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Abstract
SUMMARY and CONCLUSIONS
Schistosomiasis is a parasitic disease with a wide range of clinical manifestations affecting millions of people in Egypt due to infestation with S.mansoni and/or S.haematobium.
About one third of infected individuals with S.mansoni were found to have various stages of hepatosplenic schistosomiasis (HSS), (El-Kady et al., 1982).
HSS is primarily a mesenchymal disease due to ovideposition in the portal radicles leading to granuloma formation with subsequent in the untreated cases-periportal fibrosis resulting in presinusoidal intrahepatic portal hypertension giving rise to development of portosystemic communications, which are responsible, in addition to portal hypertension, for nearly all the manifestation of HSS as following:
1 – Variceal formation at the oesophageo-gastric junction, dudenum and rectum, which may rupture.
2 – Diversion of portal blood away from the liver deprives it from the trophic factors and nutrients coming from the splanchinic organs. This deprivation leads to hepatocyte degeneration and liver shrinkage in size and function, (Leffert et al., 1982), so:
a – Synthetic function of the liver is deranged leading to depressed synthesis of albumin, coagulation factors, apoproteins and urea. The later is important for polyamines synthesis which are essential for macromolecules synthesis.
b – Depressed detoxifying functions of the liver leading to accumulation of neurotoxic substances formed in and absorbed from the gut to be normally detoxified in the liver. These substances reach the brain in large amounts to disrupt its functions. Also, blood levels of fatty acids, hormones, bile acids and drugs are increased, potentiated more in presence of hypoalbuminaemia as they are normally carried on albumin. All these substances have deletirous effects on the C.N.S functions and the homeostasis of the body.
3 – Bilharzial eggs can reach ectopic sites mainly the C.N.S and lungs to induce granulomatous formation.
4 – Due to portal hypertension, congestion of GIT with oedema and villous atrophy and loss of adipose tissue in the intestinal submucosa, all lead to malabsorption syndrome with undernutrition potentiated more by the protein-losing enteropathy.
All these causes added to the chronic-stress-induced catabolism lead to severe degree of protein-energy malnutrition (PEM).
5 – Portosystemic shunting is mainly responsible for the acute PSE episodes.
Our study was conducted on 55 patients with hepatosplenic schistosomiasis (HSS) with portal hypertension and portosystemic communications as proved clinically, and by abdominal ultrasonography and upper GIT endoscopy. The patients were subjected to: full clinical and neurological examination, application of minimental status examination (MMSE) and number (or circle) connection test (NCT), measurement of sodium and prolactin in the serum of some patients. Brain CT scanning, and EEG for some patients were performed. Complete blood picture, renal and hepatic function tests were performed for all patients.
The main modes of presentation were ruptured varices, ascites and acute PSE.
The patients were divided according to the clinical condition into three groups. The first consisted of patients without ascites nor portosystemic encephalopathy (PSE). The second consisted of patients with ascites but no PSE. The third group consisted of patients presented in acute PSE. The study showed that although 9 of 38 patients (23%) recorded badly with MMSE, the majority had evidence of psychometric deficits as shown by NCT, a finding proving the sensitivity of this test. Neurological findings, in addition to cognitive disorders, were common mainly related to dysfunction of basal ganglia in the form of fine tremors and bradykinesia; pyramidal tract in the form of exagerated knee jerk and positive Babinski sign; periphral polyneuropathy in the form of glove and stoke hyposthesia, generalised muscle wasting and weakness, and muscle cramps. The majority of patients were undernourished as revealed by hypoalbuminaemia, lymphopenia, reduced fat stores, generalised muscle wasting in addition to presence of ascites in most of them.
By special questionnaire, sexual dysfunction were common in the form of reduced lipido, impotence and delayed pubic hair growth. By examination, there was testicular atrophy. Only one patient had unilateral gynaecomastia. Brain CT scanning of 15 patients showed mild generalised cortical atrophy in the majority (13 to 15), while all had central atrophy of mild (8 cases) to moderate (7 cases) degrees. EEG showed generalised slow rhythm of theta to delta range in 6 of 12 patients. There were no signs suggestive of focal neuro-schistosomiasis. In the group of acute PSE, the mean value of serum prolactin was significantly elevated while the mean value of serum sodium was lowered. In a trial to explain the pathogenesis of variceal bleeding we can propose the following:
In states of protein-energy malnutrition (PEM), which is common in the studied patients, tissue atrophy and loss of adipose tissue around the gastro-esophogeal varices weaken the tissue support and permits more dilatation and subsequent rupture of these varices, as this area is more exposed to traumatizing agents such as analgesics, gastric acid, some foods, in addition to the gastropathy already present.
Also, in a trial to explain the pathogenesis of PSE we can propose the following:
Acute PSE reflects the impaired protein synthesis by neurons in states of advanced PEM and negative nitrogen balance. These proteins (enzymes, receptors pumps, transport protein and others) are needed to counteract the effects of neurotoxins absorbed from the gut by renewal of what has been destroyed or inactivated. PEM in chronic liver diseases is due to many causes including chronic stress reaction, restricted amounts of nutrients, ingested or absorbed, Catabolic hormones lead to negative nitrogen balance with tissue lysis and elevated blood levels of amino acids, fatty acids and ammonia, in addition to impaired glucose tolerance. These changes in addition to the noxious effects of chronic toxaemia may be responsible for the atrophic findings of the brains of patients with advanced HSS.
So PSE reflects inability of the tissues of the brain to reutilize amino acids for synthetic purposes due to presence of high levels of counter-regulatory hormones of stress and advanced degree of PEM due to both primary and secondary causes.
Hyperammonemia has deleterious effects on oxidative phosphorylation mechanisms. With depletion of ATP stores, Na+-Pump fails-which is normally responsible for maintainance of normal structure and functions of cells. Failure of Na+-Pump lead to accumulation of Na+ inside the cells manifested as hyponatremia, and escape of K+ outside the cells. Many intracellular enzymes are inhibited by excess Na+ and low K+ as Hille (1989) mentioned. This leads to more failure of the regenerative ability of the cells. Hypokalemia can precipitate acute PSE, probably, through inhibition of the action of these important intracellular enzymes.
Na+-pump has nutritive function as it is essential for transport of amino acids and glucose across cell membranes. This pump is ATP dependent. With depletion of ATP resources either from advanced PEM state or due to hyperammonemia, many pumps fail such as Na+-pump, leading to, far example hepato-renal syndrome, sick cell syndrome, the terminal hypothermia and brain oedema in terminal states.
Hyperprolactinemia could be explained to be due to retention of the normally synthesized prolactin or due to hyposmolality, augmented ergic GABA-tone and high levels of estrogens.
The neurological and neuromuscular findings could be explained on the basis of deranged nutritional and metabolic states of the patients and the influence of the toxic substances reaching the CNS continuously from the gut, in addition to the effects of deficiency of some vitamines and trace elements and essential amino acids and fatty acids which is common among bilharzial patients.
The common finding of MR-T1 hyperintense signal of basal ganglia and other brain regions was attributed to high concentration of manganese in these regions due to portosystemic shunting and/or hyperammonaemia states. To explain this phenomenon we can assume that due to hyperactivity of the enzymes glutamine synthetase and transaminase in states of hyperammonaemia, and at the same time, these enzymes need magnesium and/or manganese as catalysts, in addition to ATP large amounts of, so in areas like basal ganglia which is crowded by cells and have high blood flow and are one of the most highly active brain areas, so it is possible that the need for manganese and/or magnesium in large amounts in states of hyperammonaemia may be responsible for this MRI phenomenon as it can be reversed when ammonia levels return to normal by portosystemic shunt resection, or liver transplantation.
Also, excessive amounts of ammonia may lead to suppression of glutamine synthetase with ATP depletion as this enzyme is ATP-consuming. At the same time, the enzyme glutamic acid decarboxylase is stimulated, due to accumulation of excitotoxic glutamate, leading to more synthesis of the neuroinhibitory GABA.
Also, benzodiazepine-like substances such as hemin and protoporphyrin IX are formed due to breakdown of haemoglobin and myoglobin of the blood and red meat, respectively, under the influence of gut bacteria. These metabolites when absorbed from the gut reach the brain to potentiate the GABA-ergic tone exactly like benzodiazepines. This could explain why blood in the gut and red meat are strong precipitants of acute PSE irrespective of the liver function.