Functions of the Liver. Defined.. Epidemiology. Etiology 3/2/2015

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1 Functions of the Liver Acute Liver Failure Rebecca Duke DNP, MSN, APN-CNP AACN Spring 2015 Transplant Surgery Nurse Practitioner Secretory 1) Bile acid from cholesterol 2)Conjugation of bili Excretory Excretion of exogenous dyes/substa nces Metabolic 1) CHO metabolism 2) Lipid metabolism 3) Ammonia acid metabolism 4) Cholesterol synthesis 5) Mineral metabolism 6) Ammonia formation 7) Vitamin metabolism 8) Nucleic acid metabolism 9) Interconversion of sugars Synthetic Synthesis of 1) Albumin 2) Alpha 1 Gamma globulins 3) Clotting factors 4) Binding proteins 5) Transport Proteins 6) Hormones 7) Cholesterol Detoxification of 1) Xenobiotics 2) Steroids 3) Thyroid hormone 4)Endogenous metabolit es Storage 1) Glycogen 2) B12 3) Vitamin A 4) Copper 5) Iron Defined.. Acute liver failure (ALF) can also be referred to as fulminant hepatic failure or necrosis, or subfulminant hepatic failure Development of severe acute liver injury with encephalopathy and impaired synthetic function (INR of >/= 1.5) in a patient without pre-existing liver disease or cirrhosis. Usually occurring in < 26 weeks For transplantation purposes needs to be < 8 weeks Does not include ETOH related disease Timeframes: Hyperacute < 7 days Acute 7-21 days Subacute > 21 days and < 26 weeks Fulminant (2 wks) vs subfulminant (2-12 wks) Epidemiology Etiology Approximately 2000 cases per year in the US Most prominent causes are drug induced, viral hepatitis, autoimmune liver disease and shock/hypoperfusion 20% have no discernible cause Often affects young people and carries high morbidity and mortality Prior to transplantation < 15% survival With transplantation survival is >65% 50% mortality overall Acetaminophen toxicity Drug reactions (drug induced liver injury DILI) Viral Hepatitis HAV, HBV, HDV Autoimmune hepatitis Wilson s disease Budd-Chiari Acute fatty liver disease of pregnancy HELLP (hemolysis, elevated liver enzymes, low platelets) Shock/Hypoperfusion 1

2 Acute Liver Failure Etiology Adults - US Acetaminophen Drug Reactions HBV HAV Indeterminant US Acute Liver Failure Study Group from 23 sites Acute Liver Failure in Children Infants Infections HSV, Adenovirus, HBV, Parvovirus, Echovirus, others Drugs/Toxins Acetaminophen Cardiovascular ECMO, Hypoplastic left heart syndrome, shock, asphyxia, myocarditis Metabolic Galactosemia, tyrosinemia, iron storage, mitochondrial condition, HFI, fatty acid oxidation, others Toddlers/Older Children Infections HAV, HBV, HDV, NANB hepatitis, EBV, CMV, HSV, Leptospirosis, others Drugs/Toxins Valproic acid, INH (isoniazid), halothane, acetaminophen, mushroom, phosphorous, aspirin, others Cardiovascular Myocarditis, heart surgery, cardiomyopathy, Budd-Chiari syndrome Metabolic Fatty acid oxidation, Reye s syndrome, leukemia, others Case Presentation 25 y/o F presents to the ER with c/o nausea, vomiting, malaise. She admits to hypothyroidism but otherwise no other medical history. Admits n/v has been going on x 1 day, malaise about the same amount of time. She has not really been able to keep any fluids down for the past 12 hours. She initially denies any medications other than oral contraceptives and synthroid, NKA. She is not accompanied by anyone in the ER Initial Labs: 6.9 X < INR 1.7 Amylase 22 Lipase 35 UA/Urine Hcg neg, Hcg neg TSH 2.6 Case Presentation Cont d She is given zofran IV and started on IVF. She states that she is not really feeling much better. When further prodded about her history, she admits to taking 12,000 grams of acetaminophen 3 days ago. She admits that she just recently had a break up with her boyfriend and has been depressed. She didn t really mean to end her life but wanted to numb the pain. She denies any other illicits, medications or alcohol intake. Psych is consulted ASAP and an acetaminophen level is ordered. Other orders include NG tube placement, activated charcoal lavage and IV n-acetylcystine was ordered. Social worker arrives at the bedside for assessment as well. They find family members to contact and call them to bedside. Synthetic Alterations/Lab Abnormalities Symptoms Synthetic Dysfunction Prolonged PT/INR Poor prognosis for rising INR despite normalization of AST/ALT Elevated AST/ALT Elevated bilirubin level Thrombocytopenia (</= 150,000) Other abnormalities Elevated creatinine Elevated amylase and lipase Hypoglycemia Hypophosphatemia Hypomagnesemia Hypokalemia Acidosis or Alkalosis Elevated ammonia level Elevated LDH Fatigue/Malaise Lethargy Anorexia Nausea and/or vomiting RUQ abd pain Pruritus Jaundice Abdominal distention Easily bruises Clay colored stools Muscle wasting Altered sensorium 2

3 Alcohol Guidance Physical Examination Findings Standards drink is any drink containing 14 grams of ETOH (0.5 ounces or 1.2 tablespoons One standard drink = 150 ml table wine, 60 ml fortified wine, 425 ml low alcohol beer, 250 ml beer gm/day for 10=20 years causes hepatitis or cirrhosis Only 15% of alcoholics develop alcoholic liver disease Generalized Fever- common in those with HSV Orthostatic hypotension volume depletion Neurological findings HEENT Kayser-Fleisher rings need slit lamp exam or optho to see usually Dermatological Jaundice, HSV lesions GI/Abdominal Abd distention RUQ tenderness Hepatomegaly Neurological Examination Findings Diagnosis and Evaluation Hepatic Encephalopathy Grade I Changes in behavior, mild confusion,slurred speech, disordered sleep Grade II Lethargy, moderate confusion Grade III Marked confusion (stupor), incoherent speech, sleeping but wakes with stimulation Grade IV Coma, unresponsive to pain Mild asterixis noted with grade I, pronounced with grade II-III, absent grade IV Cerebral edema may develop 25-35% of those with GIII HE and 75% of those with GIV Neurological exam including frequent pupil assessment vital Increase ICP can lead to: HTN, bradycardia, respiratory distress, seizures, brain stem herniation History is essential Prolonged PT/INR Climbing INR is poor prognostic indicator Do not give FFP unless prior to a procedure or active bleeding Elevated aminotransferases Decrease does not always mean recovery Highest in ischemic injury times ULN Elevated bilirubin Thrombocytopenia Hypocoagulability may occur Elevated creatinine hepatorenal syndrome Amylase and lipase secondary affect Hypoglycemia liver can not store glucagon Hypophosphatemia mass utilization of this with stress state Hypokalemia Hypomagnesemia Acidosis Elevated ammonia level Elevated LDH seen in ischemic injury most commonly Viral/Disease specific testing Diagnosis and Evaluation HAV, HBV, HDV testing Wilson s Coomb s negative and ceruloplasmin levels low, check copper level Acetaminophen level also history Imaging Head CT once mentation affected Allows ICP monitor to be placed if appropriate and r/o other etiology CXR Pulmonary edema CT/Abd imaging evaluate anatomical etiology Budd Chiari, mass Medical Management Cause based therapy Acetaminophen N-acetylcystine Hepatitis B Antiviral therapy Mushroom poisoning Charcoal Budd-Chiari Transjugular intrahepatic portosystemic shunt placement, surgical decompression or thrombolysis HSV Acyclovir Wilson s Liver Transplantation, plasma exchange with FFP AIH usually steroids are too late, but can be tried Fatty Liver Disease of Pregnancy - Delivery 3

4 Hepatic Encephalopathy Hepatic Encephalopathy Neuropsychiatric disturbance leading to coma. The cardinal feature of acute liver failure, progressing over hours to days More insidious in chronic liver failure when it is a sign of worsening liver failure Pathogenesis:- nitrogenous compounds derived from bacterial action in the colon are not metabolized in the failing liver; in addition shunting of portal blood to systemic circulation by-passes the liver. Compounds involved - ammonia and derivatives of aromatic amino acids (eg mercaptans, a cause of fetor hepaticas) Any changes in cognition warrants work-up Initial work-up for other etiology of mental status changes CT or MRI head r/o bleed, stroke Metabolic concerns TSH Hyponatremia Ammonia level Drug screen Assessment of portosystemic shunting -Asterixis-liver-flap AEIOUTIPS Alcohol, Epilepsy, Electrolytes, Encephalopathy, Insulin, Opiates, Oxygen, Uremia, Trauma, Temperature, Infection, Poisons, Psychogenic, Shock, Stroke, SAH, Space-Occupying lesion HE Classification/Grading Hepatic Encephalopathy Medications Lactulose Comes in powder/liquid formulation Can administer both orally or rectally Po through NG tube PR through enema Too much will cause diarrhea Look for electrolyte imbalances Rifaximin oral antibiotic remains almost entirely in GI tract Metronidazole no longer utilized Neuropathy, other toxicity Erythromycin no longer utilized Oto toxic Admit to ICU for grade IV or worse Can monitor airway and mentation Considerations for ICP Monitoring Airway Protection Hyperacute and acute etiology Arterial ammonia >150 mol/l Renal failure/dysfunction Fever Vasopressor Requirements Hyponatremia When do you intubate the patient When airway becomes compromised When you need to sedate a patient When mentation/cognitive function is altered and unable to protect the airway 4

5 Acetaminophen Level Treatment Nomogram Acetaminophen Toxicity Acetaminophen Toxicity: Treatment > 12 years of age GI decontamination activated charcoal Prevention of absorption If beyond 2 hours of ingestion data limited N-Acetylcysteine - Absorbed in the GI tract If acetaminophen ingested < 4 hours wait for level; if > 8 hours administer immediately regardless of quantity Peak plasma can be seen within 15 mins 20 hour protocol: 3 sequential infusions loading dose of 150 mg/kg IV (above 40 kg) over mins Dose #2-50 mg/kg IV over 4 hours Dose #3 = 100 mg/kg IV over 16 hours Can continue dose #3 until liver recovers or patient is determined to need liver transplant 72 hour PO protocol 140 mg/kg followed by 17 doses of 70 mg/kg at 4 hour intervals If patient vomits loading dose or any dose within 1 hour change them to IV dosing Can continue po dose until recovers Liver Transplant If patient took extended release acetaminophen level will be superficially lower For kids < 40 kg treatment can be recommended based on level but need to decrease fluid in IV formulation will give them too much sodium Phase I Phase II Shortly after ingestion to hours Signs of GI irritability N/V, anorexia Diaphoresis Pallor CNS depression usually not present unless massive overdose or has also simultaneously ingested CNS depressant Small children spontaneous vomiting following ingestion is common If toxicity continues this is the latent phase up to 48 hours Initial symptoms resolve and patient may feel better Hepatic enzymes, bilirubin, lactate, phosphate, and prothrombin time or INR values will progressively rise Hepatic enzymes can be strikingly elevated RUQ abd pain may develop as liver becomes enlarged and tender If given treatment most do not progress beyond this phase LFT s gradually improve to normal 5

6 Phase III A small number of patients will progress to this phase This usually occurs 3-5 days following ingestion Symptoms limited to anorexia, nausea, general malaise and abdominal pain Less severe cases Confusion,stupor, sequalae of hepatic necrosis (Jaundice, coagulation defects, hypoglycemia), encephalopathy, renal failure and cardiomyopathy More severe cases Death usually as a result of complications associated with fulminant hepatic failure Idiosyncratic Drug Reactions Idiosyncratic Drug Reactions Idiosyncratic Drug Reactions: MOA Idiosyncratic: unpredictable and dose-independent Pattern of injury varies Cholestatic (alkaline phosphatase) Hepatocellular (ALT) Mixed Mechanism of Action Covalent bonds disruption of cell membrane Inhibition of cellular pathways Abnormal bile flow Pump dysfunction Apoptosis via TNF Inhibition of mitochondrial synthesis Not an exhaustive list Over 400 drugs listed in PDR to cause liver injury ACEi, ARB s, statins very common Idiosyncratic Drug Reactions What factors influence susceptibility? <10 and >40 y/o, obesity, female gender, DM, etoh use, genetic variability Importance of discontinuing medication after liver injury. Likelihood of progression to liver failure is dependent on how long you continue to take the drug after identification of liver injury. What is the clinical course and natural history of disease? Repair varies : days to weeks to months Viral Causes of Acute Liver Failure 6

7 Viral Causes of Acute Liver Failure Factors Associated with Increased Mortality: HBV Hepatitis B: 8% +/- Hepatitis D Hepatitis A: 4% Hepatitis C: does not cause ALF Hepatitis E: in developing countries Russia, Pakistan, Mexico, India HSV, EBV Management and Prognosis Acute Liver Failure 7

8 Predicting Outcomes in Acute Liver Failure Complications of Acute Liver Failure Most important predictive factors: Degree of encephalopathy Grade II HE 65-70% Grade IV - < 20% Rising INR AST/ALT peak and then decline Suggested laboratory markers: Factor V AFP Serum Phosphate VII/V ratio > 30 Clinical algorithms: King s College Criteria APACHE II CNS disturbances Hepatic encephalopathy Cerebral edema Hemodynamic Collapse Infections Coagulopathy and bleeding Renal failure Metabolic derangements Cerebral Edema Increased ammonia level Absorbed and metabolized by the astrocytes Astrocytes use ammonia when synthesizing glutamine from glutamate Increased levels of glutamine lead to an increased in osmotic pressure in the astrocytes, which become swollen Degree of encephalopathy correlates w/ cerebral edema Grade I-II: 25-35% risk Grade III: 65% risk Grade IV: 75% risk Herniation Compromises cerebral blood flow hypoxic brain injury Treatments for Elevated ICP: How useful are they? HOB > 30º Decreased patient stimulation stimulation causes increased glucose consumption and osmotic swelling Hyperventilation - can be temporary but works fairly quickly Barbiturates use limited 2/2 hypotension Mannitol works but no survival benefit Corticosteroids - No real benefit Hypertonic Saline may decrease ICP but no survival benefit Hypothermia (32-33ºC) may show survival benefit but arrhythmias and infections can become more prevalent more studies needed Hemodynamic Failure Infections Decreased SVR Renal failure, pulmonary failure and cardiovascular collapse Restoration of hemodynamics: Crystalloid initially Once euvolemic, studies show albumin is better than crystalloid Pressors Alpha adrenergics (epi- and norepi-) might decrease O2 delivery Dopamine Increased O2 delivery Vasopressin Increase cerebral blood flow but can increase incidence of ICH Not really used: Dopamine, Vassopressin No benefit of NAC, prostaglandins and steroids Etiology Bacterial (90%): gram negative organisms, staphylococci Fungal (30%) SIRS has been shown to decrease survival rate Should we use prophylactic antibiotics? Decrease # of infections But no improvement in outcomes Routine surveillance blood, sputum, urine cultures and CXR If febrile, pan cover until cx s back 8

9 Coagulopathy Correction of Coagulopathies Coagulopathies: Prolonged PT Platelet dysfunction Reduction in factors II, VII, IX and X Defective production of procoagulant factors: Proteins C and S Antithrombin III Upregulation of factor VIII End Result: Clinically significant spontaneous bleeding is relatively unusual in ALF, even during liver transplant. Overuse of blood products Vitamin K Platelets if clinically significant bleeding or < 10k Limited role for prophylactic FFP, platelets, cryoprecipitate Giving FFP takes away your best prognostic indicator Recombinant VII cost is a factor Renal Failure Metabolic Disturbances RF contributes to mortality and overall poor prognosis Multi-factorial Pre-renal ATN (from prolonged pre-renal state vs nephrotoxic agents) HRS CVVD > HD may lead to more brain stability Lactic acidosis w/ compensatory respiratory alkalosis Hypokalemia Hypoglycemia (40%) Hypophosphatemia Hypomagnesemia Early nutrition is important APACHE II Scoring Table Portal Hypertension/Variceal Bleeding Not usually associated with acute liver failure Usually related to decompensated cirrhosis Exceptions: Acute Budd Chiari Portal Venous changes 9

10 Liver Transplant Indicated when prognostic criteria suggest a high likelihood of death Liver Transplant 2014 UNOS data 6142 liver transplants Currently of 15,913 listed only 3 for status 1a and 22 for 1b Survival rates in pre-transplant era ~ 15% vs 40% now Better prognosis: acetaminophen, HAV, ischemia, AFLP Worse prognosis: HBV, AIH, Wilson s, Budd-Chiari Criteria for Liver Transplant Surgical Management - Listing for Status 1a Candidate is at least 18 years of age Life expectancy without a transplant of < 7 days and has at least one of the following conditions: Fulminant liver failure without pre-existing disease and currently in the ICU HE onset within 8 weeks of first symptoms and at least one of the following Is ventilator dependent Requires HD, continuous veno-venous hemofiltration (CVVH), or continuous veno-=venous hemodialysis (CVVHD) Has an INR > 2.0 Primary non-function of the transplanted organ within 7 days of transplant, evidenced by at least one of the following Anhepatic Aspartate aminotransferase (AST) Hepatic Artery Thrombosis (HAT) within 7 days of transplant Acute decompensated Wilson s disease Pediatric patients can be listed as status 1b for hepatoblastoma, organic acidemia or urea cycle defect and PELD exception score of 30 points for at least 30 days; there are also other adolescent criteria for chronic disease Liver Assist Devices Liver Dialysis MARS ELAD Insurance coverage questionable as these are considered investigational 10

11 MARS Principles of MARS M = Molecular A = Adsorbents R = Recirculating S = System Albumin is a transporter protein made by the liver Able to bind to a range of different molecules Acts as a circulating depot, scavenger or transporter Plasma albumin can be deficient in quantity and quality Normal level MARS Therapy Gambro Renal Products US DG Treatment Regimen FDA approved for treatment of ALF due to drugs or toxins and for advanced HE in ACLF 8 hours of MARS therapy / day for 3 consecutive days. Albumin dialysate: 600 ml of 16 % albumin Exchange of MARS cartridges after every treatment session May continue CRRT portion of circuit after completion of MARS therapy Heparin or citrate anticoagulation 11

12 Advantages of MARS Clinical Considerations Effective and selective removal of water soluble/protein bound toxins Management of fluid, electrolyte, acid/base balance Control of glucose and lactate level Safety barrier between blood and adsorber columns Highly biocompatible membrane Minimal staff handling Cost-effective on-line regeneration of Albumin Compatible with Prisma CRRT monitors Monitor initial and regular PTT levels to maintain target (50-80) Monitor electrolyte balance Glucose, K, Mg, PO4 Monitor drug levels (Antibiotics, protein bound drugs) Monitor VS Change MARS treatment kit as ordered Beneficial Effects of MARS Improvement of jaundice and pruritus Improvement of hemodynamic instability ELAD Extracorporeal Liver Assist Device Reduction in portal pressure Reduction in ICP in ALF Improvement of renal function in hepatorenal syndrome Improvement in hepatic encephalopathy ELAD Synopsis Form of Bioartificial Liver Support (mimics both detoxifying and synthetic functions of the liver) Prior small studies demonstrate a non-statistical survival benefit in alcohol induced liver disease ( AILD) and ALF Multi-center studies in progress to study the efficacy of ELAD in AILD and ALF ELAD C3A Cells Allogeneic Cell Therapy C3A hepatocytes divide to fill available extracapillary space in the cartridges Plasma flows through semipermeable hollow fibers Bidirectional diffusion between UF and C3A cell Toxins processed and metabolites secreted across membrane to UF 13 12

13 ELAD C3A Cells ELAD C3A Cells Retain Primary Hepatocyte Function Process toxins / metabolites Consume large amounts of O 2 and glucose Active P-450 enzyme system Synthesize liver proteins including AFP Human Liver Proteins Synthesized by C3A Cells Albumin Antithrombin III α-fetoprotein Factor V α-1-antichymotrypsin Fibrinogen α-1-antitrypsin Transferrin C3 Complement Factor VII HGF TGF-α ELAD Bioartificial Liver Support System Future Directions Studies with MARS have demonstrated safety and tolerability, and may therefore foster wider application Provides continuous extracorporeal treatment of ultrafiltrated plasma for up to 5 days Larger RCTs with defined end points are needed to examine efficacy of therapy; results of current ELAD trials awaited Studies should differentiate between the disease processes of ALF and ACLF, since clinically relevant study endpoints may differ CONFIDENTIAL 17 Questions? Thank you! rduke@nmh.org 13