Acute Liver Failure

Topics

Definitions of failure and classification Aetiology- Acute versus acute on chronic Basic diagnostic workup Liver biopsy in the context ACLF-Ethical dilemma- HDU admission Treatment of complication

Hepatic encephalopathy Renal failure GI bleed Infection Coagulopathy

Aetiology specific treatment Organ support Liaison with Transplant centre

The mortality rate for acute liver failure ranges between 56% and 80%

Abnormal LFT is NOT ALF

Dear Doctor Patient’s bilirubin is 600 and has liver

failure- kindly urgently seeFamily was told transplant may be

necessary

Formal diagnosis of acute liver failure

An increase in PT by 4-6 seconds (INR>1.5)

And the development of hepatic encephalopathy (HE).

In a patient without pre-existing cirrhosis and with an illness of less than six months duration.

UK incidence of cirrhosis 17 per 100,000Prevalence of cirrhosis is 76 per 100,000ALF incidence is 1-6 per million per year

aCLF

This entity is quite common- background of cirrhosis. Innocent precipitating event culminates in MOF

EventsToxins (alcohol!)Vascular (hypotension- GI bleed,

dehydration, Portal vein thrombosis) Infection (SBP)HCC

ACLF-Ethical dilemma- HDU admission

For patients with aCLF

Young ageFirst presentationReversible pathology- sepsis, GI

bleeding or severe hepatitisA trip to ITU is a life changing

experience to some ‘alcoholics’

Few definitions

Hyperacute- <7days

Acute - >7days <21days

Subacute- >21days <6months

FHF- not used

Diagnostics:

Good history- difficult if HE

Initial Laboratory Analysis- general

Prothrombin Time/INR

Blood ChemistrySodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate,

AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin,Creatinine, ureaGlucose

Arterial blood gas Arterial lactate Full blood count Blood type and screen Ammonia (arterial if possible) HIV status Amylase and lipase

Diagnostics- specific

Paracetamol (acetaminophen) level

Toxicology screen Viral hepatitis serologies

Anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HEV, anti-HCV CMVEBVVZ/HZ

Ceruloplasmin level Pregnancy test Autoimmune markers- ANA,

ASMA, Immunoglobulin levels Doppler US- ischaemic vs

thrombosis

Liver biopsy

Importance of early biopsy- severity and aetiology

Particularly useful in Hep B, AIH, Alcoholic hepatitis, differentiate between ALF and aCLF

Transjugular route

www.gastrotraining.com

Urgent OLT is the only life saving therapy

The main role of intensive care therapy is multi-organ support

All Liver transplants

CLD – 60%Malignancy- 10%ALF- 10% ( Paracetamol)Cholestasis - 10-20%

Phase I – 0-24h Anorexia, nausea and vomiting, malaise LFT derrangement at 12h

Phase II – 18-72h RUQ pain LFT derrangment

Phase III – 72-96h Centrilobar necrosis Liver failure

Phase IV – 4d-3wk Recovery, transplant or death No chronic state

When to pick up the phone

D2- pH <7.3 INR>3 Cr >200 Hypoglycaemia

D3- HE Cr>200 INR >4.5

D4- Any rise in INR Cr >250 HE

Definition:HRS

ARF in a patient CLD, severe alcoholic hepatitis or ALF

from any cause End-stage of reduction in renal perfusion

induced by increasingly severe hepatic injury.

1. Sinusoidal portal hypertension, in the presence of severe hepatic decompensation

2. Leads to splanchnic and systemic vasodilatation-role of NO

3. Decreased effective arterial blood volume

4. Activation of RAS, and vasopressin aimed at restoring arterial filling pressure.

5. Renal vasoconstriction increases counterbalanced by the intrarenal prostaglandins.

6. When this balance is lost renal hemodynamics worsens, and hepatorenal syndrome develops

TerlipressinNSBB

HRS

Major criteria Chronic or acute hepatic disease and liver failure with portal

hypertension Serum creatinine level >133 micromoles/L Absence of shock, ongoing bacterial infection, recent use of

nephrotoxic drugs, excessive fluid or blood loss No sustained improvement in renal function after volume

expansion with 1.5 L isotonic saline solution No Proteinuria (Protein<500 mg/day) and no ultrasonographic

evidence of renal tract or parenchymal disease Minor criteria

Urine volume <500 mL/day Urine sodium <10 mEq/L Urine osmolality greater than plasma osmolality Urine red blood cell count <50 per high-power field Serum sodium <130 mEq/L

Classification of HRS

Type I is defined by a rise in creatinine level to over 221 micromoles/L in less than 2 weeks

Median survival of 2 weeks

Type II is defined as less severe renal insufficiency; it is principally characterized by ascites that is resistant to diuretics.

Median survival of 3-6 months.

Vasoactive Medical treatment

Terlipressin bolus(0.5mg/4h)-increase every 3 days if no response to 1-2mg/4h

Given until creatinine normalizes or for 15 days

Albumin 1g/kg on day1( one bag of HAS contains 20grams)

20-60g/d thereafter

Step by step guide :

Normal renal us Normal urine dipsix –

no RBC cast No nephrotoxic drugs Fluid challenge Spot Na and serum

Na Serum and urine

osmolality Urine output

PRERENAL

HRS ATN

Spot Na <10 <10 >30

Urine sediment

Nil Nil Positive

Fluid challenge

Responds Nil Nil

The stages of HE- West Haven criteria:

Stage 0. Lack of detectable changes in personality or behaviour. Asterixis absent.

Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria ordepression. Asterixis can be detected.

Stage 2. Lethargy or apathy. Disorientation. Inappropriate behaviour. Slurred speech. Obvious asterixis.

Stage 3. Gross disorientation. Bizarre behaviour. Semistupor to stupor. Asterixis generally absent.

Stage 4. Coma.

HE- Four compatible theories

Cerebral vasomotor dysfunctionOedema secondary to ammonia toxicityInflammation due to SIRSputative benzodiazepine-like molecules

The pathophysiology of HE

A large body of work points at ammonia as a key factor in the pathogenesis of HE.

Portal ammonia is derived from both the urease activity of colonic bacteria and the deamidation of glutamine in the small bowel.

The intact liver clears almost all of the portal vein ammonia, converting it into glutamine and preventing entry into the systemic circulation.

Ammonia- astrocyte swelling in brain

Patients with grade II HE should be managed in a HDU environment.

Grades III and IV HE requires definitive airway protection and appropriate monitoring.

Grade IV HE is strongly associated with elevated levels of serum ammonia, a high incidence of raised intracranial pressure and the development of uncal herniation.

GCS –HE correlation

Grade1- GCS 14-15Grade2- GCS 11-13- HDU

Grade3- GCS 8-11 (Stupor or precoma)Grade4- GCS<8 (Coma)

In acute and chronic liver disease, increased arterial levels of ammonia are commonly seen.

However, correlation of blood levels with mental state in cirrhosis is inaccurate.

Lactulose is a first-line pharmacological treatment of HE.

Lactulose – reaches colon, where bacteria will metabolize the lactulose to acetic acid and lactic acid.

This lowers the colonic pH formation of the non-absorbable NH4+ from

NH3, Other effects like catharsis also contribute to

the clinical effectiveness of lactulose.

Lactulose

For acute encephalopathy, lactulose (ingested or via nasogastric tube), 45 ml p.o.,

Is followed by dosing every hour until evacuation occurs.

Target -three soft bowel movements per day

If response to disachharide is poor- add antibiotic (metronidazole or rifaximine after 48Hrs) to reduce enteric bacterial mass.

If patient is refusing oral lactulose prescribe phosphate enemas TDS!

An excessively sweet taste, flatulence, and abdominal cramping are the most frequent subjective complaints with this drug.

The coagulopathy of liver disease

Failure to produce clotting factors II, V, VII and IX Failure of the diseased liver to clear activated clotting

factors. Degree of hypersplenism and thrombocytopaenia

often adds to the coagulopathy, especially if disseminated intravascular coagulation (dic) also co-exists.

The degree of coagulopathy is a measure of severity of liver disease and of patient prognosis.

Routine correction of coaguloapthy is therefore NOT indicated unless active bleeding or planned interventions require it

Sepsis

Infection may be the initiating event of liver failure,

Intercurrent sepsis is also a common problem . Impaired immune function, in part secondary

to reduced complement factor production and Impaired neutrophil, leukocyte and monocyte

function, can result in delayed presentation of clinical signs of infection.

The interventions required for diagnosis and management of liver disease also increase patient vulnerability to invasive infection.

Role of prophylactic antibiotic

Only patients who have an episode of gastrointestinal bleeding

or an episode of spontaneous bacterial peritonitis (SBP) have been shown to have a significant outcome benefit from prophylactic antibiotics.

In presence of sepsis

Choice of antibiotic should be guided by local microbiological surveillance.

The high incidence of mycoses - low threshold for antifungal.

Regular microbiological surveillance

Role of NAC

Efficacy of NAC is well established in PCM induced ALF

Non PCM ALF – role of NAC is controversial 175 patients of non PCM ALF received NAC

Transplant free survival at 3 weeks was 52% in NAC group compared to 30% in placebo arm ( only with coma grade of 1-2)

United States ALF study group- overall was 70% vs 66%

Artificial liver??

Extracorporeal Liver Assist Device (ELAD)

Hepatocyte bioreactor- hepatoma cells cultivated on the exterior surface of semipermeable hollow fibres

MARS (molecular adsorbent recirculating system)

ELAD

Both reduce the level of bilirubin, bile salt ammonia etc

However no of patients dying or requiring liver transplant did not improve

Devices remain experimental and large-scale phase two and three trials are awaited

Summary

• The mortality rate for acute liver failure ranges between 56% and 80%

• The main role of intensive care therapy is multi-organ support• The commonest cause of acute liver failure in the western world

is paracetamol toxicity• Hepatic encephalopathy is no longer the main cause of death but

it’s detection and management requires sophisticated cardiovascular and cerebral monitoring

• Hepatorenal failure is due to the complex interplay between splanchnic, renal and systemic circulatory responses to liver failure. Terlipressin has been shown to be of use in its treatment

• Novel hepatic replacement therapies are under development but definitive studies as to their efficacy are, as yet, unpublished.