encephalopathy in children are discussed here. The first two are closely related. Inborn (genetic) errors of metabolism can present in the newborn as severe encephalopathy from hyperammonemia alone. When a metabolic error presents months to years later, a degree of hepatic insufficiency may complicate the metabolic derangement. In acute or fulminant hepatic failure of any etiology (i.e., infections, drug-induced, toxin-related), the rise in serum ammonia may be only moderate but other factors contribute to the ensuing encephalopathy, which may be devastating within days. 

Thiamine deficiency provides a unique model to study the effects of mild impairment of oxidative metabolism on brain function and selective neurodegeneration. The acute changes provide a model in which to study the mechanisms underlying metabolic encephalopathies. In its chronic form it provides a model of selective neurodegeneration in response to mild impairment of oxidative metabolism. 

Ammonia (NH3) is just one of the toxins implicated in HE. It is a metabolic by-product of protein catabolism and is also generated by bacteria in the GI tract. In a normally functioning liver, hepatocytes take up ammonia and degrade it to form urea, which is then renally excreted. In patients with cirrhosis, the conversion of ammonia to urea is retarded and ammonia accumulates, resulting in encephalopathy. This decrease in urea formation is manifest on laboratory assessment as decreased blood urea nitrogen (BUN), but BUN levels do not correlate with degree of HE. Patients with HE commonly have elevated serum ammonia concentrations, but the levels do not correlate well with the degree of central nervous system impairment.20... 

The brain has an absolute dependence on the blood for its immediate supply of oxygen and energy substrates. Interruption of oxygen or substrate supply by compromise of pulmonary or cardiovascular function or metabolic factors results in encephalopathy and, if prolonged, neuronal cell death. The brain uses approximately 20% of the total oxygen supply of the body. While glucose remains the primary energy substrate for the brain, alternative substrates maybe used under certain circumstances (see Ch. 31). 

Defects of energy metabolism cause profound disturbances in the function of muscle and brain. Such defects may present as a myopathy, encephalopathy or encephalo-myopathy. Clinical features are best appreciated by understanding the preferred oxidizable substrates for brain and muscle. 

The resulting resistance to blood flow results in portal hypertension and the development of varices and ascites. Hepatocyte loss and intrahepatic shunting of blood results in diminished metabolic and synthetic function, which leads to hepatic encephalopathy (HE) and coagulopathy. 

Hepatic function impairment In patients with preexisting severe liver disease, hepatic encephalopathy (manifested by tremors, confusion, and coma, and increased jaundice) may occur. Because amiloride is not metabolized by the liver, drug accumulation is not anticipated in patients with hepatic dysfunction, but accumulation can occur if hepatorenal syndrome develops. 

Carnitine deficiency leads to impaired carnitine shuttle activity the resulting decreased LCFA metabolism and accumulation of LCFAs In tissues and wasting of acyl-carnitine in urine can produce cardiomyopathy, skeletal muscle myopathy, encephalopathy, and impaired liver function. 

Ethanol-related cognitive deficits in the absence of Wernicke s encephalopathy also improve with extended abstinence. Most functional neuroimaging studies of abstinent alcoholics have shown decreases in both cerebral glucose metabolism and blood flow, with the decreases being greatest in the frontal lobes (Netrakom et ah, 1999). 

The route of metabolism can also be significant, particularly in those with liver disease or who are taking concomitant hepatic enzyme inhibitors, such as erythromycin (SEDA-20, 31). The complex interaction between hepatic dysfunction and benzodiazepines has been reviewed (33) these drugs more readily affect liver function in individuals with liver disease and may also directly contribute to hepatic encephalopathy, as shown by the ability of benzodiazepine antagonists to reverse coma transiently in such patients (33). Elderly people appear to be at increased risk only if they are physically unwell, and particularly if they are taking many medications. 

Normal/reduced plasma concentration of BCAA muscle are relatively low in concentration as muscle metabolism continues normally. Aromatic amino acids which are metabolised hepatically are present in relatively high concentrations as the deranged liver is unable to perform its usual metabolic functions encephalopathy... 

There are several theories behind the cause of hepatic encephalopathy. One of these is that the accumulation of toxins in the brain, particularly ammonia, is the cause. Ammonia is produced in the intestine and is usually metabolised in the liver to urea via the urea cycle. As a result of portosystemic shunting and reduced metabolism in the liver, ammonia serum levels rise as the transformation to urea is reduced. However, the validity of this theory is questionable as not all patients with signs of hepatic encephalopathy have raised serum ammonia levels. Another theory is that patients with hepatic encephalopathy have increased permeability of the blood-brain barrier, and hence the increased toxin levels permeate the brain more than usual, leading to altered neuropsychiatric function. There are also theories relating to increased levels of neurotransmitters, short-chain fatty acids, manganese and increased GABA-ergic transmission. 

This patient has markedly impaired hepatocyte function and hence reduced metabolic and excretory capacity (raised INR, hyperbili-rubinaemia, encephalopathy). Low extraction drugs (hepatocyte dependent) are likely to accumulate and should be used cautiously. The distribution of highly protein-bound drugs may be affected by hyper-bilirubinaemia, increasing the unbound fraction. Biliary excretion may be impaired. 

This patient has a massively raised ALT, indicating considerable hepato-cyte damage. All functions of the liver are likely to be affected, including reduced secretory and excretory function, demonstrated in this case by a raised bilirubin reduced synthetic function, shown by the raised INR (albumin is imaffected at this time due to its long half life) reduced metabolic function, indicated by accumulation of ammonia and other toxins leading to encephalopathy. Blood flow through the liver is likely to be unaffected, as there is no cirrhosis/portal hypertension. As with all other functions of the liver, this patient s ability to metabolise drugs is likely to be severely affected. Renal function is also impaired secondary to paracetamol toxicity. 

Beriberi (infantile and adult) and Wernicke s encephalopathy (WE) are clinical manifestations attributed to thiamine deficiency. Beriberi is characterized by peripheral neuropathy including sensory, motor, and reflex functions affecting the distal segments of limbs more severely than proximal ones (TanPhaichitr, 1985). WE is a metabolic disease due to thiamine deficiency and is characterized by lesions in the thalamus, hypothalamus (including mammillary nuclei), and cerebellum (Victor et al., 1971 Harper and Butterworth, 1997). 

Harata N, Iwasaki Y (1995) Evidence for early blood-brain btirrier breakdown in experimental thiamine deficiency in the mouse. Metab Brain Dis 10(2) 159-174 Harper CG (1983) The incidence of Wernicke s encephalopathy in Australia A neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry 46 593-598 Harper CG, Butterworth RF (1997) Nutritional and metabolic disorders. In Graham DI, Lantos PL (eds) Greenfield s neuropathology. Arnold, London, pp 601-655 Hayton SM, Kriss T, Wase A, Muller DP (2006) Effects on neural function of repleting vitamin E-deflcient rats with alpha-tocopherol. J Neurophysiol 95(4) 2553-2559 Hayton SM, MuUer DP (2004) Vitamin E in neural and visual function. Ann N Y Acad Sd 1031 263-270... 

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