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HEPATIC ENCEPHALOPATHY

HEPATIC ENCEPHALOPATHY. Ashwini Gandhe. History of Present Illness.

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HEPATIC ENCEPHALOPATHY

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  1. HEPATIC ENCEPHALOPATHY Ashwini Gandhe

  2. History of Present Illness 63yr old white man presents with change in mental status.Patient has become increasingly more forgetful and confused over past one month.Confusion and forgetfulness started slowly over past few months and has slowly progressed. Both short and long term memory has been affected . Before this started patient was stable with clear thought process and good logic skills. Patient developed jaundice and mild pruritis over last one week. He had slight nausea ,abdominal discomfort, diarrhea (10 watery stools /day). Pt Had no wt loss or loss of appetite. Patients c/o increased fatigue and lethargy and slight temperature intolerance. Patient was started on Peg-Intron for treatment of Hepatitis C 3 weeks Back

  3. Past History -Hepatitis C secondary to blood transfusion several years back -CHF (was admitted in June for that) -CAD -Hypertension -Depression Social History -Quit Tobacco 10 yrs ago -Quit Ethanol 13 yrs ago -No IVDU -No sexual promiscuity

  4. H&P • Meds -Atenolol -Baby Aspirin -Paxil -Lasix -K-Dur -Peg-Intron

  5. Physical Examination • Vitals:99.8/52/16/114/80 • General:Alert,oriented ,sitting in bed,cooperative and in no acute distress.Pt. Had shortened attention span. • Skin:Yellow discoloration .No cyanosis or petichiae. • Eyes:scleral icterus present • Neck:Carotid pulses equal bilaterally with no bruit • Lungs:Clear to Auscultation bilaterally • Abdomen:obese,soft,nontenderActive Bowel sounds present and liver size 9-10cm.No fluid thrill or shifting dullness. • Extremeties:no congestion,cyanosis or Oedema • Neurologic:Intact reflexes,Cranial nerves II-XII intact, 15/15 on Glasgow coma scale • Stools: heme negative

  6. Labs • Na :129 LDH:285 • K:5.1 SGOT:254 • Cl:96 SGPT:128 • Bicarb:23 Bil total:15.5 • BUN:12 Bil. Conj.:11.4 • Cr:1.0 Alpha Feto Prot:19(<8.5) • WBC:3.5 Ammonia:54 Hgb:13.8 Alk phos:162 • Hct:38.9 • Platelets:68 • Prot total:6.7 • Albumin:2.6

  7. Tests USG(Jun 24th 2002):Stone in GB, wall of GB not thickened , no Ascites .Liver had homogenous echogenecity. LIVER BIOPSY:(jun,99): Chr. Active Hepatitis with Cirrhosis.Piecemeal necrosis and bridging portal fibrosis. CT SCAN ABDOMEN:Abnormal appearance of the liver suggesting Cirrhosis, no focal lesion or hepatoma,Cholelithiasis +ent. ERCP:Unremarkable, no biliary dilatation ,no biliary obstruction. USG WITH DUPLEX DOPPLER:Normal hepatic veins,normal portal veins.No obstruction or thrombosis. EGD:Distal oesophagitis,antral gastritis, portal gastropathy & multiple duodenal erosions, no oesophageal varices. Thyroid function tests:TSH:1.485microIU/ml T4 free:1.10ng/dl

  8. D/D • Hepatic Encephalopathy • Hyponatremia • Peg-Intron • Superimposed Obstructive Jaundice over Hepatitis C • Superimposed Hepatitis A or B on Hepatitis C • Hepatoma or hepatocellular CA • Hypothyroidism • Depression • Portal vein thrombosis

  9. Hepatic Encephalopathydiagnosis of HE • Hepatic encephalopathy is a diagnosis of exclusion .other metabolic,infectious ,intracranial vascular events and intracranial SOL etc. has to be ruled out . Knowledge of existence of Acute or chr. Liver d/se, existence of precipitating factors and or prior h/o HE are clinical elements needed for diagnosis • Thyroid function tests were within normal limits • ERCP and CT Scan showed no obstruction in bile duct. • USG with duplex doppler ruled out venous thrombosis. • Hyponatremia was corrected by stopping Lasix . • Peg- Intron was stopped . • Hepatitis A antibody (Ig M) and Hepatitis Bs ag –ive and Hepatitis B C Ab –ive.

  10. Pathophysiology of HE Def: HE may be defined as a disturbance in CNS function b/se of hepatic insufficiency.In both acute and chronic liver failure ,these neuropsychiatric manifestations are reversible. The main theory which is firmly accepted is that the nitrogenous substances derived from the gut adversely affect brain functoin.These compounds gain access to the systemic circulation as a result of decreased hepatic function or porto systemic shunts. Ammonia has been pointed as a key factor in pathogenesis.

  11. Ammonia in HE Metabolism in kidney ,muscle+ urease activity of colonic bacteria+ deamidation of of glutamine in the small bowel AMMONIA PORTAL VEIN SYNTHESIS OF UREA AND GLUTAMINE IN THE LIVER

  12. AMMONIA • Highest level of Ammonia is found in Portal Vein. Hepatic process of metabolism of Ammonia is efficient with a first pass extraction of Ammonia of approx. 0.8 • In ac.and chr. Liver d/se ,increased arterial level of Ammonia is seen. • In Fulminanat hepatic failure(FHF),elevated arterial levels of Ammonia usually >200micogr/dl,may lead to cerebral- oedema and risk of cerebral herniation. • Correlation of blood levels with mental status in Cirrhosis is inaccurate b/se Bld-brain barrier permeability to ammonia is increased in patients with HE. • Alteration in neurotransmission induced by ammonia occurs after metabolism of this toxin in astrocytes.Abnormalities in glutaminergic,serotonergic,GABA-ergic and catacholamine pathways have been described. • Other gut derived toxins including benzodiazepine like substances ,neurotoxic short &medium chain Fatty acids, phenols & mercaptans derived from colonic bacterial metabolism have been proposed to interact with with ammonia and result in additional neurochemical changes.

  13. Factors in HE

  14. STAGING • Stage 0: Lack of detectable changes in personality or behaviour.Asterixis absent. • STAGE 1 :Trivial lack of awareness. Shortened attention span.Hypersomnia or Insomnia or inversion of sleep pattern. Euphoria or Depression.Asterixis +ent or –ent. • STAGE 2: Lethargy or apathy.Disorientation.Inappropriate behaviour.Slurred speech.obvious asterexis. • STAGE 3:Gross disorientation.Bizarre behaviour.Semistupor or stupor.Asterexis absent. • STAGE 4:Coma

  15. Manifestations of HE • ASTEREXIS:This is the most characteristic neurologic abnormality also c/d “flapping tremor”. This is d/to impaired inflow of joint and other afferent information to the brain stem reticular formation resulting in lapses in posture.It is demonstrated with the patient’s arm outstretched and fingers separated or by hyperextending the wrists with the forearm fixed.There is rapid flexion-extension movements at metacarpophalangeal and wrist joint. • FETOR HEPATICUS: This is a sour ,faecal smell in breath ,d/to volatile substances normally formed in the stool by bacteria.These mercaptans if not removed by the liver are excreted through the lungs and appear in the breath. FH doesnot correlate with the degree or duration of encephalopathy. • Disturbed conciousness with disorders of sleep, Personality changes including childishness, irritability and loss of concern for family, Intellectual deterioration, slow and slurred speech and usually exaggerated deep tendon reflexes can be present.

  16. TREATMENT GOALS • Provision of suppotive care:Adequate supportive care is critical during all stages of HE including prevention of falls in disoriented patients, prophylactic intubation in deeper stages of HE, adequate nutrition. • Identification and removal of precipitating factors: • GI hemorrhage: stool analysis and/or placement of nasogastric tube. • Infections: Culture of all appropriate body fluids,especially ascites when present. SBP and pneumonia may present with HE. • Renal & electrolytes disturbances: These include renal failure,metabolic alkalosis, hypokalemia, dehydration & diuretic effects. • Use of psychoactive medications: Urine screen for benzodiazepines, narcotics, other sedatives. • Constipation and excessive dietary proteins.

  17. Treatment Goals • Acute deterioration of liver function in Cirrhosis: Presence of superimposed alcoholic hepatitis, development of acute circulatory disturbance(eg;portal vein thrombosis) and impairment in liver function after surgery in Cirrhosis. • Reduction of nitrogenous load from the Gut: Measures to reduce nitrogenous load from the gut should be implemented including catharsis,use of nonabsorbable disaccharides and/or antibiotics. • Assessment of the need for long term therapy: • Long term control of precipitating factors including avoidance of constipation, prophylaxis of bleeding from gastroesophageal varices, prophylaxis of SBP, judicious use of antibiotics, avoidance of psychoactive medications. • Assessment of the need of liver transplantation.

  18. Treatment options • Nutritional management:Restriction of dietary protein at the time of acute encephalopathey with subsequent increments to assess clinical tolerance is a cornerstone of therapy. Recommendation is 1-1.5g protein/kg/day. Vegetable & dairy sources are preferable to animal protein. Zinc, is a cofactor of urea cycle and may be deficient in cirrhotic patient . Zinc acetate as 220mg b.i.d. can be administered. • Reduction in the nitrogenous load arising from the gut: • A: Bowel cleansing:-B/se the toxins responsible for HE arise from the gut, bowel cleansing is the mainstay of therapy. Colonic cleansing reduces the luminal content of ammonia, decreases colonic bacterial counts and lowers bld ammonia levels in cirrhotic patients. • B:Non-absorbable Disaccharides :Lactulose is a first line pharmacolgic t/t of HE. Lactulose is not broken down by intestinal disaccharidases and thus reaches the colon ,where bacteria will metabolize the sugar to acetic acid and lactic acid. Acidification of colon may underlie it’s cathartic effect.

  19. Treatment of HE • Lactulose:For ac. Encephalopathy, lactulose(ingested or via nasogastric tube or by enema) 45ml p.o. is followed by dosing every hour until evacuation occurs.Then dosing is adjusted to an objective of two to three soft bowel movements per day(generally 15-45ml every 8-12 hr).For Chr. Encephalopathy the hourly intial administration is not needed. • C:ANTIBIOTICS: Antibiotics are a therapeutic alternative to Lactulose for t/t of ac. and chr. Encephalopathy. Benefits from Neomycin are attributed to effects on colonic bacteria.Neomycin also affects the small bowel mucosa and may impair the activity of glutaminase in intestinal villi. • dose:For ac. Encephalopathy ,neomycin 3-6g/day po shd be given for a period of 1-2 w. For Chr. Encephalopathy,neomycin 1-2g/day p.o. shd be given with periodic renal and annual auditory monitoring b/se inspite it’s poor absorption it can c/se auditory loss and renal failure.

  20. Treatment cont.. D:Other therapies: L-ornithineL-Aspatate stimulates heaptic ureagenesis from Ammonia.D/to the different mechanism of action,the combination of Ornithine aspartate and lactulose may produce additive effect in HE.Oais not available in United states. Drugs that affect Neurotransmission: Flumazenil and bromocriptine may have a role in selected patients.An enhanced GABA-ergic tone has been postulated to contribute to the development of encephalopathy. Endogenous benzodiazepines have been proposed to be present in patients with HE and exert neuroinhibitory effects by binding to GABAa receptor. Flumazenil(1mg bolus I.v.) is indicated for patients with HE and suspected benzodiazepine intake. The recent observation of manganese accumalation in basal ganglia may underlie the frequent finding of extrapyramidal symptomatology in patients with liver d/se.Bromocriptine (30mg p.o. b.I.d)is indicated for the t/t of chronic encephalopathy in patients unresponsive to other therapy and with extrapyramidal symptoms.

  21. Treatment cont… Branched Chain AA:Reduced ratio of branched chain to aromatic aa has been related to HE. Infusions of solutions with high conc. Of br. Chain aa has been used to treat HE. Manipulation of the splanchnic circulation: In patients with recurrent episodes of encephalopathy despite medical therapy where a precipitating factor is not found,presence of large spontaneous portal-systemic shunt shd be soughtVisualization of the collaterals can be obtained withultrasound techniqueand confirmed with visceral angiography.These shunts are amenable to occlusion via radiologic techniques,including placement of occlusive coils only after all other medical measures have failed. Liver transplantation:This may be an ultimate answer to the problem of chr.hepatic encephalopathy.Intractable or frequently recurrent HE can be a primary indication for Liver transplant.

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