ACUTE PARENCHYMAL LIVER DISEASES : PATHOPHYSIOLOGY, PRE-OPERATIVE

CONSIDERATIONS AND PATIENT PREPARATION

University College of Medical Science & GTB Hospital, Delhi

Dr. Manisha Desai

INTRODUCTION

• Acute hepatitis is a common condition

• India is endemic for certain types of viral hepatitis

• Frequency of unsuspected liver disease – 1 in 700 of otherwise healthy surgical candidates

ACUTE HEPATITIS

• Recent infection or inflammation of liver - < 6 months

• Viral hepatitis – Hepatitis A, B, C, D and E– Herpes Simplex virus– Cytomegalovirus– Epstein Barr virus– Adenovirus

• Non viral infection– Bacterial infections – pyogenic abscesses

• Alcohol• Toxins – Amanita toxin in mushrooms,Carbon tetra

chloride• Drugs – Acetaminophen , Halothane, antitubercular

drugs • Ischemic hepatitis• Pregnancy• Metabolic disease – Wilson’s disease

HAV HBV HCV HDV HEV

TYPE Picorna RNA Hepadna ,DNA Hepaci, RNA Delta, RNA RNATRANSMISSION Feco-

OralPercutaneous, perinatal, sexual

Injection drug use ,perinatal

Percutaneous, perinatal, sexual

Feco-oral

ONSET Acute Insidious or acute

Insidious Insidious or acute

Acute

AGE Children,young adults

Young adults, babies

Any age.Adults mainly

Any age Young adults

INCUBATION PERIOD DAYS

15 -45 30- 180 15 – 160 30- 180

14 – 60

SEVERITY Mild Occ severe Moderate Occ severe Mild

FULMINANT 0.1% 0.1 – 1% 0.1% 5-20% 1-2%

CHRONICITY/CA

None / - 1-10%. 90% neonates / +

85% / + Common / ± 1-2% / -

CARRIER None 0.1 – 30% 1.5 -3.2% Variable None

PROGNOSIS Excellent Worse with age, debility

Moderate Acute-goodChronic-poor

Good

Clinical features in viral hepatitis Clinically all types present in same manner:1. Prodromal symptoms - anorexia, nausea and vomitting,

fatigue, malaise, myalgia, photophobia,low grade fever. Serum sickness like syndrome (fever,arthralgia,rash) in HBV Dark urine, clay coloured stools 1-5 days before onset of jaundice LAB : AST, ALT are elevated. 2. Jaundice- prodromal symptoms diminish. Liver enlargement

and tenderness LAB : AST, ALT attain their peak; Se. bilirubin – 5-20 mg/dl3. Recovery phase – symptomatic improvement. Hepatomegaly

and abnormal LFT’s may persist.

HEPATITIS A Acute phase :•anti-HAV (IgM) positive from onset of symp and persists for 4 months•Se. aminotransferase ↑•Fecal HAV shedding

anti-HAV (IgG) – Present indefinitely Immune to re-infection.90-100% population in India acquire antibody and become immune by adolescence.

Complete clinical and biochemical recovery in 60% pts by 2 months; almost all by 6 months.

HEPATITIS B

• Intermediate endemicity in India.Major cause of CLD and HCC.• Hepadnavirus . DNA virus• Compact structure with overlapping genes permits HBV to

code for multiple proteins

Antigens – 1) HBsAg- envelope protein. coded by S gene.

2) HBeAg- nucleocapsid protein. coded by precore region. secreted in bld 3) HBcAg- nucleocapsid protein, not secreted.

…… Hepatitis B

Population at high risk :• Hemophiliacs• Drug addicts• Health care workers• Infants born to HBsAg + mothers or mothers

with acute Hep B in 3rd trimester/early post partum.

…..Hepatitis B

•HBsAg preceeds increase in enzyme levels by 2-6 wks. Persists for entire symptomatic phase. Usually disappears 1 month after onset of jaundice. Rarely persists for 6 months. Anti-HBs persists for life. Window period may exist.• HBcAg is not seen. Anti-HBc seen 1-2 wks after appearance of HBsAg. Maybe the only marker seen in window period.•HBeAg appears concurrently with HBsAg. Indicates active replicative infection• Among healthy adults, acute HBV is self-limited in 95-99%. Complete clinical and biochemical recovery 3-4 months after onset of jaundice in 75% of uncomplicated cases.•Persistence of HBsAg beyond 6 months- Carrier state

HEPATITIS C

Population at high risk:• patients requiring hemodialysis• organ transplantation• drug addicts• More severe disease in alcoholics, co-infection

with HBV and HIV

……Hepatitis C

HCV RNA – within few days of exposure

Episodic pattern of aminotransferase elevation

Anti-HCV demonstrated in early phase

HEPATITIS D

• Defective virus; requires HBV for transmission.

• Co-infection with HBV or superinfection of HBsAg carrier

• Superinfection can transform inactive or mild chronic Hep B into severe, progressive disease and cirrhosis or even fulminant hepatitis.

• In Co-infection: HDV RNA PCR is the most sensitive ;Anti-HDV IgM followed by IgG . anti-HBc will be of IgM class.

• In super infection: both IgM and IgG anti-HDV rise and persist . anti-HBc will be of IgG class

• Loss of HBsAg is a reliable marker for resolution of Hep D

HEPATITIS E

Population at risk :• Those exposed to contaminated water supplies • Pregnancy- HEV is the MC cause of viral hepatitis

and FHF in pregnancy in India. pregnant pts in 2nd/ 3rd trimester have a worse

outcome. Incidence of FHF - 22%. Mortality rates of 15-25%. Abortions, stillbirths,neonatal death increased

serology in hepatitis E

• Serum HEV RNA - in pre icteric phase , disappears after peak in aminotransferases

• ALT rises 10 days before onset of symptoms, peaks when jaundice occurs, then declines

• IgM ab seen just before peak ALT. Disappears 5-6 months later.

• IgG ab detectable 1 year after acute infection

Other hepatitis causing pathogens

• Cytomegalovirus- perinatal/blood transfusions/organ transplantation/ immunocompromised. CMV IgM ab

• Epstein-Barr virus- transmission via oral secretions. Monospot test, EBV IgM ab

• Herpes Simplex virus- immunocompromised. Rapid and lethal course.

• Bacteria- E.coli, Klebsiella,Streptococcus viridans, anaerobic bacteria --- pyogenic liver abscess

LAB TESTS• Hemogram – transient neutropenia and lymphopenia followed by relative lymphocytosis.

(atypical lymphocytes)• RBS- vomitting, poor intake, poor glycogen contribute to hypoglycemia.• Se.aminotransferases• Se.ALP - usually normal• PT- if prolonged, worse prognosis• Gama globulin- mild elevation• Se. Albumin- usually normal• Hep A – IgM anti-HAV• Hep B- HBsAg- titre has little relation to severity HBeAg- indicator of relative infectivity. HBV DNA is a better indicator Anti-HBc- in window period Anti-HBsAg- rarely detectable in acute hepatitis• Hep C – HCV RNA- gold standard anti-HCV • Hep D- HDV antigen-detectable only briefly Anti-HDV

Morphologic lesions (common to all viral hepatitis)

• Panlobular infiltration with mononuclear cells. • Hepatic cell necrosis, ballooning of cells, acidophilic degeneration of

hepatocytes( Councilman or apoptotic bodies)• Hyperplasia of kupffer cells• Variable degree of cholestasis (marked in Hep E)• Hepatic regeneration- mitotic figures, rosette or pseudoacinar

formation• Bridging/subacute/confluent necrosis or interface hepatitis -

bridging between lobules as a result of large areas of cell dropout. bridge formed by condensed reticulum, cell debris. → prognostic significance in chronic hepatitis, NOT in acute hepatitis.

TREATMENT OF VIRAL HEPATITIS

• Specific treatment is not necessary• High calorie diet• Severe acute hepatitis B- Lamivudine• Acute hepatitis C- long acting pegylated

interferon + ribavirin…. Mainly to decrease progression to chronicity

• Glucocorticoid therapy- no value; maybe deleterious increasing risk of chronicity

ALCOHOLIC HEPATITIS

• Alcohol → Acetyldehyde → Acetate• Asymptomatic → life threatening decompensation• Decompensation precipitated by vomitting,

diarrhea, increased alcohol intake, infection• Tender smooth hepatomegaly• ↑ bilirubin, AST, GGT, ALP , PT• Histology- Neutrophilic infiltrate around necrotic

hepatocytes- Mallory bodies ; pericellular fibrosis – chicken wire appearance

DRUG INDUCED HEPATITIS

• Drug induced liver injury (DILI)• Liver principal site for metabolism of compounds

extrinsic or intrinsic• Phase 1- hydroxylation Phase 2- conjugation Phase 3- transport into bile /blood• Pattern of injury : hepatocellular,

cholestatic,mixed,steatosis (micro and macro)• The hepatocellular pattern resembles acute hepatitis

Pathogenesis of DILI

DRUGClassDose

Duration

ENVIRONMENTDiet

Other toxins,chemicals

HOSTAge

GenderBMI

Genetic factorsImmnol factorsOther diseases

TYPES OF DILIINTRINSIC IDIOSYNCRATIC

With immunoallergic features

Without immunoallergic features

Dose dependent Yes No No

Asso features Other tissues too Fever,rash,eosinophil No extrahepatic features

Risk factors Induction of enz ↓ metabolism, excretion

Allergy, genetic Genetics, underlying liver disease

Pattern Hepatocellular, acute

Hepatocellular, acute > cholestatic

Hepatocellular, acute > cholestatic

Response to rechallenge

Prompt Rapid (1-3 doses) Variable

Duration of exposure

< 1 week 1-5 weeks Variable

Acetaminophen,Amanita, CCl4, Chloroform

Amoxiclav, diclo, Alphamethyldopa, Doxycycline, Halothane, Penicillin

Amoxiclav, Enflurane, INH, Glitazones, Nifedipine, Quinidine

• On liver biopsy, Acute Zone 3 necrosis Indistinguishable from acute viral hepatitis• C/f: similar to viral hepatitis• Lab tests : normal hemogram; eosinophelia with allergic type reactions ALT and AST markedly ↑ ALP normal or mildly elevated Se.bilirubin variable. High levels negative prognosis• Course : rapid improvement clinically and biochemically• Rx: stop offending drug. N acetylcysteine for acetaminophen;

prednisolone , azathioprine

ACETAMINOPHEN HEPATITIS

• Hyperacute LF. • Dose- variable. usually 15 g. • Renal failure in 70% • ↑ AST > ALT within 12-24 hrs, peak at 3 days

and resolve rapidly• Centrilobular (zone 3) necrosis without

inflammation• Rx – N-acetylcysteine

Mechanism of Acetaminophen toxicity

Acetaminophen 80% (N) <5% (N) ; Glucuronidation Oxidation by CYP2E1

excreted in urine NAPQI → non toxic by GSH In toxicity, GSH ↓, NAPQI ↑

(P/W saturated in toxicity) Rx – N- Acetyl Cysteine (↑ GSH)

HALOTHANE HEPATITIS

• Immune mediated • Risk factors : - Females -Middle aged -Obese -Enzyme induction -Prior anesthetic exposure -Genetics

• After 7-10 days of anaesthesia• fever, rash, arthralgia, jaundice, Mild hepatomegaly with liver tenderness• leucocytosis, eosinophilia• Cross sensitivity to other inhalational anesthetics has been noted• Committee on safety of medicines (CSM) recommends that halothane must not

be used within 3 months of previous exposure unless there s a definite reason to do so and it should not be used if there was history of unexplained pyrexia or jaundice within 1 week of previous exposure .

MILD FORM FULMINANT FORM

Incidence , 1:5 Incidence 1:10,000

Repeat exposure not necessary

Multiple exposures

Mild ↑ ALT, AST ↑↑ ALT, AST,bilirubin,ALP

Focal necrosis Massive necrosis

Self limited Mortality – 50%

ISCHEMIC HEPATITIS

• Misnomer. Centrilobular necrosis in absence of inflammation• Increases O2 uptake by increasing extraction- 95% O2

extracted in single pass → resistance to ischemia• Compensation diminished in severe ischemia – MI,

tamponade, hypovolemic shock, septic shock• Budd Chiari syndrome, intrahepatic sickling in SCA • Clinical picture dominated by the cause• Serum AST, ALT ↑↑ (> 200 times normal)• Serum LDH ↑ (30 times normal) • Mortality – 75%

PREGNANCY RELATED CONDITIONS Acute Fatty liver of pregnancy • Rare ; usually 3rd trimester• encephalopathy, coagulation disorder, DIC,liver

failure• Following delivery, liver function improves PIH• HELLP syndrome – 10%• Rapidly resolves after delivery

WILSON’S DISEASE

• AR disorder , mutations in ATP7B gene-membrane bound copper transporting ATPase

• ↑ hepatic Cu, ↓ serum Cu, ↓ ceruloplasmin• Widespread hepatic necrosis → Cu being

released into circulation → hemolysis• Presentation- children. May mimic acute

hepatitis• ↑ serum bilirubin (mainly indirect), ↑ serum

aminotransferases

ACUTE LIVER CELL FAILURE• All causes of acute hepatitis can cause Acute liver cell failure (ALF)• ALF – jaundice, coagulopathy, encephalopathy• Mortality – 40-95%• Worldwide, viral hepatitis - most common UK, acetaminophen toxicity – most common• depending on time interval between onset of jaundice and

encephalopathy: Hyperacute (0-7 days) ALF Acute (8-28 days) Subacute (> 28 days)• Fulminant hepatitis – encephalopathy within 8 weeks of onset of

symptoms

Effects on all organ systems

• Metabolism – hypoglycemia, protein breakdown, lipolysis• CVS- hyperdynamic state, ↑ C.O., ↓SVR ↓ CVP , MAP maintained profound vasodilation – collapse• RS – Hyperventilation – resp.alkalosis V-Q mismatch, pulm edema , ARDS• Kidneys – ARF in 40-80%.due to ↓ effective bld volume, sepsis , hepatorenal syndrome • Bleeding diathesis• ↑ susceptibility to infection

• CNS : Hepatic encephalopathy

Accumulation of endogenous toxins – altered brain metabolism and neurotransmission.

Most imp- Ammonia.

Cerebral autoregulation fails – cerebral edema and ↑ ICP

Precipitants- Excessive dietary protein, Constipation, Diarrhoea n vomiting, GI bleeding, Infection, Azotemia, Diuretic therapy, Paracentesis, Hypoxia, hypotension, Anemia, Hypoglycemia, Sedatives, Hypnotics, Surgical stress

• Etilology specific therapy• Correction of fluid and electrolyte imbalance• Nutrition- 35-40Kcal/day enteral or parenteral• Frequent blood glucose monitoring• Prevention of bleeding and infection• Mannitol infusion• Hemodialysis• Orthoptic liver transplantation

CONCERNS FOR SURGERY IN A PATIENT WITH LIVER DISEASE

• Multiple functions of the liver : - synthesis of serum proteins, - metabolism of drugs, - excretion - detoxification -filtering of portal venous blood• Any or all of this may be disturbed • Alteration in the pharmacokinetics of anaesthetics,

muscle relaxants, sedatives and analgesics → post –operative hepatic dysfunction and delayed recovery.

• Greater risk of bleeding, infection• Mild elevations of aminotransferase, ALP, bilirubin

levels are frequent after surgeries whether under GA/Regional anaesthesia → transient and of no significance if there’s no pre-existing liver disease

• However, clinically important hepatic dysfunction is more likely to occur in patients with pre-existing liver disease – precipitation of ACUTE LIVER CELL FAILURE .

• Concern of occupational exposure of medical personnel

• Assessment of perioperative risk remains inexact because of paucity of prospective studies

• Harville and Summerskill in 1963 reported mortality rates of 9.5% to 13% in acute viral hepatitis patients who underwent laparotomy and major post-op complications in 11%

• alcoholic hepatitis, mortality rates as high as 55%• alcoholic or nonalcoholic fatty liver does not

contraindicate elective surgery

Ref : Friedman L.S. Hepatology June 1999 ; 1617-1623

PRE-OP EVALUATION• history-taking to identify risk factors -H/O jaundice- remote history of Hep A – no significance - previous blood transfusions - tattoos - illicit drug use - sexual promiscuity - a family history of jaundice or liver disease - a history of jaundice or fever after anesthesia - alcohol use - complete review of current medications.

• Symptoms like fatigue, malaise, pruritus, fever, passage of dark urine or clay coloured stools, jaundice

• Physical examination : - vital signs - ICTERUS - ascites,hepatic tenderness,hepatomegaly - any evidence of encephalopathy, coagulopathy• Nature of surgery – abdominal surgeries esp

laparotomy are high risk surgeries.

PRE-OP WORKUP

• Complete hemogram with platelet count• Blood sugar• KFT – Blood urea, Se.creatinine, Se.electrolytes• LFT • Prothrombin time• Serology – viral markers• ECG• CXR – pleural effusion• Se.ammonia- in encephalopathy

ALGORITHM FOR PRE-OP EVALUATION OF PATIENT WITH KNOWN OR SUSPECTED LIVER DISEASE

• Abstinence from alcohol is advised to avoid - alcohol withdrawal in the

postoperative period - enhancement of halothane hepatotoxicity by alcohol - toxicity with therapeutic doses of acetaminophen in alcoholics• No good evidence for duration of abstinence

that should occur

Patient Preparation

Goal

Preserve existing liver function and avoid factors that may be detrimental to liver

Optimization

– correct anemia

– Correct metabolic, fluid & electrolytes imbalance

– Correct coagulation abnormality – Vit K (1-5mg oral/subcutaneous for 1-3 days), FFP, platelets (PLT count > 50,000/mm3 and INR < 1.5)

– Syp. Lactulose 30 ml every 6 hrs orally – first line therapy in encephalopathy

- Thiamine , folate and Vit B supplementation in alcoholics if nutrition or glucose has to be given

- Frequent blood glucose monitoring – to avoid hypoglycemia

-Antibiotics be started for infection

- Informed high risk consent

- Arrange blood

- Preoperative medication – Sedation – should be avoided, it can precipitate or exacerbate

encephalopathy

SUMMARY

• Acute hepatitis especially of viral etiology is a common disease entity.

• Patients of acute hepatitis of any cause undergoing surgery are at an increased risk of developing hepatic dysfunction and acute liver cell failure, remarkably increasing mortality rates. Diagnosis, pre-operative evaluation and optimization of the patient is therefore of great importance.

REFERENCES• Miller RD. Anesthesia. Philadelphia, Elsevier, 2010: pp 1026-1028• Zakim, Boyer. Hepatology – A textbook of liver disease.

Philadelphia, Elsevier, 2006 : ch 21, 31-35• Harrison. Principles of Internal Medicine. McGraw Hill, 2008 : ch :

295,298,299• Freidman LS. The Risk of Surgery in Patients With Liver Disease.

Hepatology 1999; 29:1617-23. • Martin P. Perioperative considerations for patients with liver

disease. Cleveland clinic journal of medicine 2009; 76:S93-97• Keegan MT. Preoperative Assessment of the Patient with Liver

Disease. American Journal of Gastroenterology 2005; 100:2116–27