Liver failure


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Liver failure

  1. 1. Acute Liver Failure
  2. 2. Acute Liver Failure • Acute liver failure describes the clinical syndrome of severe impairment of liver function Encephalopathy Coagulopathy  jaundice • Within 6 months of the onset of symptoms.
  3. 3. DEFINITION (PALF study group) 1.The acute onset of liver disease with no known evidence of chronic liver disease. 2. Biochemical and/or clinical evidence of severe liver dysfunction: • Hepatic-based coagulopathy – prothrombin time [PT] ≥15 seconds or international normalized ratio [INR] ≥1.5 that is not corrected by parenteral vitamin K in presence of clinical hepatic encephalopathy • PT is ≥20 seconds or INR is ≥2.0 in presence or absence of HE .
  4. 4. Classification
  5. 5. • An alternative classification  fulminant and sub-fulminant • liver failure - time from jaundice to encephalopathy less or more than 2 weeks Late onset liver failure describes encephalopathy developing more than 8 weeks (but lessthan 24 weeks) after the first symptoms
  6. 6. Acute vs acute on chronic liver failure Acute liver failure Acute on chronic liver failure History Short Long Nutrition Good Poor Liver Increased /normal Hard / increased Spleen Increased /normal Increased Spiders naevi Absent Present
  7. 7. Causes
  8. 8. Causes Neonates Infectious Herpes Virus , Hepatitis B virus Inborn Error of Metabolism Hereditary Fructose Intolerance , Galactosemia (Common) Immune Mediated Neonatal Hemochromatosis Ischaemia CHD , Cardiac Surgery , Myocarditis Infants Infectious Hep A , Hep B , Herpes Virus , NANB Hepatis (Common) Drugs Valproate , Isoniazide , Paracetamol (Common) Inborn Error of metabolism Hereditary Fructose Intolerance Immune Mediated Autoimmune Hepatitis
  9. 9. 2-18 years old Infectious NANB Hepatitis ,Hep A , Hep B (common) Drugs Same As Infants Immune mediated Autoimmune Ischaemia Budd Chiari Syndrome Metabolic Wilson’s Disease
  10. 10. • In India , infectious hepatitis is the most important cause of ALF • In Infants , main causes are inherited metabolic disorders and infections
  11. 11. Pathogenesis • Massive destruction of hepatocytes – direct cytotoxic effect or immune response to antigens • Contributing factors to liver failure – impaired hepatocyte regeneration , altered parenchymal perfusion , endotoxemia
  12. 12. Clinical features • The patient, previously having been well, typically develops non-specific symptoms such as nausea and malaise. • Progressive Jaundice. • Vomiting is common • Abdominal pain . • Rapid decrease in liver size without clinical improvement is an omnious sign • Ascites • Tachycardia, hypotension, hyperventilation and fever are later features • Later coma & encephalopathy features
  13. 13. Signs of Liver cell failure • Progressive Jaundice
  14. 14. Fetor hepaticus • Sweetish, slightly faecal smell of the breath • Of intestinal origin • Normal demethylating processes being inhibited by liver damage. • Methyl mercaptans excreted through lungs • Frequent in patients with an extensive portal-collateral circulation • Often precedes coma
  15. 15. Skin changes - Vascular spiders • Found in the vascular territory of the superior vena cava. • Common sites are the necklace area,the face, forearms and dorsum of the hand • An arterial spider consists of a central arteriole, radiating from which are numerous small vessels resembling a spider’s legs
  16. 16. • Pressure on the central prominence with a pinhead causes blanching of the whole lesion • Disappear with improving hepatic function, whereas the appearance of fresh spiders is suggestive of progression. • A few spiders are not sufficient to diagnose liver disease, but many new ones, with increasing size of old ones, should arouse suspicion.
  17. 17. Palmar erythema (liver palms) • The hands are warm and the palms bright red in colour,especially the hypothenar and thenar eminences and pulps of the fingers • The mottling blanches on pressure and the colour rapidly returns.
  18. 18. • Vascular spiders and palmar erythema - attributed to oestrogen excess. • Oestrogens have an enlarging, dilating effect on the spiral arterioles of the endometrium, and such a mechanism may explain the closely similar cutaneous spiders • Liver inactivates oestrogen– in liver failure it leads to increase in oestrogen levels – leads to cutaneous manifestations of liver failure
  19. 19. Endocrine changes - Hypogonadism • Diminished libido and potency are frequent • The testes are soft and small. Seminal fluid is abnormal in some cases. • Secondary sexual hair is lost • The female has ovulatory failure. • Loses feminine characteristics, particularly breast and pelvic fat. • Gynaecomastia - Alcoholic liver disease is the commonest association.
  20. 20. • Steroid hormones are conjugated in the liver. • Derivatives of oestrogens, cortisol and testosterone are conjugated as a glucuronide or sulphate • So excreted in the bile or urine. • Failure of hormone metabolism in liver failure results in a rise in blood hormone levels. • This alters the normal homeostatic balance between secretion rates of hormones and their utilization.
  21. 21. Investigations Haematology • The prothrombin time (together with the degree of encephalopathy) refractory to vitamin K treatment central to the assessment of the severity of the clinical situation, and its progress. • Haemoglobin and white count are obtained. • A falling platelet count may reflect disseminated intravascular coagulation.
  22. 22. Biochemistry • Blood Glucose • Blood Urea • Serum Electrolytes • Serum Creatinine • Serum bilirubin • Serum Albumin – initially normal but later low albumin carries poor prognosis • Transaminases – of little prognostic values as levels tends to fall as condition worsens
  23. 23. Etiological Work Up • Virological markers – Serum HBsAg IgM Anti HBc IgM anti HAV Anti HCV HCV RNA
  24. 24. EEG • The Guidelines now used for decision on management no longer depend on EEG • Continuous EEG has shown 50% of patients with subclinical seizure and epileptiform activities • Recommended for Grade 3 and 4 Encephalopathy
  25. 25. Liver Biopsy & CT Brain • Hepatic Parenchymal necrosis more than 50% indicates poor prognosis • Hepatic Regenerative changes on histology (<50% Necrosis ) indicates good Prognosis • From Practical point of view – clinical & laboratory data rather than biopsy are used for decision making • CT – unreliable in detecting early cerebral oedema so movement of patient to radiology carries the risk of deterioration
  26. 26. General measures • Volume resuscitation should be carried out aggressively • Fluids should be glucose based with infusion rate at least 6-8 mg/kg/min • Strict input output charting
  27. 27. Associations / complications
  28. 28. Hepatic encephalopathy • The brain is exposed to increased levels of ammonia, neurotransmitters and their precursors because of failed hepatic clearance. • Neurological and psychiatric components. • Features of encephalopathy can be separated into changes in consciousness, personality, intellect and speech.
  29. 29. • Disturbed consciousness with disorder of sleep is usual. • Hypersomnia appears early and progresses to reversal of the normal sleep pattern. • Reduction of spontaneous movement, a fixed stare, apathy, and slowness and brevity of response are early signs. • Further deterioration results in reaction only to intense or noxious stimuli. • Coma at first resembles normal sleep, but progresses to complete unresponsiveness.
  30. 30. Personality & intellect changes • Irritability and loss of concern for family. • Intellectual deterioration varies from slight impairment of organic mental function to gross confusion. • Isolated abnormalities appearing in a setting of clear consciousness relate to disturbances in visual spatial gnosis. • Most easily elicited as constructional apraxia, shown by an inability to reproduce simple designs with blocks or matches • Writing is oblivious of ruled lines and a daily writing chart is a good check of progress • Failure to distinguish objects of similar size, shape, function and position • Micturating and defaecating in inappropriate places
  31. 31. Speech • Speech is slow and slurred and the voice is monotonous.
  32. 32. Asterixis • The most characteristic neurological abnormality is the ‘flapping’ tremor (asterixis). • This is due to impaired inflow of joint and other afferent information to the brainstem reticular formation resulting in lapses in posture.
  33. 33. • It is demonstrated with the patient’s arms outstretched and fingers separated or by hyperextending the wrists with the forearm fixed . The rapid flexion–extension movements at the metacarpophalangeal and wrist joints are often accompanied by lateral movements of the digits.
  34. 34. • ‘Flapping’ tremor is not specific for hepatic pre-coma. • It can also be observed in uraemia, in respiratory failure and in severe heart failure • Deep tendon reflexes are usually exaggerated. • Increased muscle tone is present at some stage and sustained ankle clonus is often associated with rigidity. • During coma , patients become flaccid and lose their reflexes. • The clinical course fluctuates, and frequent observation of the patient is necessary. • Clinical grading should be used as a part of the clinical record
  35. 35. Staging
  36. 36. Pathogenetic mechanisms • The basic processes are failure of hepatic clearance of gut derived substances, either through hepato-cellular failure or shunting, and altered amino acid metabolism • Result in changes in cerebral neurotransmission. • Several neuroactive toxins, in particular ammonia, and neurotransmitter systems are thought to be involved and inter-relate.
  37. 37. Portal systemic Encephalopathy
  38. 38. • In patients with poor hepato-cellular function, such as acute hepatitis, the shunt is through the liver itself. • The damaged cells are unable to metabolize the contents of the portal venous blood completely so that they pass unaltered into the hepatic veins • In patients with more chronic forms of liver disease the portal blood bypasses the liver through enlarged natural ‘collaterals’. • The portal– hepatic vein anastomoses, developing around the damaged liver, act as shunt.
  39. 39. • Patients going into hepatic coma are suffering from cerebral intoxication by intestinal contents which have not been metabolized by the liver - portal-systemic encephalopathy
  40. 40. Pathogenesis • Ammonia is produced from the breakdown of proteins,amino acids, purines and pyrimidines. • Ammonia arising from the intestine is synthesized by bacteria, dietary protein and glutamine. • The liver normally converts ammonia to urea and glutamine through the urea cycle. • Liver failure causes disorder of the urea cycle lead to an encephalopathy. • Blood ammonia levels &Brain levels are also increased • Increase in the cerebral metabolic rate for ammonia and an increase in the blood– brain barrier permeability to ammonia
  41. 41. Effects of ammonia on brain • The primary mechanisms proposed for ammonia in hepatic encephalopathy - direct effect on neural membranes or on postsynaptic inhibition • An indirect neuronal dysfunction due to disturbance of glutamate neurotransmission.
  42. 42. Brain- Glutamate • No urea cycle in the brain • Ammonia removal involves a different pathway. • In astrocytes, glutamine synthetase converts glutamate plus ammonia to glutamine . • With excess ammonia, glutamate (an important excitatory neurotransmitter) is depleted, and glutamine accumulates.
  43. 43. GABA • Principal inhibitory neurotransmitter • GABA is synthesized by gut bacteria, and that entering the portal vein is metabolized by the liver. • Liver failure or portal-systemic shunting - enters the systemic circulation. • There are increased GABA levels in the plasma of patients with liver disease and hepatic encephalopathy – neuroinhibition
  44. 44. • Receptor is part of a larger receptor complex which also has binding sites for benzodiazepines and barbiturates. • The binding of any of these ligands - opens a chloride channel - hyperpolarization of postsynaptic membrane - neuroinhibition. • Endogenous benzodiazepines are present in patients with hepatic encephalopathy - interact with the receptor complex and cause neuroinhibition.
  45. 45. • No unifying mechanism explains hepatic encephalopathy. The brain controls neuropsychiatric behaviour through multiple inhibitory and stimulatory receptor mediated pathways.
  46. 46. Investigations • Cerebrospinal fluid - usually clear and under normal pressure , cell count is normal • Electroencephalogram(EEG) - bilateral synchronous slowing of the wave frequency. • EEG changes occur very early even before psychological or biochemical disturbances. • CT scan to show cerebral oedema and cortical atrophy even in those with subclinical portal-systemic encephalopathy.
  47. 47. EEG changes
  48. 48. Treatment of Hepatic Encephalopathy • Treatment broadly divides into three areas. 1 Identification and treatment of the precipitating cause. 2 Intervention to reduce the production and absorptionof gut-derived ammonia and other toxins. • Involves reduction and modification of dietary protein, • Alteration of enteric bacteria and the colonic environment antibiotics,lactulose/lactilol • Stimulation of colonic emptying - enemas, lactulose/lactilol. 3 Agents to modify neurotransmitter balance directly- bromocriptine, flumazemil limited clinical value at present.
  49. 49. Diet Energy 150% of recommended allowance Carbohydrates 15-20g/kg/d Fats 8g/kg/day Protein (non-encephalopathic state) 2-3 g /kg/d It promotes growth & maintain positive nitrogen balance Vegetable Proteins - preferred Protein (encephalopathy) Grade 1 & 2 – 1-2 g/kg/d Grade 3 &4 – 0.5 g /kg/d Further protein restriction exacerbate HE by causing breakdown of endogenous proteins
  50. 50. Antibiotics • Neomycin, given orally, is very effective in decreasing gastrointestinal ammonium formation - used for the acute case for 5–7 days • In acute hepatic coma, lactulose is given -- neomycin added if the response is slow or partial. • Metronidazole seems to be as effective as neomycin. • Rifaximin, a non-absorbed derivative of rifamycin, is effective for grade 1–3 hepatic encephalopathy
  51. 51. Lactulose and lactilol • Given by mouth lactulose • Reaches the caecum where it is broken down by bacteria predominantly to lactic acid . • The faecal pH drops. • Faecal acidity would reduce the ionization and hence absorption of ammonia • The growth of lactose-fermenting organisms is favoured and organisms such as bacteroides, which are ammonia formers, are suppressed.
  52. 52. • The aim of treatment with lactulose is to produce acid stools without diarrhoea. • The dose is 10–30ml three times a day and is adjusted to produce two semi-soft stools daily. • The effects of lactilol compared with lactulose  Colonic effects similar  As effective in encephalopathy  Quicker action  More convenient (powder)  Less sweet  Less diarrhoea and flatulence  No longer routinely available Purgation to prevent constipation - Lactulose or lactose enemas may be used and are superior to water . All enemas must be neutral or acid to reduce ammonium absorption.
  53. 53. Sodium benzoate and L-ornithine -L-aspartate • Sodium benzoate promotes urinary excretion of ammonia and is as effective as lactulose and is less expensive. • L-ornithine-L-aspartate treatment promotes hepatic removal of ammonia by stimulating residual hepatic urea cycle activity and promoting glutamine synthesis, particularly in skeletal muscle
  54. 54. Recent Advances • Flumanezil - benzodiazepine-receptor antagonist which can induce transient, variable but distinct improvement in some patients with hepatic encephalopathy • Clinical situation has yet to be established. • Patients are extremely sensitive to sedatives and whenever possible these are avoided • Zinc Supplementation – deficiency may reduce metabolism of ammonia to urea because of the dependency on zinc of some of the enzymes involved • Studies of zinc therapy in hepatic encephalopathy have not established benefit
  55. 55. Cerebral edema (intracranial hypertension) • Uncommon in patients with grade 1 or 2 encephalopathy • Develops in the majority with grade 4. • Raised intracerebral pressure can lead to brainstem herniation and is the most common cause of death, being found in 80% of fatal cases • Two mechanisms have been proposed: cytotoxic and vasogenic. o The cytotoxic hypothesis - accumulation of osmolytes such as glutamine, in astrocyte subsequent osmotic uptake of water into the cells. o In the brain astrocytes are the site of ammonia metabolism by amidation of glutamate to glutamine. o In acute liver failure cerebral glutamine concentrations rise.
  56. 56. • The vasogenic hypothesis - changes in cerebral blood flow and the blood–brain barrier • Cerebral blood flow autoregulation (maintained blood flow despite falling or rising blood pressure) is lost in patients with fulminant hepatic failure . • Loss of this protective mechanism could exacerbate cerebral changes due to systemic hypotension (giving cerebral ischaemia) and cerebral hyperperfusion- increasing cerebral blood volume and interstitial water • If not controlled - progresses to loss of pupillary reflexes and respiratory arrest from brainstem herniation.
  57. 57. Treatment • Head should be elevated to 30 degrees • High levels of PEEP should be avoided – it may increase hepatic venous pressure & intracranial pressure • Mannitol bolus of 0.5 g/kg as 20 % solution over 15 minutes – can be repeated if serum osmolality less than 320 mOsm/L • Other methods 3% hypertonic saline • STEROIDS ARE NOT INDICATED IN TREATMENT OF INTRACRANIAL HYPERTENSION in ALF – as it may complicate infection & cause gastric erosions
  58. 58. Coagulopathy • The liver synthesizes all the coagulation factors (except factor VIII) inhibitors of coagulation and proteins involved in the fibrinolytic system. • The coagulopathy of fulminant hepatic failure is complex • Not only to factor deficiency, but also to enhanced fibrinolytic activity • The platelet count may fall due to increased consumption or reduced production, and platelet function is also abnormal in hepatic failure. • The resulting coagulopathy predisposes to bleeding- potential cause of death • The prothrombin time is the most widely used test to assess coagulation. It is a guide to prognosis.
  59. 59. Treatment • Iv vitamin K to correct any reversible coagulopathy • FFP – to be given in case of haemorrhage or if coagulopathy is severe (PT>60sec) • Thrombocytopenia to be corrected • Prophylaxis for GI bleed – administration of PPI , sucralfate , ranitidine
  60. 60. Metabolic , electrolyte and acid base disturbances • Hyponatremia • Hypokalemia – decreased dietary intake , chronic illness , secondary hyperaldosteronism , frequent GI losses • Hypophosphatemia – due to amount of regenerative liver mass as phosphate be a substrate for various kinase enzymes that phosphorylate proteins for liver regeneration • Hypoglycemia – failure of hepatic gluconeogenesis , high plasma insulin levels due to decreased uptake • Respiratory alkalosis – due to hyperventilation – direct stimulation of respiratory centre by toxic substances
  61. 61. Treatment Hypokalemia 3 Meq (1.5 ml kcl ) if K+ >3 Meq 4 Meq (2 ml kcl ) if K+ is 2.5 - 3 Meq 5 Meq (2.5 ml kcl ) if K+ is 2 – 2.5 Meq 6 Meq (3 ml kcl ) if K+ is < 2 Meq Hyponatremia Restrict sodium infusion to < 2 Meq /kg/day Hypoglycemia Increase GIR Maintain blood sugar levels between 100 – 200 mg/dl
  62. 62. Infections • Ninety per cent of patients with acute liver failure and grade 2 or more encephalopathy have clinical or bacteriological evidence of infection • The majority of infections are respiratory. • The high rate of infection can be related to poor host defences with impaired Kupffer cell and polymorph function
  63. 63. Renal • Hepatorenal syndrome is the most common cause of renal insufficiency in ALF • Secondary to renal vasoconstriction • Type 1 – rapidly progressive in renal function , doubling of s. creatinine to a level > 2.5 mg/dl or 50 % reduction in CrCl to < 20 ml/min in less than 2 weeks • Type 2 – progression slow , > 2 weeks
  64. 64. Treatment • Primarily focussed on decreasing splanchic circulation – 1. Vasoconstrictors – Terlipressin 2. Alpha agonist- nor-epinephrine , medodrine Very effective in reversal of functional renal insufficiency
  65. 65. Prognosis • Overall survival for those reaching grade 3 or 4 encephalopathy is 20% without transplantation. • If only grade 1 or 2 coma is reached, survival is around 65%. • Aetiology is important - 66% for hepatitis A, 38.9% for hepatitis B and 50% for acetaminophen overdose • Decerebrate rigidity, with loss of the oculovestibular reflex and respiratory failure are particularly ominous • Prothrombin time is the best indicator of survival • The association of a clotting factor V concentration of less than 15% with coma is also ominous
  66. 66. • Liver biopsy -Hepatic parenchymal necrosis of more than 50% is associated with a reduced survival • The causes of death are: cerebral oedema, infection, bleeding, respiratory and circulatory failure, renal failure, hypoglycaemia and pancreatitis • Hyper-acute liver failure - the chance of survival without transplantation is more than in acute liver failure
  67. 67. Auxiliary liver transplantation • The native liver is left in place • Donor liver graft either placed in the right upper quadrant alongside the native liver (heterotopic), or part of the native liver is resected and replaced with a reduced size graft (orthotopic). • The intention - to provide viable liver function from the graft, giving the native liver time to recover and regenerate. • The advantage over conventional transplantation is the temporary need for immunosuppression