Acute & chronic liver failure

PRESENTER: FELISTERS BOSIBORI
FACILITATOR: DR. SOME

OUTLINE
 DEFINITION
 ANATOMY AND PHYSIOLOGY
 ETIOLOGY AND EPIDEMIOLOGY
 PATHOPHYSIOLOGY
 CLINICAL FEATURES
 DIAGNOSTIC EVALUATION
 TREATMENT
 COMPLICATIONS
 PROGNOSIS

DEFINITION
A clinical syndrome that results from massive necrosis
of liver cells leading to hepatic encephalopathy and
impaired synthetic function causing coagulopathy
(INR>1.5) in a person with previous normal liver or
compensated liver disease.
ALF includes;
(1)Biochemical evidence of acute liver (usually <8 wks
duration)
(2) no evidence of a known chronic liver disease;

(3)hepatic-based coagulopathy that is not corrected
by parenteral administration of vitamin K;
(4) hepatic encephalopathy must be present if the
uncorrected prothrombin time (PT) is ≥ 15 seconds
or international normalized ratio (INR) is 1.5 to 1.9,
respectively; and
(5) hepatic encephalopathy is not required if the
PT is ≥ 20 seconds or INR ≥2.0, respectively.

CLASSIFICATION
 Fulminant HF is acute hepatic decompensation
within 8wks from onsent of illness.
 Subfulminant HF/ late onset HF is liver disease up
to 26wks prior to development of encephalopathy.

Blood Supply
 The liver receives a blood supply from two sources.
 The first is the hepatic artery which delivers oxygenated blood
from the general circulation.
 The second is the hepatic portal vein delivering deoxygenated
blood from the small intestine containing nutrients.

 The blood flows through the liver tissue to the hepatic cells
where many metabolic functions take place.
 The blood drains out of the liver via the hepatic vein.
 The liver tissue is not vascularised with a capillary network
as with most other organs, but consists of blood filled
sinusoids surrounding the hepatic cells.

EPIDEMIOLOGY
 approximately 2000 cases annually occurring in the United
States.
 Acetaminophen or paracetamol overdoses are prominent
causes of FHF in Europe and, in particular, Great Britain.
 In the developing world, acute HBV infection dominates as
a cause of fulminant hepatic failure because of the high
prevalence of HBV.
 more often in women (73%) than in men
 Patients younger than 10 years and older than 40 years tend
to fare relatively poorly
 women with acute liver failure- older (39 y) than men (32.5
y)

ETIOLOGY
Idiopathic – 15%
Acetaminophen overdose: commonest in developed
countries.
Viral Hepatitis:
 Hepatotrophic viruses: HBV, HDV, HEV, HAV
 Non-hepatotrophic viruses: adenovirus, CMV, HSV,
EBV, Paramyxovirus, Hemorrhagic fever virus.
Pregnancy: acute fatty liver of pregnancy
HELLP syndrome

Drugs: idiosyncratic hypersensitivity or dose
dependent.
Toxins: Aflatoxicosis, Aspergillus Flavus
Vascular: Portal V thrombosis, Budd Chiari Syn
Metabolic: wilsons disease
Autoimmune disease
Malignancy: primary and metastatic
Miscellaneous: heat stroke, graft failure.
NB: Broadly classified as Acetaminophen and non-acetaminophen causes
for prognostication.

Etiology of ALF In different age group
Neonates Infants
Infection
Inborn errors of
metabolism
Immune mediated
Ischemia
& abnormal
Perfusion
Drugs & toxins
other
HSV, Adeno virus
HBV
Galatosemia,
tyrosinaemia,
Hereditary fructose
Intolerance.
Neonatal
Hemochromatosis,
Hemophagocytic
syndrome
Congestive heart failure,
severe aspyxia
HAV, HBV, HSV
hereditary fructose
Intolerance
Autoimmune hepatitis
Congestive heart
Failure,
Acetaminophen,INH,
valproate malignancy

Etiology Cont….
2-10 year old 10-18 yrs old
Infection
Drugs & toxins
Immune mediated
Ischemia
& abnormal
Perfusion
Metabolic
other
HAV, HBV, HSV
Acetaminophen,INH,
valproate
Autoimmune hepatitis,
hemophagocytic
syndrome
Budd-Chiari syndrome,
Heart failure, cardiac
Surgery, myocarditis
Wilson’s disease, Reye’s
syndrome,
Hemophagocytic
syndrome, septicemia,
heat stroke
HAV, HBV, HSV, HCV
Acetaminophen,INH,
valproate
Autoimmune hepatitis,
hemophagocytic
syndrome
Budd-Chiari syndrome,
Heart failure, cardiac
Surgery, myocarditis
Wilson’s disease, Reye’s
syndrome,
Hemophagocytic
syndrome, septicemia,
heat stroke

Important drugs responsible for ALF
•Dose dependant:
Acetamenophen
CCBs
Mushroom ( aminata
phalloides)
•Idiosyncratic:
INH
Valproic acid
Phenytoin
Carbamazepine
Propylthiouracil
Halothane
Nitrofurantoin
Herbal drugs

Wilson disease
 It is an autosomal recessive disorder.
 The condition is due to mutations in the Wilson
disease protein (ATP7B) gene
 May present as ALF in young adults
 ALF due to wilson disease should be suspected in any
pt with.
-ALF + Coomb’s negative hemolytic anemia.

Mechanisms of hepatic injury
 Immune mediated hepatocellular injury
- Viral infections
- Drug hepatotoxicity (dihydralazine, halothane)
 Direct hepatocellular injury
- Hepatotrophic virus family-HAV, HBV, HCV
- Toxic or reactive metabolites- acetaminophen
- Toxic metabolites of compounds-metabolic
diseases
 Ischemic hepatocellular Injury
- Shock states, SIRS

Effects are:
• Impaired hepatocyte regeneration
• Altered parenchymal perfusion
• Endotoxemia
• Decreased hepatic reticulo-endothelial function
Hepatic failure

Pathophysiology ctd…
CEREBRAL EDEMA
 development of cerebral edema/intracranial hypertension is the
major cause of morbidity and mortality of patients suffering
from acute liver failure- ?etiology- multifactorial
 increase of intracranial blood volume and cerebral blood flow-
because of disruption of cerebral autoregulation- elevated
systemic concentrations of nitric oxide, bacterial endotoxin,
tumor necrosis factor-alpha (TNF-a), and interleukin-1 (IL-1) and
-6 (IL-6)
 Accumulation of glutamine in astrocytes leads to swelling and
edema.
MULTISYSTEM ORGAN FAILURE
 Hyperdynamic circulation state leads to low systemic vascular
resistance (mimics sepsis) circulatory insufficiency and poor organ
perfusion may initiate FHF or lead to complications

Pathophysiology ctd…
ENCEPHALOPATHY
Wide variety of agents, including ammonia, free fatty
acids, mercaptans, phenols, bile acids and aromatic
amino acids combine to produce hepatic
encephalopathy by several different mechanisms:
 direct cellular effect
 indirect: cause metabolic derangement
 conversion to false neurotransmitters
 alteration of permeability of BBB: allows entry of toxic
metabolites into the brain and thus contributes to
cerebral oedema - major cause of death: present in
32% of patients at PM.

CLINICAL PRESENTATION
HISTORY
 Duration of illness.Onset of jaundice and
encephalopathy.
 Risk factors for hepatitis: eg- street food, sanitation,
BT, surgery.
 Drug & immunization history
 H/O any bleeding episode.
 Features of hepatic encephalopathy-Initially reduced
alertness and poor concentration, progressing through
behavioural abnormalities such as restlessness and
aggressive outbursts, to drowsiness and coma

 weakness, nausea and vomiting
 Right hypochondrial discomfort
 Family history
 Systemic enquiry

Physical examination
 Jaundice
 Anaemia
 Vital signs: Hypotension, tachycardia, tachypnoea.
 Mental status.
 Hepatomegaly –uncommon, liver usually N size - smaller
 Splenomegaly
 Stigmata of chronic liver disease- ALF 2’ to compensated
diseases(caput medusa, spider nevi, spider angiomata, ascites,
contractures, palmar erythema)
 Ascites
 Features of raised ICP- unequal n fixed pupils
 flapping 'hepatic' tremor
 profuse sweating, local or general myoclonus, focal fits or
decerebrate posturing
 Papilloedema occurs rarely and is a late sign
 Fetor hepaticus

 Cardiovascular- hypotension with low SVR
 Pulmonary- resp alkalosis, impaired peripheral O2
uptake, pulmonary edema, ARDS
 GIT- GI bleeding( decreased clotting factors &
platelets, DIC), pancreatitis due to ischaemia
 Renal-ATN, hepatorenal syndrome, hyponatremia,
hypokalemia, hypophosphatemia
 Hematology- coagulopathy, infection
 Endocrine- hypoglycemia, adrenal insufficiency

Investigation
a. Complete blood count: Leucocytosis ,
thrombocytopenia
b. LFT: Serum bilirubin 
 ALT: raised
 AST :raised esp in paracetamol- 100-500x normal
 Alkaline phospatase: may be normal or 
 PT and INR:prolonged, to see the severiry of
coagulopathy and to asses prognosis.
 Albumin: usually normal unless in prolonged course
c. Blood grouping and cross matching
d. blood cultures
e. Blood sugar levels

Inv.continued
E . Biochemical test:U/E/Cs
 S. Electrolytes- Hypokalaemia and others.
 S. Glucose- Hypoglycaemia.
 S. Creatinine
 S. Ammonia- 
 S. Calcium , Phosphate, Magnesium
 S. lactate: At 4 hours(>3.5) or at 12 hours(>3)
are early predictors of outcome in
acetamenophan induced ALF.
F . Blood gas analysis.

To detect cause
G . Serological marker
 Anti HAV IgM
 HBsAg, AntiHBcore IgM antibody
 Anti HEV IgM
 Screening for other viruses- HSV, CMV etc.

Immunological test
 S. immunoglobulin, ANA, anti SMA, antiLKM1
J . Serum acetamenophen level
K . USG of HBS
L . Screening for metabolic disease.
M . EEG- encephalopathy has xteristic pattern
N . Liver biopsy :in auto-immune, metabolic
causes of liver failure. Transjugular,
Percutaneous CI due to coagulopathy

Screening for Wilsons disease
 Slit Lamp Eye examination for KF ring &
cataract
 Serum copper levels
 Serum Ceruloplasmin
 24 hours urinary copper

Management of ALF
 Medical: To maintain physiological functions of liver
 Supportive care
 Specific treatment
 Surgical:
 Extracorporeal systems
 Liver transplantation

Supportive care.
 quiet environment.
 ICU- hemodynamic n ventilatory support
 Avoid sedation and stimulation.
 Fluid restriction- 60-80% of daily requirement.
Choice of fluid: 0.225% Nacl in 10% dextrose.
 Prevention of hypoglycemia(maintain glucose level >4
mmol/L).

 IV H2 blocker or PPI.
 Antibiotics: Cefuroxime, amoxicillin, fluconazole or
Cefotaxime+ flucoxacillin
 Anaemia should be corrected to ensure maximum oxygen
supply to tissue.
 Lactulose-metabolized to organic acids by colonic
bacteria.Reduces ammonia prodn by bacteria & traps
ammonia in acidic intestinal contents. Avoid diarrhea!
 IV N-acetylcysteine benefits pts after paracetamol
overdose even with encephalopathy and
coagulopathy- same dose as PCM

 early intubation, as soon as gag reflex lost or patient develops grade
III/IV encephalopathy
 IV midazolam or propofol can be used for intubated patients who
require sedation. Sedatives should not be used in patients who are not
intubated.
 Immunosuppressive RX- steroids may help in auto-immune hepatitis
 Antivirals e.g pleconaril for enteroviral hepatitis,Acyclovir for HSV.
 Consider plasma exchange in Wilson’s disease
 AminataPhylloides poisoning- Gastric lavage, High dose Pen G
 Budd Chiari- Ttansjugular intrahepatic portocaval Shunt and
Anticoagulation
 Management of complications!

Close Monitoring
 Continous O2 saturation
 Clinical status: Pulse & BP hourly, liver size 12 hrly
 Strict input-output chart : Avoid fluid overload
 CVP, Foley’s and arterial line : MAP >60 mmHg
 Frequent evaluation of blood glucose and
neurological status.
• 12 hourly electrolyte and coagulation studies

Plasmapharesis
 Blood purification procedure
 High volume plasmaphoresis associated with rise in
conscious level, haemodynamics and reduction in
arterial ammonia concentrations
 Disadv. is that possible hepatic growth factors are
removed along with hepatotoxic mediators

Liver transplantation
 Pts with anticipated survival of < 80% and no
contraindication to transplantation should be
placed on waiting list as soon as possible.
 Multiorgan failure is major C/I to transplantation.
 Cerebral perfusion pressure <40 mmHg is a relative
contraindication.

ALF: common complications
 Encephalopathy
 cerebral edema
 Raised ICP
 Infection
 Coagulapathy
 Hypoglycemia
 Dyselectrolytemia
 Acid base disturbance.
 Multi-organ failure

Hepatic encephalopathy
 Complex neuropsychiatric manifestation in a pt with liver
disease, after exclusion of brain disease.
 Ranges from altered mental status to coma.
 Failure of liver to detoxify toxins from intestines
 Pathogenesis multifactorial but ammonia major factor
 Rapid progression to coma, seizures and decerebrate
rigidity. Ass with cerebral edema in late stages.
 Death due to both herniation and hypoxia

Stages of encephalopathy
Encephalopathy Symptoms Signs
Stage I (mild)
Stage II
Stage III
Stage IV
Alert, euphoric, occasionally depression.
Poor concentration,Insomnia
slow mentation and affect,reversed
sleep rhythm.
Drowsiness, lethargic, inappropriate
behavior, disorientation, slurred speech
Stuporous but easily arousable, marked
confusion/disorientation, incoherent
speech
Coma, unresponsive but may respond to
painful stimulus.
Trouble drawing figures,
performing mental task,
EEG-normal
Asterexis,fetor
hepaticus,EEG slowing of
wave.
Asterexis, hyperreflexia,
rigidity, EEG-Triphasic wave
Planter extensor,
Rigidity ,Areflexia,
Flacidity.EEG-delta wave.

Aggravating factors of HE
 GI bleeding
 Hypovolemia
 Hypokalemia
 Hypoglycemia
 Sedatives
 Uremia
 Sepsis
 High protein diet
 Constipation
 Paracentesis

Encephalopathy
Treatment
 Low protein diet
 Lactulose 10-50ml 2-4 hourly
 Acid enema: Lactulose enema, vinegar-can be given 6
hourly
 Treat sepsis, bleeds and electrolyte imbalance.
 Avoid sedation esp benzodiazepines
 Intubate in Grade 3 and 4- risk aspiration
 Oral Neomycin, Metronidazoleor Vancomycin to decrease
colonic conc. Of ammoniagenic bacteria
 Flumazenil : Short lived results.

Cerebral edema
 Occurs in 80% of pts who
eventually develop stage 4
encephalopathy.
 Hyperammonia induces accumn
of glutamine within the cells
 Diagnosis usually difficult,usually
at postmotrtem
 Antemoterm dx suggested by
deterioration of
conciousness,neurological signs
eg increased muscle
tone,myoclonus,focal seizures.
 Signs of increased intracranial
pressure

Cerebral Edema
 Treatment
• Head elevated 20-30°  ICP
• IV mannitol
• Hypertonic saline
• Hyperventilation may help  ICP
• Hypothermia  ICP
• Avoid hyperthermia.

BLEEDING
 Due to inability of liver to synthesize the clotting factors, abnormality in
platelet structure and function, mild DIC
 Pts have a tendency to bleed at venupuncture sites
Treatment
 Inj. Vitamin K
 Fresh frozen plasma (FFP)- necessary if spontaneous bleeding occurs ( 5%
pts). Prophylactic use not assocd with reduction in morbidity or mortality.
Avoidance of FFP has advantage that PT remains valid prognostic marker.
 Platelet transfusion –Indicated in severe thrombocytopenia;If
platelet<10000/mm3 or platelet count<50000 with bleeding. Fresh whole
blood transfusion.
 Recombinant factor VII.

ELECTROLYTE 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 – due to impaired hepatic glucose release due to
glycogen depletion (failure of hepatic gluconeogenesis) , high plasma
insulin levels due to decreased uptake

ACID BASE IMBALANCES
 Respiratory alkalosis – due to hyperventilation – direct
stimulation of respiratory centre by toxic substances
 Metabolic acidosis-due to lactate accumulation
Treatment
• Volume expansion.
• Dopamine infusion.
• NaHCO3.
• Mechanical ventilation for M. acidosis.
• Plan for liver transplantation.

SEPTICAEMIA
Gram-positive (in 2/3rd cases):
Staphylococcus
Streptococci
Gram-negative (in 1/3rd cases):
Fungal infection

Septicemia ctd…
• Septic workup : culture blood, sputum & urine
• Cefuroxime, Amoxycillin, Fluconazole.
• Fungal infection : IV amphoterecin .
• We use fluconazole orally.
• Iv cefuroxime and flucloxacillin
• late rise in INR is usually a pointer to
uncontrolled sepsis and anti-fungals should be
introduced if a comprehensive regime of
antibacterials is already being used.

RENAL COMPLICATIONS
 Renal failure may occur in 50% pt. with ALF especially
in paracetamol poisoning.
Due to
 Hepatorenal syndrome.
 ATN by due to sepsis, endotoxemia, bleeding
hypotension.
 Directly by nephrotoxic drug.

 Treatment
• Dopamine infusion.
• Correct fluid overload, acidosis & hyperkalemia.
• Avoid nephrotoxic drugs.
• Dialysis

HEPATORENAL SYNDROME
Development of renal failure in pts with advanced liver
disease.
-common, associated with Spontaneous Bacterial Peritonitis
-may rapidly progress
-often associated with cerebral edema
-functional, due to vasoconstriction of renal vessels
-plasma urea/creat unreliable
RX: Ideal Rx is liver transplant

HEPATOPULMNARY SYNDROME
Syndrome of shortness of breath and hypoxemia coased by
vasodilation in lungs in patients with liver disease.
-decreased vascular resistance
-pulmonary edema.
-Hypoxaemia
-hyperventilation
-aspiration with progression

Prognosis
Without transplantation
 up to 80% die
 in specialist units approx 30% survive
Following transplantation
 up to 80% 1 year survival.
 long term prognosis is good

 High mortality
-severe encephalopathy
-EEG abnormalies
-severe coagulopathy ptt>100sec
-age <5yrs and >40yrs
-halothane,paracetamol
-major complications eg ARF,GI h'age

Non acetaminophen predictors
Poor prognosis in;
Age younger than 10yrs or >40yrs
Halothane hepatitis or idiosyncratic drug reactions
Jaundice present for > 1wk before onset of
encephalopathy
Prothrombin time > 50s
Serum bilirubin > 300mmol/L

Cirrhosis
 A consequence of CLD
 Characterized by replacement of liver tissue by fibrosis
& regenerative nodules
 Leads to irreversible loss of liver function & its
complications
 Micronodular- alcohol or Macronodular- chronic viral
hepatitis
 Decompensated= jaundice, variceal bleed,
encephalopathy and ascites

Causes
 Alcoholic liver disease
 Chronic viral hepatitis- C or B
 Non-alcoholic steatohepatitis
 Autoimmune hepatitis
 PBC & PSC
 Hemochromatosis, Wilson’s disease
 α1-antitrypsin deficiency
 Cystic fibrosis

Stigmata of CLD
 Muscle wasting
 Scratch marks
 Pallor, jaundice
 Parotid enlargement
 Xanthelasma
 Clubbing
 Palmar erythema
 Dupuytren’s contracture
 Spider nevi/angiomata
 Petechiae, purpura
 Decreased body hair
 Gynecomastia
 Testicular atrophy
 Caput medusae
 Edema, ascites
 Splenomegaly
 Asterixis
 Fetor hepaticus

Investigation
 Liver biopsy- gold standard, but not always
necessary
 Deranged LFT-
 ± elevated AST, alkaline phosphatase, ALT
 Increased bilirubin
 Low albumin, increased globulins
 Increased PT/INR
 Thrombocytopenia
 Low sodium
 Ultrasound- shrunken liver, ± portal HT/HCC

Staging of CLD
 Based on Child-Turcotte-Pugh scoring system
 Includes- each given score of 1-3
 Ascitis
 Encephalopathy
 Bilirubin
 Albumon
 PT/INR
 Class- total score
 A- 5-6
 B- 7-9
 C- 10-15

Treatment
 To retard progression & reduce complications
 Abstinence from alcohol
 Vaccination- Hep A & B
 Treat underlying cause

Complications
 Ascites
 Spontaneous bacterial peritonitis- SBP
 Variceal bleed
 Hepatic encephalopathy
 Hepatorenal syndrome
 Hepatocellular carcinoma- HCC

Ascitis
 Diagnostic paracentesis- SAAG >1.1
 Causes
 Portal HT
 Hypoalbuminemia- nephrotic, malnutrition, protein
loosing enteropathy.
 Raised renin-angiotensin-aldosterone levels
causing Na retention by kidneys

Ascitis- treatment
 Salt ± fluid restriction
 Diuretics- Spironolactone ± Furosemide
 Large volume paracentesis-
 With massive or refractory ascitis
 >5 lit. fluid removed in one go
 Albumin- ~8 gm/lit. fluid removed
 Avoid hepatorenal syndrome
 TIPS- transjugular intrahepatic portosystemic shunt
 For refractory ascitis or refractory variceal bleed
 Preferred for short duration, pending liver transplant
 Increases risk of hepatic encephalopathy, shunt
occlusion/infection

Spontaneous Bacterial Peritonitis
 s/s-
 Abdominal pain, fever,worsened ascitis & encephalopathy
 Dx- paracentesis
 PMN >250/microlitre
 Ascitic fluid culture- bedside,commonly Gram –ve bacteria
 Rx- Cefotaxime/Ciprofloxacin
 Prophylaxis- Ciprofloxacin/Co-trimoxazole
 Prognosis- 30% mortality during hospital stay &
70% within 1 year

Variceal bleed
 Varices- dilated submucosal veins, in esophagus or
stomach
 Cause- portal HT
 Causes ~80% of UGI bleed in Chronic Liver Dse
 Risk factors for bleed-
 Size of varices
 Severity of liver disease
 Continued alcohol intake
 UGIE- wale markings, hematocystic/red spots on varix
 Dx- UGI Endoscopy

Management
 Acute-
 Resuscitation
 FFP, platelets, vit. K
 Terlipressin/octreotide
 Lactulose
 Banding/sclerotherapy
 Balloon tamponade
 TIPS
 Surgery
 Prevent rebleed-
 Band ligation- over repeated
sessions
 Non-selective β- blockers-
Propanolol/Nadolol
 TIPS- for recurrent bleed or
bleed from gastric varices
 Surgery- portosystemic shunts
 Liver transplantation

Hepatic encephalopathy
 Confusiondrowsinessstuporcoma
 Ammonia is an identified/measurable toxin
 Precipitants-
 GI bleed
 Constipation
 Alkalosis, hypokalemia
 Sedatives
 Paracentesishypovolemia
 Infection
 TIPS
 Dx- clinical- s/s of CLD
with asterixis & altered sensorium

Management
 Correct underlying precipitating factor
 Avoid sedatives
 Restrict dietary protein intake
 Lactulose- 2-3 loose stools a day
 Oral antibiotic- Metronidazole, Rifaximin, Neomycin

Hepatorenal syndrome
 Occurs in patients with advanced CLD & ascitis
 Marked by renal impairment in the absence of any
renal parenchymal disease or shock
 Oliguria, hyponatremia & low urinary Na
accompany raised creatinine
 Albumin infusion, with vasoconstrictors
(norepinephrine, terlipressin/ornipressin,
octreotide) may help
 Liver transplantation is Rx of choice

Hepatocellular carcinoma
 Associated with cirrhosis in ~80%
 Suspect if- worsening of CLD, enlarged liver,
hemorrhagic ascitis, weight loss
 Dx-
 CT/MRI with contrast-
 Raised AFP- α-fetoprotein
 Liver biopsy
 Rx-
 Early-resection
 Advanced- liver transplantation or local palliative treatment
 Screening- US & AFP q 6 months

Liver transplantation
 Donor, cost, technical expertise
 Option in ESLD
 GVHD, recurrence

Acute & chronic liver failure

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