Download o Liver cell failure:

Faculty of Pharmacy- Clinical Pharmacy
Program - level 5 - Spring 2016
o Gastroenterology
5th Lecture:Liver
Cell Failure & HEPATIC
ENCEPHALOPATHY
o Prof.Dr. Nader El-Malky
Professor of internal medicine, Gastroenterology & Hepatology
Faculty of medicine -Mansoura University
Liver Cell Failure&HEPATIC
ENCEPHALOPATHY
Liver Cell Failure:
 Definition:Chronic injury to the liver, regardless of the cause, results in a wounding response that leads to
fibrosis(Cirrhosis), and ultimately
Liver Cell Failure
 Pathologically:Described prev. in lecture(Cirrhosis)
 Etiology: Described prev. in lecture(Cirrhosis)
 Clinical Presentation
1- Compensated cirrhosis: No symptoms & the case is discovered accidentally on
physical examination.
2- Decompensated cirrhosis: may present with one of the following:
a. Liver cell failure& hepatic encephalopathy.
b. Portal hypertension.
c.
Combination of them.
o Liver cell failure:

The following features are as a direct consequence of liver cells not
functioning.
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Spider angiomata or spider nevi are vascular lesions consisting of a central
arteriole surrounded by many smaller vessels (hence the name "spider") and
occur due to an increase in estradiol.
Palmar erythema is a reddening of palms at the thenar and hypothenar
eminences also as a result of increased estrogen.
Gynecomastia, or increase in breast gland size in men that is not cancerous,
is caused by increased estradiol.
Hypogonadism, a decrease in sex hormones manifest as impotence,
infertility, loss of sexual drive, and testicular atrophy, can result from
primary gonadal injury or suppression of hypothalamic/pituitary function.
Liver size can be enlarged, normal, or shrunken in people with cirrhosis.
Ascites, accumulation of fluid in the peritoneal cavity, gives rise to flank
dullness . This may be visible as increase in abdominal girth.
Fetor hepaticus is a musty breath odor resulting from increased dimethyl
sulfide.
Jaundice is yellow discoloration of the skin and mucous membranes (with
the eye being especially noticeable) due to increased bilirubin. Urine may
also appear dark.
hepatic encephalopathy
Hepato-cellular carcinoma

Investigations:
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1- Liver function tests: show pattern of cirrhosis in cases of liver cell-failure.
2- Investigations for portal hypertension: To assess the presence & degree of portal
hypertension.
3- Liver biopsy: It shows the aetiology.
4- Special investigations to detect the cause:
Hepatic encephalopathy (HE):
 Definition:Hepatic encephalopathy is a metabolically induced, potentially reversible,
functional disturbance of the brainfunction (neuropsychiatric abnormalities), which may
occur during the course of chronic and acute liver disease.
 Clinical features of chronic hepatic encephalopathy (HE):
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Reversal of sleep pattern
Disturbed consciousness
Personality changes
Intellectual deterioration
Fetor hepaticus
Astrexis= Flapping Tremor
minimal hepatic encephalopathy
 Diagnosis of chronic hepatic encephalopathy
(HE):
o Laboratory tests:
 Electrolytes. Blood glucose.Creatinine,
urea.Blood picture.
 Plasma ammonia levels: consistently raised
in patients with HE;
o MRI:
Magnetic resonance imaging of the brain proved
an abnormally high signal on T1-weighted
imaging in the basal ganglia, particularly the globuspallidus.
 Differential diagnosis of hepatic encephalopathy:
1- Other metabolic encephalopathies:
 Hypernatraemia.
 Hyponatraemia.
 hyperglycaemia or hypoglycaemia.
 Hypercapnia.
 uraemia.
 Hypoxic-ischemic encephalopathy:
 Bilateral hippocampal damage causes Korsakoff's amnesia.
 Diffuse cortical, thalamic, or combined neuronal loss (with intact
brainstem) results in persistent vegetative state.
2- Wilson's disease:
An autosomal recessive disorder in copper metabolism, typically appearing in
late adolescence. Copper is increased to saturation levels in the liver, brain,
cornea and kidney.
 Brain: Degeneration of basal ganglia:
• incoordination (especially involving fine movements),
• slowness of voluntary limb movements and speech,
• tremor, dysarthria, ataxia,
• excessive salivation, dysphagia,
• mask-likefacies.
3- Drugs:
CNS depressants: (narcotics, tranquilizers, antianxiety and antidepressants).
Intoxication with sedative/hypnotic drugs:
4- Consequences of head trauma (postconcusive syndrome):
 Delirium and wishing not to be moved.
 Severe memory loss.
 Focal deficit.
5- Organic intracranial lesions:
In some cases the symptoms are relatively nonspecific and usually are
characterized by:
 intermittent headache
 personality change,
6- Alcohol intoxication and with-drawal syndromes:
 Wernicke's encephalopathy (Thiamine (vitamin B-1)
deficiency):nystagmus, ataxia, confusion and ophthalmoplegia
(acute/subacuteconfusional state and often reversible).
 Korsakoff's syndrome: is a profound defect (persistent and irreversible)
in memory and learning in many of the alcoholic patients who recover
from the acute encephalopathy
 Delirium tremens (DTs): may occur in a patient with underlying
alcoholic liver disease.
 Diagnosis of minimal hepatic encephalopathy(MHE):
o In the grade of MHE, the patient has no complaints and on direct questioning has
no symptoms belonging to grade 1. Sleep, concentration, fine motor functions,
general performance and neuropsychological tests show subtle abnormalities,
providing evidence of cerebral disturbance in the sense of retardation of
psychomotor functions.
o MHE is present in 30-70% of people with cirrhosis. The burden of this disturbance
depends on the demonds made on the individual.
o Neuropsychological tests: Can detect and quantitate abnormalities of mental
function in patients with liver diseases, who have MHE or early prestupor stages of
HE.
 Number connection tests part A (NCT-A); measures the cognitive function.
Patients perform the test by connecting numbers printed on paper consecutively
from 1-25.
 Digit symbol test (DST); measures motor speed and accuracy. The patient is given
a list of digits associated with symbols from 1-9 and is asked to fill in blanks with
symbols that correspond to each number.
o Neurophysiological assessment:
 The EEG: Patients were graded into the different stages of HE according to
their Mean Dominant Frequency (MDF), and the relative powers of delta and
theta activity.
 Evoked potentials testingis of greatest utility in detecting subclinical spinal
cord and optic nerve lesions. However, it could be also useful in diagnosis of
MHE.
 Neuroimaging techniques: such as magnetic resonance spectroscopy and
positron emission tomography have been used in the assessment of MHE,
but at the moment they are more useful in research and in further establishing
the patho-physiology of the condition.
 Common Precipitants of Hepatic Encephalopathy
o Renal failure
o Gastrointestinal bleeding: The presence of blood in the upper gastrointestinal
tract results in increased ammonia and nitrogen absorption from the gut.
o Infection: Infection may predispose to impaired renal function and to increased
tissue catabolism, both of which increase blood ammonia levels.
o Constipation: Constipation increases intestinal production and absorption of
ammonia.
o Medications: Drugs that act upon the central nervous system, such as opiates,
benzodiazepines, antidepressants, and antipsychotic agents, may worsen hepatic
encephalopathy.
o Diuretic therapy: Decreased serum potassium levels and alkalosis may facilitate
the conversion of NH4+ to NH3.
o Dietary animal protein overload: This is a frequent cause of hepatic
encephalopathy.
 Treatment of hepatic encephalopathy:
o Approach Considerations
 Exclude nonhepatic causes of altered mental function.
 Consider checking an arterial ammonia level in the initial assessment of a
hospitalized patient with cirrhosis and with impaired mental function.
 Precipitants of hepatic encephalopathy, such as hypovolemia, metabolic
disturbances, gastrointestinal bleeding, infection, and constipation, should be
corrected.
 Avoid medications that depress central nervous system function, especially
benzodiazepines.
o Treatments to Decrease Intestinal Ammonia Production:
 Diet
• Protein restriction may be appropriate in some patients immediately
following a severe flare of symptoms (ie, episodic hepatic encephalopathy)..
• Diets containing vegetable proteins appear to be better tolerated than diets
rich in animal protein, especially proteins derived from red meats. This may
be because of increased content of dietary fiber, a natural cathartic, and
decreased levels of aromatic amino acids. Aromatic amino acids, as
precursors of the false neurotransmitters tyramine and octopamine, are
thought to inhibit dopaminergic neurotransmission and worsen hepatic
encephalopathy.
 Cathartics
• Lactulose (beta-galactosidofructose) and lactilol (betagalactosidosorbitol) are nonabsorbable disaccharides that have been in
common clinical use since the early 1970s). They are degraded by intestinal
bacteria to lactic acid and other organic acids.
• Lactulose appears to inhibit intestinal ammonia production by a number of
mechanisms. The conversion of lactulose to lactic acid results in
acidification of the gut lumen. This favors conversion of NH4+ to NH3 and
the passage of NH3 from tissues into the lumen.
• Initial lactulose dosing is 30 mL orally, daily or twice daily. The dose may
be increased as tolerated. Lactulose may be administered as an enema to
patients who are comatose and unable to take the medication by mouth. The
recommended dosing is 300 mL lactulose plus 700 mL water, administered
as a retention enema every 4 hours as needed.
• Lactulose also appeared to be effective as primary prophylaxis against the
development of overt hepatic encephalopathy,
 Antibiotics
1- Neomycin and other antibiotics, such as metronidazole, are administered in
an effort to decrease the colonic concentration of ammoniagenic bacteria.
Initial neomycin dosing is 250 mg orally 2-4 times a day. Doses as high as
4000 mg/d may be administered. Neomycin is usually reserved as a secondline agent, after initiation of treatment with lactulose.
2- Rifaximin,
 In 2005, rifaximin was approved by the FDA as a treatment for
hepatic encephalopathy. In March 2010, rifaximin was approved to
reduce recurrence of hepatic encephalopathy
 Rifaximin at a dose of 400 mg taken orally 3 times a day was as
effective as lactulose or lactitol at improving hepatic encephalopathy
symptoms. Rifaximin had a tolerability profile comparable to
placebo.
o Treatments to Increase Ammonia Clearance
 L-ornithine L-aspartate (LOLA)
LOLA (Hepa-Merz) is available in both intravenous formulations and oral
formulations. LOLA is a stable salt of the 2 constituent amino acids. Lornithine stimulates the urea cycle, with resulting loss of ammonia (effective in
treating hepatic encephalopathy).
 Zinc
Zinc deficiency is common in cirrhosis. Even in patients who are not zinc
deficient, zinc administration has the potential to improve hyperammonemia by
increasing the activity of ornithine transcarbamylase, an enzyme in the urea
cycle.
 Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate, glycerol
phenylbutyrate
• Sodium benzoate interacts with glycine to form hippurate. The subsequent
renal excretion of hippurate results in the loss of ammonia ions. Dosing of
sodium benzoate at 5 g orally twice a day can effectively control hepatic
encephalopathy. Use of the medication is limited by the risk of salt
overload and by its unpleasant taste.
• Sodium phenylbutyrate is converted to phenylacetate. Phenylacetate, in
turn, reacts with glutamine to form phenylacetylglutamine. This chemical
is subsequently excreted in the urine, with the loss of ammonia ions.
 L-carnitine
L-carnitine improved hepatic encephalopathy symptoms in several small
studies of patients with cirrhosis. Whether the medication works by improving
blood ammonia levels or whether it works centrally perhaps by decreasing
brain ammonia uptake remains unclear.
o Minimal Hepatic Encephalopathy
Minimal hepatic encephalopathy is most likely the result of hyperammonemia.
Elevated ammonia levels are detected in most patients. Similarly, the subtle
neurological changes of minimal hepatic encephalopathy can be improved by
the administration of lactulose&rifaximin.
o Liver Transplantation