Hepatobiliary Mbchb4


• Liver disease where viral replication and hepatic necroinflammation continues for >6 months
• Hep B and Hep C

Hepatitis B
• Inflam of liver caused by HBV
• Acute sxs – liver inflammation, vomiting, jaundice, death (rare)
• Chr Hep B → liver cirrhosis → liver ca

• ½ worlds popn have past or present HBV inf
• 350 mil chr HBV carriers, 35,000 in NZ (~7% of NZ popn)
• Prev rate = 5% M/PI/Asian; <1% European

• Exposure to infectious blood or body fluids containing blood
• Eg. unprotected sex, blood transfusion, re-use of contaminated needles/syringes, vertical transmission (mother→child during birth)
• W/o intervention – a mother who is HBsAg+ confers a 20% risk of passing inf to offspring at birth (risk may be as high as 90% if mother is also HBeAg
• HBV can also be transmitted betw family members within households, possibly by contact of nonintact skin or mucous membrane with secretion or saliva
• In low prevalence areas → inf is usu the result of injection drug abuse or unprotected sex
• In high prevalence areas → transmission during childbirth is most common or during childhood

• During HBV inf → host response causes both hepatocellular damage and viral clearance
• While innate immune response does not play sig role in these processes, the adaptive imm response (esp cytotoxic T cells - CTLs) contribute to nearly all liver injury assoc w HBV inf
• By killing infected cells and by producing antiviral CKs capable of purging HBV from viable hepatocytes, CTLs also eliminate the virus

Risk factors for Chronicity
• Inversely related to age (95% neonate, 80% child, <5% adult)
• Male sex
• Immunosuppression – eg renal dialysis, organ transplant, HIV+

Three Phases of Infection
1. Immunotolerant HBsAg+ HBeAg+ HBV DNA+ Normal ALT
2. Active hepatitis HBsAg+ HBeAg+/- HBV DNA+ High ALT
3. Post sero-conversion HBsAg+ HBeAg- HBV DNA- Normal ALT

Spontaneous HBeAg seroconversion = 7-15% pa
Spontaneous HBsAg seroconversion = 1% pa
Seroconversion = devt of detectable specific antibodies in the serum due to either infection or immunisation

Disease Progression in HBsAg carriers
1. 20% cirrhosis (within 20y)
2. If cirrhosis → 3-5% risk of LF pa
3. If cirrhosis → 3-5% risk of HCC pa (200x ↑ risk of HCC in all HBsAg+ vs HBsAg-)

Sxs and Complications
• HBV inf may either by acute (self-limited) or chr (long-standing)
• Persons w self limited inf clear the inf spontaneously within weeks/months
• Children are less likely than adults to clear the inf
• >95% of those infected as adults/older children make full recovery and develop protective immunity to the virus
• Only 5% of newborns that acquire infected vertically clear the inf
• Infection may be asx
• Acute inf → begins with general ill health, loss of apetite, n/v, body aches, mild fever, dark urine, then progresses to jaundice
• Illness lasts a few weeks then gradually improves in most
• A few pts may have more severe liver dis (fulminant hepatic failure) → death is possible
• Chr infection may lead to chr inflammation of liver → cirrhosis → HCC
• Hep D inf usu only occurs w a concomitant inf w HBV (co-inf ↑ the risk of cirrhosis and HCC)

1. HBsAg
a. Used for screening
b. First detectable HBV antigen to appear
c. Early in inf, may not be present, may also be undetectable later if cleared by the host
2. HBcAg
a. Inner core particle enclosing viral genome
3. HBeAg
a. Appears shortly after HBsAg
b. Assoc w much higher rates of viral replication
c. However, some HBV variants do not produce e antigen, so this does not always hold true
4. Anti-HBc IgM
a. During window when host remains infected but is successfully clearing the virus
b. This may be the only serologic evidence of the disease at this point
5. Anti-HBs
a. If host unable to clear the inf, eventually the HBsAg will become undectable
b. This will be followed by antibodies to the HBsAg
A person neg for HBsAg but positive for anti-HBs as either cleared an inf or has been vaccinated
PCR tests detect and measure ethe amount of viral nucleic acid in clinical specimens, useful for assessing person’s inf status + monitor tx

Pre-core mutant
• Mutation in pre-core region of genome which codes for HBeAg protein
• Selection of mutated virus over wild-type (overwhelming common ie standard characteristic) to evade effect of anti-HBe antibody by not producing e antigen
• Pre-core HBV inf → HBV DNA+, HBeAg-, anti-HBe+, high ALT

Goals of therapy in chr Hep B
• Sustained suppression of HBV replication (HBeAg and HBV DNA); If pre-core mutation, endpoint more difficult (defined by low/undectable HBV DNA)
• Loss of HBsAg rarely achieved
• Normalisation of aminotransferase activity and resolution of hepatic inflammation
• Improvement in sxs (often asx)
• Prevention of progression of liver dis + HCC
• Improved survival

1. Interferon
a. Works by enhancing own immune response
b. Seroconversion usu preceded by flare in hepatitis
c. Seroconversion rate 30-40% w subsequent loss of HBsAg in about 10%
d. Only effective for pts who are HBeAg+ and have elev ALTAST levels and/or chr hepatitis histologically
e. Duration tx 4-6months (5-10 MU 3x per week subcut)
f. Pegylated interferon better tolerated and more effective; once daily dosing – not yet funded in NZ for hep b
2. Nucleoside Analogues → inhibition of HBV reverse transcriptase (RT)
a. Lamivudine (3TC)
i. V effective at ↓ viral load – usu HBV DNA neg after 4/52
ii. Low rate of seroconversion (<10%) after 1y tx but up to 30% after 2 yrs tx
iii. Lamivudine resistance – up to 50% after 5yrs; HBV breakthrough leading to ↑ HBV DNA + ↑ ALT
iv. Caused by mutations in HBV reverse transcriptase
b. Adefovir
i. Used for lamivudine resistance
ii. Best used as an addition to lamivudine
iii. NZ – only funded as sole agent in setting or proven lamivudine resistance (except if resistance – then co-tx)
c. New Drugs
i. Purine analogues eg entecavir
ii. Pyramidine analogues eg telbividine
iii. Very effective
d. Combination Txs
i. May become standard Rx
ii. Lamivudine + Interforon not better than interferon alone
iii. Combinations of oral agents may be tx of choice in future
iv. Main issue is prevention of resistance and goal of LT viral suppression

• Available, cheap and effective (>99%)

• RFs – HBV inf, Cirrhosis, F.hx, exposure to alfatoxin B1
• Serum test – alpha fetoprotein


Hepatitis C
• Most common cause of cirrhosis and HCC in nth America/Europe and Australia – but not in NZ where HBV is most common
• 25% of the 10,000 liver transplants performed annually
• No vaccine available

• 300 mil people worldwide affected
• NZ popn – 0.45% anti-HCV+, 0.3% HCV RNA+ (no cultural differences)
• IVDU – 70% (currently declining due to safer practices)
• Haemophiliacs – 75%
• Prison inmates – 30%, Haemodialysis – 5-40%, Sex workers – 20% (sexual transmission not common)

Risk Factors
• Transmission – blood-to-blood contact w infected person’s blood
• Most pts have parenteral risk factors
• 75% → hx of IVDU
• 10% → hx of blood transfusion <1992
• 5-10% other RFs → tattoos in prison or in SE asia, haemophilia (receiving F8>1987), haemodialysis <1992, organ transpl recipient <1992

• Asx – presented for screening due to RFs or abnormal LFTs
• Non-specific sxs – eg lethargy
• End-stage liver dis - cirrhosis; variceal bleed, ascites, peripheral adema or HCC
• Extrahepatic manifestations – cryoglobulinaemic vasculitis (skin rash, raynauds sxs, other vasculitic injury), membranoproliferative GMN, prophyria, cutanea tarda
Acute Hep C
• Asx during acute phase – 2/3 of people
• 1/3 develop sxs – mild + non-specific (sxs include ↓ appetite, fatigue, abdo pain, jaundice, itching, flu-like sxs)
• HCV detectable in blood at 1-3 wks post inf; antibodies detectable in 3-12 wks
• Approx 20-30% of pts clear the virus during acute phase (normalisation of LFTs and HCV-RNA clearance) – “spontaneous viral clearance”
• Remaining 70-80% develop chr hep c (>6 months)
Chr Hep C
• Often axs – Øjaundice
• Natural course of dis varies considerably
• Rate of progression of liver scarring (fibrosis) variable
• 1/3 progress to cirrhosis in <20yrs, another 1/3 progress to cirrhosis within 30yrs, 1/3 progress so slowly that no issue in lifetime
• Once chr hep c progressed to cirrhosis → s/s of decr liver func or incr pres in liver circ (portal HTN)
• Ascites
• Bruising + bleeding
• Bone pain
• Varices
• Fatty stools – steatorrhea
• Jaundice
• Hepatic encephalopathy
• LFTs may show variable elev of ALT, AST, GGT or may occasionally be normal (no correlation betw LFTs and degree of liver injury)
• Albumin and prothrombin results are normal

Natural Hx + Prognosis
• 90% will develop chr inf (healthy carrier state does not exist)
• Only 10% will die in their lifetime
• 1/3 develop cirrhosis in their lifetime; risk of developing cirrhosis – 1% pa; factors –
a. inf duration >10y
b. age >50y at infection
c. alcohol (altered imm resp)
d. immunosuppression
e. HIV
f. Obesity (metabolic syndr)
• 1/3 develop fibrosis
• 1/3 no active fibrosis
• risk of cirrhotic decompensating – 5% pa
• risk of cirrhotic developing HCC – 3% pa

General Management
• counselling re low infectivity
• ↓ or eliminate alcohol
• vaccinate against Hep A/B
• Need to be off IDU and stable on methadone (>6/12) before starting tx
• Goal of therapy → eradication
• Previous results from interferon monotherapy were poor – 50% HCA RNA- during therapy (initial response), only 15% HCV RNA- one yr post-tx (sustained response, virological cure)
• Standard therapy = Combination tx – Interferon + Ribavirin (oral nucleoside analogue)
• 24-48 wks (depending on genotype of virus) – sustained response rates of 30-70% (results better for genotype 2 and 3)
• Reversible anemia main side-effect of ribavirin (50% of cases in nz)
• Pegylated interferon (given once/week) + ribavirin → improved cure rates esp in difficult to manage grps (genotypes 1,4, cirrhotics, high viral load) – dose may be limited by neutropenia/thrombocytopenia
• Other interferon side-effects – flu-like sxs, muscle aches, headache, irritability, depr (early or prophylactic tx w SSRI recommended), thyroid probs, alopecia, skin rash (exacerbates psoriasis)
• Side-effects from both ribavirin and interferon → may limit compliance and ↓ efficacy – pts able to take full dose for recommended duration have better results


Clinical assessment of patient with suspected liver disease

1. Sxs of a hepatic illness – eg prodromal flu-like sxs vs a cholestatic illness (eg pale stool, pruritis)
2. Episodic upper abdo pain – favours dx of biliary colic; pts w acute viral hepatitis may also have marked RUQ pain
3. Any sxs suggestive of complications of end-stage liver dis – eg abdo swelling, subtle evidence of encephalopathy (poor concentration, awake at night, sleeping during day)
4. Concurrent ilnness – DM, CHF
5. Recent overseas travel – consider amoebic liver abscess
6. Prev hx of jaundice, hepatitis
7. Details of previous abnormal liver tests
8. Exposure to blood products
9. Pareteral exposure – IV drug use, tattooing, body piercing
10. Detailed drug hx – prescription/herbal/homeopathic/recreational
11. Occupational exposures
12. Contact w known hepatitis carriers or jaundiced pts noted
13. High risk sexual practices
14. F.hx liver dis – hep B, haemochromatosis, auto-imm dis
15. Co-existing dis – DM, hyperlipidaemi (RFs for fatty liver), Autoimm dis

1. Body weight – BMI, waist circumference
2. Palmar erythema, Dupytrens, Leukonychia, Clubbing
3. Hepatic flap
4. Spider naevi, scratch marks, bruising
5. Jaundice (best detected in sclera)
6. Venous pres
7. Ascites, Gynaecomastia
8. Liver size – texture, tenderness
9. Palpable spleen – may suggest portal HTN or infiltrative dis
Note – pts may have advanced liver dis in absence of physical signs

Differential Dx varies according to clinical presentation
1. Portal HTN → cirrhosis
2. Encephalopathy → severe acute or chronic hepatocellular dysfunction
3. Age of pt impt in jaundice → infancy (physiological jaundice), adolescence (gilberts or viral hepatitis), young adults (viral hepatitis), elderly (malignancy)

Sxs and Signs of Liver Disease
1. Often no or non-specific sxs – lethargy, pain
2. Cholestatic liver disease – jaundice, pruritis, pale stool, dark urine
3. Hepatitis – jaundice, malaise, pain
4. Complications of cirrhosis – portal HTN, ascites, SBE, hepatic encephalopathy, hepatorenal syndr
5. Complications of ALF – as for cirrhosis (esp hepatic encephalopathy), hypogly, sepsis, hepatorenal syndr

Liver Enzyme Tests

See fig 1 – Intepretation of liver enzyme tests

1. Single enzyme elevation
1. GGT
a. Alcohol - check for MCV as further evidence
b. Drugs – esp phenytoin, carbamazepine, OC, rifampicin
c. Fatty liver – RFs incl obesity, DM, elev lipids (U/S may confirm by showing ↑ echogenicity)
2. ALP
a. Elev of ALP w/o elev of GGT → v suggestive of bone dis (eg recent #, pagets dis)
3. ALT
a. Mild elev w obesity + does not represent liver dis (both AST and ALT relate directly to BMI)
b. Mild chr hepatitis – ALT may be elev while AST normal (due to higher sens of ALT to hepatic inflame)
4. AST
a. Recent muscle injury or bruising – may have acute rise of 2-3x after strenuous exercise
b. Check for hemolysis – blood screen, haptoglobins, Coombs test
c. If persistent + no suggestion of liver dis → chr mus diseases (eg polymyositis – measure Creatinine)
5. Bilirubin
a. Gilberts syndr – persistent mild elev; commonly elev further w illness + fasting (levels usu <50 umol/l)
b. Predominantly a measure of unconjugated bilirubin – measurement of direct/indirect fraction rarely used in adult practice

Two impt questions -
A. Hepatocellular (AST/ALT) vs Cholestatic (ALP/GGT)
1. If a mixture of both patterns – there may be hepatocellular inflame or biliary obstr
2. Mild cholestasis is common w chr hepatitis but the pattern is predominantly hepatocellular
3. In acute biliary obstr, a ↑ in AST/ALT occurs early (first 5 days) but returns to near normal if obstr persists (acute obstr usu assoc w biliary-type pain)
B. Is there evidence of persistent elev of AST/ALT over >6 months
1. Arbitary cut-off duration but does define acute vs chronic hepatitis
2. Many pts w newly discovered elev of ALT/AST will prove to have chr liver dis
3. If AST/ALT level >10x normal – v likely to be acute injury

2. Tests for acute hepatitis
1. Usu assoc w acute illness – commonest cause of acute elev of ALT/AST in community is infectious mononucleosis
2. Main tests for acute viral hepatitis
a. Hep A IgM
b. Hep BsAg
c. Note – Hep C does not cause acute hepatitis but is almost always asx; Hep D only occurs in presence of Hep B inf
3. Consider drugs – may also have rash, fever and eosinophilia (phenytoin, isoniazid, diclonfenac, piriroxicam, allopurionol)
4. Consider alcoholic hepatitis – 80-90% will have AST/ALT ratio >2; AST/ALT levels are relatively low for acute hepatitis (100-300 U/l); look for disproportionately elevated GGT, macrocytosis and ↑ wcc (dx of hazardous alcohol intake rests primarily on hx + high index suspicion)

3. Tests for chronic hepatitis
1. Confirm ALT elev for >6 months (usu 1.5-3x upper limit normal range)
2. Request
a. Hep BsAg
b. Hep C Ab (followed by Hep C PCR if antibody positive)
c. Auto-antibodies (ANA and smooth muscle antibody)
d. Serum ferritin + iron studies (serum Fe + TIBC)
3. Commonest cause of raised ALT/AST is fatty liver (usu assoc w mild cholestasis ie mixed pattern)
a. if fat deposition in liver is assoc w hepatic inflammation then called steato-hepatitis
b. this occurs w excess alcohol intake but often present in absence of alcohol (non-alcoholic steatohepatitis – NASH)
c. RFs → DM, elev lipids, obesity
d. Measure fasting glucose, HbA1c + fasting lipids
e. U/S → detects 60-70% of case
4. ↑ ferritin may be due to hemochromatosis but also occurs w liver inflammation (common with fatty liver + excess alcohol consump)
5. Consider drugs – can be any drug, esp statins, isoniazid, nitrofurantoin, ketaconazole, NSAIDs, illicit drugs (anabolic steroids)
6. Auto-imm hepatitis – assoc w raised serum globulins (often 2x normal); check auto-antibodies (ANA and smooth mus antibody)
7. Check a-fetoprotein (elev in primary hepatocellular cancer) – esp if suspicion of cirrhosis

4. Evidence of cirrhosis – impaired hepatic function or portal HTN
1. Serum albumin and Prothrombin ratio (even borderline abnormal levels are likely to be sig in a setting of chr hepatitis)
2. Thrombocytopenia – suggests portal HT
3. Spleen may be enlarged but detected only on U/S

5. Cholestasis pattern of elev liver enzymes, Ø pain or jaundice, U/S N
1. Normal U/S does not completely exclude biliary tract dis → ERCP may be reqd if clinical scenario suggestive
2. Drugs –
a. Phenothiazines – can continue if less than 2x normal; remember stemetil
b. Augmentin + flucloxacillin – may be progressive condition w slow resolution over several months
c. Erythromycin – may present as acute RUQ pain + may mimic cholecystitis
3. Non-specific elev in sepsis + chr inflammatory conditions (eg IBD)
4. CHF – mild elev common w predominant R-sided HF related to hepatic congestion
5. Malignancy – may be a non-specific feat of disseminated ca; metastatic dis of liver usu has a mixed pattern; mild elevations only; usu detected by U/S (further exmn by CT may be reqd; esp for solitary lesions)
6. If chr (>6m) + progressive cholestasis → consider chr liver disorderssuch as primary biliary cirrhosis and sclerosing cholangitis (requires specialist referral for liver biopsy +/- ERCP; also order anti-mitochondrial antibody)

Other comments on Ix of liver disease
1. Albumin/Globulin
a. ½ life of serum albumin ~20 days
b. is normal in acute hepatitis (unless severe + prolonged)
c. low albumin reflects prolonged depr of liver func
d. elev globulins indicate chr hepatitis
2. INR + Glucose
a. International normalised ratio (equiv to prothrombin ratio), after IV Vit K = most sens indicator of hepatocellular synthetic reserve
b. Malabsorption of Vit K may occur in setting of severe cholestasis
c. INR is the most sens indicator of severity of an acute hepatic illness, and progressive elev is an indicator of severe (fulminant) hepatitis
d. Severe acute hepatitis (destr of most hepatocytes) impairs gluconeogenesis → hypoglycaemia (rarely seen in chr LF)
3. Indications for liver biopsy
a. Assessment of severity of liver dis (etiology unknown)
b. Dx test in a pt w liver test abnormalities of unknown cause
c. To obtain a dx of focal liver dis (U/S guided)
d. Portal HTN of unknown cause
e. May rarely be diagnostic in pts w systemic illness – eg pyrexia of unknown origin, amyloidosis, sarcoidosis, TB
4. Contraindications to percutaneous liver biopsy
a. Dilated bile ducts, ascites, coagulopathy (platelet <100, INR > normal, bleeding time > 10mins)
b. Transjugular liver biopsy may be safe alternative if coagulopathy cannot be corrected

Acute Liver Failure

1. Viral
a. nonA-nonB – 35% (20% recover)
b. HBV – 40% (50% recover)
c. HAV – 2% (70% recover)
d. Hepatitis E (rare)
2. Drugs – Paracetamol 15% (40% recover); others – ectasy, diclofenac, halothane
3. Other – 8% (<10% recover)

Based on interval betw onset of jaundice and encephalopathy
1. Hyperacute LF - <7 days
2. ALF – 8-28 days
3. Subacute LF – 4-12 wks
Best prognosis for those with most rapid onset of encephalopathy

1. RUQ pain + tenderness
2. Jaundice
3. Encephalopathy
4. Coagulapathy, Sepsis, Hypogly, Oliguria

1. Supportive – may require ICU, vent support, monitoring for cerebral edema, prevention of RF, correction of hypogly
2. Liver transplantation – if fulfilling critieria for poor survival
Note – best predictor of developing fulminant hepatitis and LF is prothrombin ratio and impaired consciousness (level of peak AST/ALT not useful)

Consequences of chronic liver disease

1. Portal HTN
2. Hepatic encephalopathy
3. Ascites
4. SBP – spontaneous bacterial peritonitis
5. Hepatorenal syndrome
6. Hepatopulmonary syndrome

A. Portal HTN
1. Portal blood blood flow
a. Normal – 1L/min 70% O2 supply to liver by portal sys, 100% of blood goes to hepatic v
b. Cirrhosis - <15% goes through liver to hepatic v, rest goes into porto-systemic shunts
2. Portal pressure – Normal 5 mmHg, Cirrhosis >12 mmHg
3. Prevalence
a. Varices develop in ~30% or cirrhotics (Child’s A <10% → Childs C >50%)
b. Risk of bleed from varices ~20% pa
c. Bleeding risk greater if large varices with red spots and Childs C cirrhosis
d. Risk of death – 20-50% per bleed
e. Risk of rebleeding relates to severity of liver disease (early rebleeding <6wks = 40% / late rebleeding >6wks = 85% at 2 yrs)
4. Clinical features
a. Often silent until pres w haematemesis
b. Pts w known cirrhosis should be screened if – platelets <140, INR >1.4 or ↑ portal v diameter on U/S
c. May suspect dx because of effect of hyperslenism → ↓ platelets, ↓ WBC
d. Ixs
i. Gastroscopy – to detect varices (most useful)
ii. U/S – splenomegaly, dilated portal vein, collaterals
iii. Doppler – portal v thrombosis
5. Tx of bleeding esophageal varices
a. Pharmacological – octreotide (somatostatin) or terlipressin
b. ST A/B prophylaxis – norfloxacin
c. PPI – to prevent bleeding from esophageal ulceration
d. Variceal banding (preferred) or sclerotherapy (usu continued until varices obliterated)
e. Less freq used techniques – TOPPS (radiological shunt), Snegasteaken-blackmore tamponade (temporary measure)
6. Prevention of re-bleeding
a. Non-selective b-blocker (eg porpranolol) + ISMN
b. ↓ resting PR by 25% or to 50-60/min
c. Aim to obliterate varices w variceal banding as reqd
d. Porto-caval shunt (mesocaval if portal v thrombosis) for recurrent bleeding if not candidate for liver transpl
e. Liver transplant
7. Primary prophylaxis (prevention of 1st variceal bleed)
a. Non-selective b-blocker → ↓ risk by 45%
b. ↓ overall mortality by 15%

B. Hepatic Encephalopathy
1. Complex neuro-psyhiatric syndr assoc w poor hepatocellular func in chr liver failure (may also be found in ALF + porto-systemic venous shunting in absence of liver failure)
2. Usu reversible w medical mgt
a. Grade 1 – mood/personality change, inverted sleep pattern
b. Grade 2 – drowsy, inappropriate beh, constructional apraxia, asterixis
c. Grade 3 – irritable, bizarre beh, hyper-reflexia
d. Grade 4 - coma
3. Prevalence – overt in 5-10% of cirrhotics; subclinical in up to 70%
4. Cause
a. ↓ hepatocellular func + porto-systemic shunting → failure to detoxify substances presumed to be colonic in origin
b. Substances which are related to nitrogen metab and intestinal bacteria (normally metab by liver) able to pass bbb + disturb normal brain func
c. Accum of unmetabolised ammonia, production of false NTs
d. Activation of central GABA-benzodiazepine Rs by endogenous ligands
5. Mgt
a. Excl alternative dxs
b. Identify + tx any precipitating factor – eg GI hem, drugs, inf, elyte abnormalities
c. Restr of dietary protein to 20g/day, meet daily energy requirements w carbs (if coma → NBM + 10% dextrose IV)
d. Remove nitrogen substances from bowel using lactulose – osmotic cathartic effect empties GI tr of dietary and endogenous aminogenic compounds; ↓ pH in gut lumen → inhibition of ammonia prodn

C. Ascites
1. Etiology
a. ↓ plasma colloid osmotic pres
b. ↑ portal venous pres
c. salt + water retention (2ndry hyperaldosteronism)
d. renal changes (1’ or 2’) – renal vasoconstr, water + Na retention
2. Differential Dx
a. 80% due to cirrhosis (rate of developing ascites in compensated cirrhosis 30% by 5 yrs); once ascites develops – 1 yr survival ~50% (cf 90% for compensated cirrhosis)
b. 20% due to inf, cardiac, hypoalbuminaemia (nephrotic syndr), carcinomatosis, pancreatitis
c. Dx by paracentesis (to determine cause of ascites + exclude infection (SBP))
d. If serum albumin-ascetic fluid albumin is –
i. >11 g/L → portal HTN
ii. <11 g/L → NO portal HTN
e. If WBC >500 /mm3 → SBP likely
f. Check also gram stain (+ <10% SBP??) + positive culre in >75% w SBP)
3. Tx of ascites
a. Fluid + Na restr
b. Diuretics – aldactone +/- frusemide
c. Therapeutic paracentesis
i. For ascites resistant to fluid/salt restr + diuretic therapy
ii. Adv over diuretic therapy – rapid sx relief, rapid improvement in systemic + portal hemodynamics, ↓ hyponatremia + renal impairment, ↓ hosp days + cost
d. Rarely need to consider – Le veen shunt, TIPPS, liver transpl

1. 20-30% of cirrhotic pts w ascites get SBP
2. Usu single organism – 90% G- bacilli (E.coli, Klepsiella), 10% G+ (pneumococcus, enterococcus)
3. RFs – cirrhosis, low ascetic protein <10 g/L (↓ complement, opsonins), variceal hemorrhage
4. Dx – by paracentesis
5. Tx
a. A/Bs – empirical (cefuroxime or 3rd gen cephalosporin) until culture results, avoid aminoglycosides
b. Watch for renal impairment / encephalopathy
c. Start prophylactic A/Bs – eg norfloxacin (50% recurrence in 1 yr w/o prophylaxis)
d. Consider transpl bec <40% 1 yr survival for cirrhotics who had one episode of SBP

E. Hepatorenal Syndrome
1. Functional RF in setting of cirrhosis in absence of intrinsic renal dis
2. Tx – optimise fluid mgt, treat precipitating factors, optimise renal hemodynamics (vasoactive drugs – eg terlepressin, paracentesis)
3. Reversible on improvement of liver function (eg after transpl)
4. Assoc w extremely poor prog (>90% mortality)

F. Hepatopulmonary Syndrome
1. Low PaO2 (<70 mmHg) – due to intra-pulmonary vascular dilatations
2. Tx –liver transpl only


1. Alcoholic liver disease
• Common cause of liver disease and liver-related death in most western countries
• Mechanisms not clearly understood – oxidative stress (perioxidative damage to membr phospholipids), release of TNFa, immunological mechanisms, toxic metabolite (acetaldehyde)
• Wide inter-individual susceptibility but MOST pts have had intake of >80g/d for 15 yrs (ie 8 beers or 1L wine or one cup whiskey daily)
• Safe levels – 21 units (men), 14 units (women) weekly; 1 unit = 10g
• Only 10-20% of alcoholics develop cirrhosis
• Genetic susceptibility (specific HLA types) - ↑ risk in females
• Aldehyde dehdrogenase 2 deficiency in Asians protective
• Nutrition and concurrent viral liver dis impt co-factors
1. Asx, incidental finding of fatty liver on U/S
2. Abnormal liver enzymes ALT/AST usu <5x normal; AST/ALT ratio >2 (only in 60%)
3. GGT may be disproportionately raised
4. May present initially as alcoholic hepatitis or complications of cirrhosis
5. Liver histology ranges from fatty liver → alcoholic hepatitis → cirrhosis
1. Alcohol abstinence (5y survival rates if cirrhosis - 60% if abstinent vs continued drinking <20%)
2. Correct vitamin deficiencies – eg thiamine
3. Control complications of cirrhosis
4. ? liver transplant for decompensated cirrhotics if abstinent >6 months

2. Non-Alcoholic fatty liver disease
• Spectrum from non-alcoholic fatty liver (non-progressive, benign) to steatohepatitis (sig necro-infalmmatory reaction; may progress to cirrhosis)
• New term NAFLD inclusive term for whole spectrum of dis
• Histology identical to alcohol induced dis; may have mildly abnormal LFTs (usu mixed pattern; often ↑ GGT and ALT)
• RFs – obesity, T2DM, Hyperlipidemia (esp ↑ TGs), ↑ waist circumference, linked to metabolic syndr
• Can be caused by drugs – amiodarone, perhexiline, methotrexate, assoc w weight losing operations that cause malabsorption
• Pathogenesis – insulin resistance and lipid peroxidation (if sig inflame)
• Common cause of chr abnormal LFTs; ↑ prev as obesity becomes more common in community
• Ix by U/S – diffuse echogenicity found in 2/3; role of liver biopsy controversial
• Dx – by excl of other causes of liver disease, presence of RFs + U/S appearances
• Tx – considered as part of metabolic syndr → weight loss, regular exercise, low fat diet
• Rx of DM + lipid abnormalities helpful
• Weight reduction surgery – could be considered when severe NAFLD
• Risk of cirrhosis – 2-5% over lifetime, ↑ risk w ALT >150 and if sig steato-hepatitis on liver biopsy

3. Autoimmune hepatitis
• D/o of unknown etiology
• Characterised by hypergammaglobulinaemia, circulating autoantibodies, female preponderance
• Dx
• Elev ALT/AST >6m
• 2x elev of gammaglobulins
• ANA, SMA, LKM-1 antibody >1:40
• Excl of other liver dis
• Compatible liver histology
• Pres
• 2x age peaks – 20-40s and 60-70s
• Mode of onset – insidious 2/3, acute 1/3
• Assoc w other auto-imm diseases; DM and thyroid d/os
• Tx
• Corticosteriods +/ azathioprine
• 80% overall response rate
• Tx LT – relapse in 80% if stopped
• Goal – to suppress signs of dis activity while minimising side-effects

4. Haemochromatosis
• AR
• 70% of pts possess HLA-A3
• Gene freq 1/20 caucasians, 1/400 individuals homozygotes
• HFE gene encodes for a major histocompatibility complex class 1 molec that requires interaction w 2-microglobulin
• Main mutation is Cys282Tyr; 8% of pts w haemochromatosis have this mutation, other minor mutations identified
• Main grp with iron overload – homozygous Cys282/Cys282; however some probs with compound heterozygotes (Cys282/other mutation)
• Defect in mucosal iron absorption – iron balance escapes the usual control mechanisms; iron absorbed despite absence of anemia and presence of excess iron in marrow and liver
• Direct toxicity a result of excess accumulation of iron
• Normal iron stores ~4g
• Hb in red cells makes up ~50% of body stores (1 unit blood = 500 ml, contains 250 mg of iron)
• Remainder in storage form as ferritin or haemosierin – in liver + reticuloendothelial cells
Clinical Feats
• Multi-system dis w s/s depending on organs affected
• Full clinical expression only in homozygotes
• Liver – asx, abnormal LFTs, hepatomegaly, cirrhosis, HCC
• Pituitary hypofunction, skin bronzing, cardiomyopathy, DM, testicular atrophy, athropathy
• F.hx
• Initial screening tests – serum Fe, IBC, % transferring saturation (males >0.6, females >0.5, serum ferritin)
• Abnormal screening tests → genetic testing
• Liver histology and liver iron (liver biopsy not reqd in younger pts w normal LFTs and Ferritin <1000)
• Confirmation by response to phlebotomy (gradual ↓ in ferritin to normal range)
Tx + Prognosis
• Phlebotomy 1-2/52 until low normal serum ferritin achieved, then titrated to prevent reaccumulation of iron (~2-3/12)
• Preventable – all clinical manifestations
• Reversible – cardiac dysfunction, glucose intol, hepatomegaly, skin pigmentation
• Irreversible – cirrhosis, athropathy, hypogonadism, HCC risk

5. Wilson’s disease
• AR d/o of copper metabolism resulting in excessive accum of copper in liver and brain
• Prev of homozygotes – 1/30,000; calculated gene freq 1/180
• Pathogenesis
• ↓ in hepatic excretion of copper
• Impaired syn of the copper protein ceruloplasmin
• Clinical feats
• Liver – acute and chr hepatitis, cirrhosis, fulminant hepatic failure
• Neuropsychiatric d/os
• Hemolytic anemia
• Consider dx in any persoon 3-40 yrs age who has hepatic, neurologic or psychiatric dis of undetermined etiology or persistent unexplained raised transaminases
• Initial test – serum ceruloplasmin <20 mg/dl
• Tx
• D-penicillamine 25—500 mg QID PO + Pyridoxine 25 mg
• Life is prolonged and liver/CNS dis may be improved by therapy
• Pre-sx tx prevents onset of multi-organ injury
• Liver transpl results in cure

6. Primary biliary cirrhosis (PBC)
• Prev – 50-100/million
• F:M = 9:1, mean age dx = 50y
• Clinical pres - 70% symptomatic – pruritis, fatigue, decompensated cirrhosis, other autoimm d/o; 30% asx – present w deranged LFTs, hepatomegaly, splenomegaly
• Histology - chr cholangitis affecting predominantly the middle-sized bile ductules; assoc w granuloma in 40% of cases
• Serology – AMA (anti mitochondrial antibody) detected in 95%, raised serum IgM
• Management
• Pruritis – difficult to tx (antihistamines, cholestyramine, rifampacin)
• Ursodeoxycholic acid – well tolerated, safe, improves LFTs, slows histological progression, may not improve sxs of pruritis or fatigue, probably improves overall pt survival and transplant free survival

7. Sclerosing cholangitis
• Primary (idiopathic) - PSC – may be assoc w IBD
• PSC in 5% of chr ulcerative colitis (pan-colitis); UC in 80% of PSC
• PSC in 1% of crohns; Crohns in 7% of PSC
• 2ndry – assoc w immunodeficiency, biliary stricture or hepatic artery thrombosis
• Clinical feats
• Axs until advanced dis
• May present with either acute cholangitis (fever, pain, jaundice) OR gradually with pruritis and lethargy
• ↑ ALP/GGT (cholestatic enzymes), ↑ bilirubin and ALT during acute cholangitis
• Low albumin and ↑ INR with end-stage cirrhosis
• Dx
• ERCP or PTC (percutaneous transhepatic cholangiogram) → multifocal strictures and dilatations of extrahepatic and intrahepatic biliary tree
• Liver biopsy – infiltration of duct epith followed by concentric fibrosis (onion skinning); inflame and fibrosis into periportal areas; ductopaenia
• Mgt
• Cholestyramine, antihistamine (for pruritis)
• A/Bs for acute cholangitis
• Ursodeoxycholic acid for domiant stricture
• Dilatation +/- stenting of dominant stricture by ERCP or PTC
• Orthotopic liver transplantation for endstage liver dis
• Note – cholangiocarcinoma develops in 10-15% of all PSC


Liver disease – clinical presentation and complications

1. Diff dx according to presentation
a. Portal HTN → cirrhosis
b. Encephalopathy → severe acute or chr hepatocellar dysfunction
c. Jaundice →adolescence (gilberts or viral), young adults (viral), elderly (malignancy)
2. Signs of liver dis – palmar erythema, dupytrens, clubbing, hepatic flap, spider naevi, scratch marks, bruising, jaundice, ascites, gynaecomastia
3. LFTs
a. Hepatocellular inflammation = AST/ALT
i. Most common cause for ↑ = fatty liver (often a mixed pattern, assoc w a mild cholestasis)
ii. Most common cause for ↑ in community is GF
b. Cholestatic (eg biliary obstruction) = ALP/GGT
c. Alcoholic hepatitis – only minor elev AST/ALT (100-300) – look for elev GGT + macrocytosis
d. A-fetoprotein (elev in primary HCC) – esp if suspicion of cirrhosis
4. Approach to Elevated LFTs
a. Hepatocellular pattern (predominantly ↑ ALT/AST)
i. Acute → EBV, Hep A/B, Alcohol, Drugs
ii. Chronic (>6/12) → Hep B/C, Fatty liver, Haemochromatosis, Alcohol, Drugs, Autoimmune → check for evidence of cirrhosis (ie albumin, prothrombin ratio)
b. Cholestatic pattern (↑ ALP +/- GGT)
i. Jaundice or Pain → urgent US
ii. Ø abdo pain, normal bilirubin and US → drugs, inflammation, malignancy
5. Viral Hepatitis
a. HAV IgM
b. HBsAg
c. Hep C almost always asx
6. Albumin – ½ life 20 days, normal in acute hepatitis, low albumin = prolonged depr of liver function
7. INR – malabsorption in severe cholestasis → most sens indicator of acute hepatic illness
8. Glucose – severe acute hepatitis impairs gluconeogenesis → hypoglycaemia
9. Cholestasis pattern of liver enzymes, Ø pain or jaundice and US normal → cannot completely excl biliary tr dis → ERCP
10. Gilberts syndrome – mild elev <50
11. Acute LF
a. Def – Hyperacute <7 days, acute 7-28 days, subacute 4-12 wks
b. Etiology
i. Viral – nonA-nonB, HBV, HAV
ii. Drugs - paracetamol
c. Presentation
i. RUQ pain + tenderness
ii. Jaundice
iii. Encephalopathy
iv. Coagulapathy
v. Sepsis
vi. Hypoglycaemia
d. Mgt
i. Supportive
ii. Liver transplant
12. Consequences of chr liver disease
a. Portal HTN – in cirrhosis, <15% blood through liver to hepatic vein (remainder goes through porto-systemic shunts)
i. Pres – often asx until hematemsis (esophageal varices)
ii. Mgt of varices – PPI to prevent bleeding from esophageal ulceration, variceal banding, sclerotherapy
b. Hepatic encephalopathy – mood, personality change → drowsy, inappropriate beh, constructional apraxia, asterixis → irritable, bizarre beh, hyper-reflexia → coma (cirrhosis → porto-systemic shunts → failure to detoxify substances of colonic origin)
i. Mgt – restrict dietary protein, lactulose removes nitrogen substances from bowel
c. Ascites – 80% of ascites due to cirrhosis
i. Dx – paracentesis (determine ascites cause + excl SBP)
ii. Tx – fluid and salt restriction, aldactone +/- furosemide, therapeutic paracentesis
d. SBP – spontaneous bacterial peritonitis
i. 20-30% of cirrhotic pts w ascites get SBP
ii. Usu G-bacilli eg E.coli
iii. Tx - cef
e. Hepatorenal syndrome
f. Hepatopulmonary syndrome

Hepatitis B

1. Def – inflammation of liver caused by HBV
2. Epidem – 7% prev in nz (50% of worlds popn past or present inf)
3. Transmission – exposure to infectious blood or body fluids containing blood (eg unprotected sex, blood transfusion, vertical transmission)
a. Low prevalence areas – injection drug abuse and unprotected sex most common causes
b. High prevalence areas – vertical transmission
4. Pathogenesis
a. HBV infection – host response causes hepatocellular and viral clearance
5. Sxs and complications
a. HBV may be either acute (self limiting) or chronic
b. Self limited infection clears spontaneously within weeks/months
c. >95% of adults clear the infection while most young children will not clear the infection
d. Acute infection may be asx or begin with general ill health, loss of appetite, n/v, body aches, mild fever, dark urine progressing to jaundice
e. Illness lasts a few weeks then gradually improves in most
f. Chronic infection may lead to chr liver inflammation → cirrhosis → HCC
g. Hep D co-infection occurs only with HBV → ↑ risk of cirrhosis and HCC
6. Acute infection
a. Asx or general feelings of being unwell etc
b. If HBsAg positive → full viral profile performed
c. Most pts recover completely (as demonsntrated by disappearance of HBsAg and the devt of anti-HBs)
d. A minority of pts do not clear HBsAg from the serum and become chr carriers (risk inversely related to age at time of infection)
7. Hep B Serology Patterns
a. Acute infection vs Chronic infection
i. Acute inf – HbsAg +ve, Anti-HBcore +ve, IgM anti-HBcore +ve, Anti-HBs –ve
ii. Chr inf - HbsAg +ve, Anti-HBcore +ve, IgM anti-HBcore –ve, Anti-HBs -ve
b. Immunisation vs Natural immunity
i. Immunisation – HbsAg –ve, Anti-HB core –ve, Anti-HBs +ve
ii. Natural immunity – HbsAg –ve, Anti-HB core +ve, Anti-HBs +ve
8. Chronic HBV carriers
a. Persistence of HBsAg in serum for >6 months
b. If carriers also have HBeAg or viral DNA in the serum (active viral replication) → highly infectious and at greatest risk of developing chr hepatitis and cirrhosis
c. These pts would have abnormal liver enzymes, should receive tx
9. Pre-core mutant
a. Mutation in pre-core region of genome which codes for the HBeAg protein
b. Selection of mutated virus over wild type to evaded effect of anti-HBe by not producing e antigen
10. Tx
a. Indications – pts w HBsAg and HBV DNA in the serum, abnormal serum aminotransferases and chr hepatitis on liver biopsy
i. Most of these pts will be HBeAg +ve unless mutant virus
b. Aims of tx
i. Eliminate HBeAg in serum
ii. Reduce inflammatory necrosis of hepatocyte
iii. These drugs do not clear the infection, rather they stop viral replication thus preventing liver damage
c. General
i. Ø alcohol consumption due to ↑ risk or cirrhosis + HCC
ii. Infants born to mothers known to carry hep b treated with hep b immune globulin (HBIg) at birth followed by hep b vaccination → ↓ risk of contraction by 95%
d. Interferon
i. Enhance own immune response (immune sys modulator)
ii. Duration 4-6 months
e. Nucleoside analogues (anti-virals) → ↓ viral load in blood thus ↓ viral replication in liver
i. Lamivudine (3TC)
1. ↓ viral load, usu HBV DNA neg after 4/52
2. Low rate of seroconversion after 1 year (10%), but up to 30% after 3 yrs
3. Lamivudine resistance – up to 50% after 5 yrs
ii. Adefovir
1. Used for lamivudine resistance

Hepatitis C

1. Prevalence – nz 0.3% HCV RNA+ve
2. Most common cause of cirrhosis and HCC in most western countries but not in nz where HBV is more common
3. Risk factors
b. Blood transfusion <1992
c. Others incl tattoos in prison, hemophilia, hemodialysis
4. Presentation
a. Asx – present after RF screening or abnormal LFTs
b. Non-specific sxs – eg lethargy
c. End stage liver dis – eg variceal bleed, ascites, peripheral edema, HCC
5. Acute hep c
a. Asx in 2/3s
b. Sxs mild + non-specific - ↓ appetite, fatigue, abdo pain, jaundice, itching, flu-like sxs
c. Approx 20% clear the virus, the remaining 80% develop chr hep c (>6 months)
6. Chr hep c
a. Often asx
b. Rate of progression to cirrhosis variable –
i. 1/3 progress to cirrhosis <20 yrs
ii. 1/3 progress to cirrhosis <30 yrs
iii. 1/3 progress so slowly that not an issue in lifetime
7. Cirrhosis – signs of decr liver function and portal HTN
a. Ascites
b. Bruising and bleeding
c. Varices
d. Steatorrhea
e. Jaundice
f. Hepatic encephalopathy
8. Mgt
a. Decr or eliminate ETOH
b. Off IDU and stable on methadone >6/12 before starting tx
c. Vaccinate vs hep a/b
d. Goal of therapy → eradication
i. Standard tx – peglylated interferon + ribavirin (oral nucleoside analogue) – pegylated = added polyethylene glycol (PEG)
ii. 24-48 wks depending on genotype
iii. Sustained response rates in 30-70% (better for genotypes 2 and 3)
iv. Reversible anemia = main side effect from ribavirin

Non-viral causes of liver disease

1. Alcoholic liver disease
a. Only 10-20% of alcoholics develop cirrhosis
b. Presentation
i. Asx, incidental finding on liver US
ii. Abnormal liver enzymes – ALT/AST <5x Normal, GGT may be disproportionately raised
c. Liver histology – ranges from fatty liver → alcoholic hepatitis → cirrhosis
d. Mgt – alcohol abstinence, correct vitamin deficiencies, control cirrhosis complications
2. Non-alcoholic fatty liver disease (NAFLD)
a. Def - Spectrum from non-alcoholic fatty liver (benign, non-progressive) to steatohepatitis (fat deposition in liver, necro-inflammatory reaction, may progress to cirrhosis)
b. Epidem – common cause of chr abnormal LFTs
c. Histology – identical to alcoholic induced liver disease
d. RFs – obesity, T2DM, hyperlipidemia (assoc w metabolic syndrome)
e. Ixs – US +/- liver biopsy (controversial)
f. Tx – as per metabolic syndrome (weight loss, exercise, low fat diet, diabetes control, statins, anti-hypertensives etc)
g. Prognosis – risk of cirrhosis 2-5% over lifetime
3. Haemochromatosis
a. Etiology – genetic, 70% possess HLA-A3, AR, 1/20 caucasian gene frequency, 1/400 homozygotes
b. Pathogenesis – excess iron accumulation
c. Presentation
i. Liver – asx, abnormal LFTs, hepatomegaly, cirrhosis, HCC
ii. Pituitary hypofunction, skin bronzing, cardiomyopathy
d. Ixs – f.hx, iron studies, genetic testing, liver histology and liver iron
e. Mgt – phlebotomy 1-2/52 until low normal serum ferritin achieved, then titrated to prevent reaccumulation of iron – usu 2-3/12
f. Prognosis – cirrhosis, HCC irreversible
4. Other non-viral causes of liver disease
a. Autoimmune hepatitis
b. Wilson’s disase
c. Primary biliary cirrhosis (PBC)
d. Sclerosing cholangitis

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