Acute Liver Failure

TopicsDefinitions of failure and classificationAetiology- Acute versus acute on chronicBasic diagnostic workupLiver biopsy in the contextACLF-Ethical dilemma- HDU admissionTreatment of complicationHepatic encephalopathyRenal failureGI bleedInfectionCoagulopathyAetiology specific treatmentOrgan supportLiaison with Transplant centre

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

Abnormal LFT is NOT ALFDear Doctor Patients 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

aCLFThis entity is quite common- background of cirrhosis. Innocent precipitating event culminates in MOFEventsToxins (alcohol!)Vascular (hypotension- GI bleed, dehydration, Portal vein thrombosis)Infection (SBP)HCC

ACLF-Ethical dilemma- HDU admission

For patients with aCLFYoung ageFirst presentationReversible pathology- sepsis, GI bleeding or severe hepatitisA trip to ITU is a life changing experience to some alcoholics

Few definitionsHyperacute- 7days 21days

Diagnostics:Good history- difficult if HE

Initial Laboratory Analysis- general Prothrombin Time/INR

Blood Chemistry

Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate, AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin,Creatinine, ureaGlucose

Arterial blood gas Arterial lactate Full blood countBlood type and screenAmmonia (arterial if possible) HIV statusAmylase and lipase

Diagnostics- specificParacetamol (acetaminophen) levelToxicology screenViral hepatitis serologies

Anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HEV, anti-HCV CMVEBVVZ/HZCeruloplasmin levelPregnancy testAutoimmune markers- ANA, ASMA, Immunoglobulin levelsDoppler US- ischaemic vs thrombosis

Liver biopsyImportance of early biopsy- severity and aetiologyParticularly useful in Hep B, AIH, Alcoholic hepatitis, differentiate between ALF and aCLFTransjugular route

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Urgent OLT is the only life saving therapyThe main role of intensive care therapy is multi-organ support

All Liver transplantsCLD 60%Malignancy- 10%ALF- 10% ( Paracetamol)Cholestasis - 10-20%

Phase I 0-24hAnorexia, nausea and vomiting, malaiseLFT derrangement at 12hPhase II 18-72hRUQ painLFT derrangmentPhase III 72-96hCentrilobar necrosisLiver failurePhase IV 4d-3wkRecovery, transplant or deathNo chronic state

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When to pick up the phoneD2- pH 3Cr >200HypoglycaemiaD3- HECr>200INR >4.5D4-Any rise in INRCr >250HE

Definition:HRSARF 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.

Sinusoidal portal hypertension, in the presence of severe hepatic decompensation

Leads to splanchnic and systemic vasodilatation-role of NO

Decreased effective arterial blood volume

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

Renal vasoconstriction increases counterbalanced by the intrarenal prostaglandins.

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

TerlipressinNSBB

HRSMajor 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

Classification of HRSType 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 daysAlbumin 1g/kg on day1( one bag of HAS contains 20grams)20-60g/d thereafter

Step by step guide :

Normal renal usNormal urine dipsix no RBC castNo nephrotoxic drugsFluid challengeSpot Na and serum NaSerum and urine osmolalityUrine output

PRERENAL HRS ATN Spot Na

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

The pathophysiology of HEA 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 correlationGrade1- GCS 14-15Grade2- GCS 11-13- HDU

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

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 diseaseFailure to produce clotting factors II, V, VII and IXFailure 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 antibioticOnly 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 sepsisChoice of antibiotic should be guided by local microbiological surveillance. The high incidence of mycoses - low threshold for antifungal.Regular microbiological surveillance

Role of NACEfficacy of NAC is well established in PCM induced ALFNon PCM ALF role of NAC is controversial175 patients of non PCM ALF received NACTransplant 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)

ELADBoth reduce the level of bilirubin, bile salt ammonia etcHowever no of patients dying or requiring liver transplant did not improve

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

SummaryThe mortality rate for acute liver failure ranges between 56% and 80%The main role of intensive care therapy is multi-organ supportThe commonest cause of acute liver failure in the western world is paracetamol toxicityHepatic encephalopathy is no longer the main cause of death but its detection and management requires sophisticated cardiovascular and cerebral monitoringHepatorenal 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 treatmentNovel hepatic replacement therapies are under development but definitive studies as to their efficacy are, as yet, unpublished.

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