Finally, there is a group of patients (most of whom have experienced repeated attacks of hepatic coma) in whom an irreversible mild dementia and a disorder of posture and movement (grimacing, tremor, dysarthria, ataxia of gait, choreoathetosis) gradually appear. This condition of chronic acquired hepatocerebral degeneration must be distinguished from other dementing and extrapyramidal syndromes (see further on). A few cases of isolated spastic paraplegia (so-called hepatic myelopathy, or more correctly hepatic paraplegia) have been described. Pant et al attributed the syndrome to a loss of Betz cells in the frontal cortex; in other words, a restricted encephalopathy seen in some patients with portal-systemic encephalopathy. Indeed, the spasticity of the legs, increased tendon reflexes, and Babinski signs that are found with portal- systemic encephalopathy, suggest that “hepatic paraparesis” is a common feature.
The MRI in chronic portal-systemic encephalopathy often demonstrates symmetric high signal intensity on T1-weighted sequences in the globus pallidus, likely the result of manganese deposition. In acute portal-systemic encephalopathy, regions of abnormal T2 hyperintensity throughout the cerebral hemispheres are seen, most often involving the insula, thalamus, and cingulate.
The concentrations of blood NH3, particularly if measured repeatedly in arterial blood samples, usually are well in excess of 200 mg/dL, and the severity of the neurologic and EEG disorders roughly parallels the ammonia levels. With treatment, a fall in the NH3 levels precedes clinical improvement.
The striking finding by Adams and Foley in patients who died in a state of hepatic coma was a diffuse increase in the number and size of the protoplasmic astrocytes in the deep layers of the cerebral cortex, lenticular nuclei, thalamus, substantia nigra, cerebellar cortex, and red, dentate, and pontine nuclei, with little or no visible alteration in the nerve cells or other parenchymal elements. With periodic acid-Schiff (PAS) staining, the astrocytes were seen to contain glycogen inclusions. These abnormal glia cells are generally referred to as Alzheimer type II astrocytes, having been described originally in 1912 by von Hosslin and Alzheimer in a patient with Westphal-Strümpell pseudosclerosis (or Wilson disease). These astrocytes have been studied by electron microscopy in rats with surgically created portacaval shunts (Cavanagh; Norenberg); the cells show a number of striking abnormalities—swelling of their terminal processes, cytoplasmic vacuolation (distended sacs of rough endoplasmic reticulum), formation of folds in the basement membrane around capillaries, and an increase in both the number of mitochondria and enzymes that catabolize ammonia. Also, some degeneration in myelinated nerve fibers in the neuropil and an increase in the cytoplasm of oligodendrocytes are seen. In chronic cases, neuronal loss in the deep layers of the cerebral and cerebellar cortex and lenticular nuclei is found, as well as vacuolization of tissue (possibly astrocytic) resembling the lesions of Wilson disease.
The ubiquitous astrocytic alterations occur to some degree in all patients who die of progressive liver failure and the degree of glial abnormality corresponds generally to the intensity and duration of the neurologic disorder. Possibly, the astrocytic changes affect the synaptic activities of the neurons. The clinical and EEG features of hepatic encephalopathy as well as the astrocytic hyperplasia are more or less specific features of this metabolic disorder. Nevertheless, taken together in a setting of liver failure, they constitute a distinctive clinicopathologic entity.
Pathogenesis of Hepatic Encephalopathy