Liver failure, cirrhosis and HH

Question 2

Liver failure - definition

Answer 2

Can occur suddenly in a previously healthy liver – acute hepatic failure or more commonly as a result of decompensation of chronic disease – acute on chronic hepatic failure.

Fulminant hepatic failure is a clinical syndrome resulting from massive necrosis of liver cells leading to severe impairment of liver function – encephalopathy in 7 days – hyperacute, 8-28 days – acute, 5-26 weeks – subacute.

Question 3

Liver failure - causes

Answer 3

• Infections – viral hepatitis (especially B, C and cytomegalovirus), yellow fever or leptospirosis.
• Drugs / toxins – paracetamol, halothane, isoniazid, mushrooms or carbon tetrachloride.
• Vascular – Budd-Chiari syndrome or veno-occlusive disease (e.g. antiphospholipid syndrome).
• Others – alcohol, primary biliary cirrhosis, haemochromatosis, autoimmune hepatitis, α1-antitrypsin deficiency, Wilson’s disease, fatty liver of pregnancy, malignancy or HELLP.

Question 4

Liver failure - signs

Answer 4

Jaundice, hepatic encephalopathy, fetor hepaticus (pear drops), asterixes, constructional apraxia (test with 5 pointed star) and signs of chronic liver disease (cirrhosis) when acute on chronic failure.

Question 5

Hepatic encephalopathy

Answer 5

As the liver fails nitrogenous waste (ammonia) builds up in the circulation and passes to the brain. It is converted to glutamine by astrocytes causing an osmotic imbalance. Fluid moves into the cells leading cerebral oedema and symptoms – grade 1 – mood and sleep disturbance, grade 2 – drowsiness and slurred speech, grade 3 – stupor and confusion and grade 4 – coma.

Question 6

Liver failure - investigations

Answer 6

• Bloods – FBC for infection or GI bleeding, Us and Es, LFTs, clotting, glucose, paracetamol level, hepatitis, CMV and EBV serology, ferritin, α1-antitrypsin, caeruloplasmin or autoantibodies.
• Microbiology – blood cultures, urine cultures and ascitic tap for microscopy, culture and sensitivity – if neutrophils >250/mm3 it indicates bacterial peritonitis.
• Radiology – CXR, abdominal ultrasound and Doppler flow studies of portal and hepatic veins.

Question 7

Liver failure - general management

Answer 7

• Be sure to rule out sepsis, hypoglycaemia, GI bleeds (due to varices) and encephalopathy.
• Treat the cause where possible e.g. GI bleed, sepsis, paracetamol poisoning or malignancy.
• If the patient is malnourished get dietician input as good nutrition decreases mortality rates.
• If renal failure (hepatorenal syndrome) develops may require haemofiltration or haemodialysis.
• Avoid sedatives (and other drugs with hepatic metabolism) but treat seizures with lorazepam.
• Consider a PPI as prophylaxis against stress ulceration e.g. 40mg Omeprazole IV/PO OD.
• Liase early with the nearest transplant centre for appropriateness (King’s college criteria).

Question 8

Liver failure - complication management

Answer 8

• Bleeding – give 10mg Vitamin K IV OD for 3 days, platelets, FFP and blood PRN and endoscopy.
• Infection – give 1-2g Cefuroxime IV OD until sensitivities are known (avoid gentamicin).
• Ascites – fluid restriction, low salt diet, daily weight and prescribe diuretics e.g. Furosemide.
• Hypoglycaemia – check regularly and give 50mL 50% Glucose if <2mmol or symptomatic.
• Encephalopathy – avoid sedatives and give 30-50mL Lactulose TDS OD and regular enemas (decreases number of nitrogen forming bowel organisms) – aim for 2-4 soft stools per day.
• Cerebral oedema – give 20% Mannitol IV and hyperventilate.

Question 9

Liver failure - prognosis

Answer 9

Poor prognostic features are grade 3 or 4 encephalopathy, age >40 years, albumin <30 g/L, raised INR, drug induced or late onset hepatic failure.

There’s a 65% survival rate post-transplantation.

Question 10

Hepatorenal syndrome

Answer 10

Renal failure in patients with chronic liver disease. It is not well understood but the initial event appears to be splanchnic arterial vasodilation followed by renal vasoconstriction.

Question 11

Liver failure - prescribing

Answer 11

Avoid opiates, diuretics (increased risk of encephalopathy), oral hypoglycaemics or saline containing IV infusions. The effects of warfarin are enhanced.

• Hepatotoxic drugs – paracetamol, methotrexate, phenothiazines, isoniazid, azathioprine, oestrogen-6-mercaptopurine, salicylates, tetracycline and mitomycin (chemotherapy drug).

Question 12

Kings college criteria for liver transplantation

Answer 12

• Paracetamol liver failure – arterial pH <7.3 24 hours after ingestion or all of the following – pro-thrombin time >100 seconds, creatinine >300 μmol/L and grade 3 or 4 encephalopathy.
• Non-paracetamol liver failure – PT >100 secs and 3 out of 5 of the following – drug induced, aged <10 or >40 years, >1 week to encephalopathy, PT >50 secs or bilirubin >300μmol/L.

Question 13

Cirrhosis - definition

Answer 13

Kirrhos means yellow in Greek - cirrhosis implies irreversible liver damage. Histologically there is loss of the normal hepatic architecture with bridging fibrosis and nodular regeneration.

Question 14

Cirrhosis - causes

Answer 14

Most common causes are chronic alcohol abuse and hepatitis B or C infection.

Rarer causes include non-alcoholic steatohepatitis, autoimmune diseases (PBC or PSC), genetic diseases (Wilson’s disease, haemochromotosis or α1-antitrypsin deficiency), cryptogenic (unknown), Budd-Chiari syndrome or drugs (e.g. amiodarone, methotrexate or methyldopa).

Question 15

Cirrhosis - signs

Answer 15

Range from only deranged LFTs to decompensated end-stage liver disease.

• Hands – clubbing, palmar erythema, Dupuytren’s contracture, leuconychia (due to hypo-albuminaemia) or Terry’s nails (white proximally but distal third is red due to telangiectasia).
• Other signs - hyperdynamic circulation, spider naevi, xanthelasma, gynaecomastia, atrophic testes, loss of body hair, parotid enlargement, hepatomegaly or a small liver in later stages.

Question 16

Cirrhosis - complications

Answer 16

• Hepatic failure – coagulopathy and raised INR (due to decreased factors II, VII, IX and X), encephalopathy causing confusion and asterixes, hypoalbuminaemia causing oedema and leuconychia, sepsis, spontaneous bacterial peritonitis or hypoglycaemia.
• Portal hypertension – ascites, splenomegaly and porto-systemic shunt which can lead to oesophageal varices (± upper GI bleeding) and caput medusae (enlarged peri-umbilical veins).
• Renal function – reduced hepatic clearance of immune complexes leads to them getting trapped in the kidneys causing IgA nephropathy. In addition hepatitis C virus and α1-antitrypsin deficiency are known to cause membranoproliferative glomerulonephritis.

Question 17

Cirrhosis - investigations

Answer 17

• Bloods – LFTs can range from normal to all raised, synthetic function is affected later – low albumin and raised PT/INR and low WCC and platelet count indicate splenomegaly.
• Identify the cause – ferritin, iron and total iron-binding capacity, hepatitis serology, immunoglobulins, autoantibodies, α-fetoprotein, caeruloplasmin and α1-antitrypsin levels.
• Liver ultrasound ± duplex – to look for hepatomegaly or a small liver, splenomegaly, focal liver lesions, hepatic vein thrombosis, reversed flow in the portal vein and ascites.
• Ascitic tap – always send fluid for MC+S - >250/mm3 neutrophils indicates bacterial peritonitis.
• Liver biopsy – can help to confirm the clinical diagnosis of cirrhosis.

Question 18

Screening tests for chronic liver disease

Answer 18

• HBV and HCV serology.
• Iron studies for haemochromoatosis - high ferritin and iron and low total iron bindnig capacity.
• Alpha1-antitrypsin deficiency - test plasma for genetics.
• Wilson’s disease - decreased serum copper and caeruloplasmin.
• PBC - raised anti-mitrochondrial antibody.
• PSC - raised ANA, AMA and ANCA +ve.
• AIH - raised ANA, ASMA and IgG.
• Immunoglobulins - IgA raised in alcoholic liver disease, IgG raised in autoimmune hepatitis and IgM raised in PBC.
• HCC - raised alpha-fetoprotein.
• Gilbert’s - conjugated and unconjugated bilirubin.

Question 19

Cirrhosis - Child-Pugh score

Answer 19

Child-Pugh grading of cirrhosis and risk of variceal bleeding – grade A = 5-6 points, grade B = 7-9 points and grade C = >10 points. Risk of bleeding is much higher if the patients scores >8 points.

• Bilirubin (μmol/L) - <34, 34-51 or >51.
• Albumin (g/L) - >35, 28-35 or <28.
• PT (secs > normal) - 1-3, 4-6 or >6.
• Ascites - None, Slight or Moderate
• Encephalopathy - None, Grades 1-2 or Grades 3-4.

Question 20

Cirrhosis - general management

Answer 20

Good nutrition, abstinence from alcohol – 10mg Baclofen TDS to help cravings is not contraindicated in cirrhosis (unlike naltrexone), 4g Colestyramine 1 hour after taking other meds can help with pruritis and consider 3-6 monthly ultrasound ± α-fetoprotein for HCC risk.

Question 21

Cirrhosis - specific management

Answer 21

Interferon-α improves LFTs and may slow progression to HCC in HCV induced cirrhosis, UDCA (ursodeoxycholic acid) can be given to normalise LFTs in primary biliary cirrhosis but has no effect on disease progression and Penicillamine for Wilson’s disease.

Question 22

Cirrhosis - complication management

Answer 22

• Ascites – bedrest, fluid restriction (Spironolactone OD and increase dose every 48 hours to 400mg OD. Monitor daily weights and aim for loss of
• Spontaneous bacterial peritonitis – common organisms are E coli, Klebsiella and Strep. Give 2g Cefotaxime QDS for 5 days or until sensitivities known. Give prophylaxis to high risk patients.

Question 23

Cirrhosis - prognosis

Answer 23

Overall 5 year survival is 50%.

Poor prognostic indicators are any grade encephalopathy, serum sodium <110 mmol/L, serum albumin <25 g/L and raised INR.

• Liver transplantation – only definitive treatment and raises the 5 years survival rate to 70%.

Question 24

Iron metabolism

Answer 24

The average adult absorbs 1-1.5mg of iron per day from an average intake of between 12-20mg.

Sources of iron – red meat, liver, seafood, enriched breakfast cereals, pulses and some spices. Most dietary iron is Fe3+ which is reduced by low gastric pH and ascorbic acid (vitamin C) to the better absorbed Fe2+.

The majority of absorption occurs in the duodenum and jejunum. 60-70% of iron circulates in haemoglobin but it is also found in myoglobin, bound to enzymes and proteins, in mitochondria and hepatocytes (as ferritin and haemosiderin).

Question 25

Hereditary haemochromatosis - definition

Answer 25

An inherited disorder of iron metabolism in which increased intestinal absorption leads to deposition in multiple organs – heart, liver, pancreas, pituitary, adrenals, joints and skin.

Middle aged males are most commonly affected as menstruation is protective in women.

Question 26

HH - genetics

Answer 26

One of the most common inherited disorders in those of Northern European (especially Celtic) ancestry with a carrier rate of 1 in 10. The gene responsible in the HFE gene on chromosome 6.

Question 27

HH - clinical features

Answer 27

Asymptomatic in early stages before tiredness, arthralgia and impotence develop.

Later signs include – slate grey skin pigmentation, diabetes mellitus (bronze diabetes), signs of chronic liver disease, hepatomegaly, cirrhosis, dilated cardiomyopathy, hypogonadism (from pituitary dysfunction or cirrhosis) and associated osteoporosis.

Question 28

HH - investigations

Answer 28

• Bloods – deranged LFTs, raised serum ferritin and iron and reduced total iron binding capacity, transferrin saturation >80%, HFE genotyping and blood glucose to detect diabetes.
• Liver biopsy – Perl’s stain quantifies iron loading and disease severity and MRI can also help.
• Joint x-rays – if you suspect joint involvement and Echo if you suspect cardiomyopathy.

Question 29

HH - management

Answer 29

• Venesection – take 1 unit per week until mildly iron deficient then will need 1 unit per 2-3 months for life as iron will continue to accumulate. Aim to maintain haematocrit <0.5, serum ferritin <100μg/L, total iron binding capacity >50μmol/L and transferrin saturation <40%.
• Diabetes – monitor serum glucose – HbA1c may be falsely low due to venesection.
• Dietary intake – ensure any vitamin supplements do not contain iron, maintain a well-balanced low iron diet, drink tea, coffee or red wine with meals to increase absorption but avoid fruit, fruit juice (high in vitamin C) and white wine as these will increase iron absorption.
• Screening – perform genetic testing on 1st degree relatives even if asymptomatic.

Question 30

HH - prognosis

Answer 30

Regular venesection returns life expectancy to normal in the absence of cirrhosis and diabetes. Patients with cirrhosis have a >10% chance of developing hepatocellular carcinoma.

Question 31

Secondary haemochromatosis

Answer 31

May occur in patients with haematological conditions requiring regular transfusions – around 40L in total have to be given to develop haemochromatosis. If condition can be treated with erythropoietin or bone marrow transplantation then iron overload can be avoided.

Question 32

Liver transplantation - indication and contraindications

Answer 32

Unfortunately the limiting step for the procedure is the waiting list for a donor organ (live or cadaveric).

• * Indications* – liver cirrhosis (2° to alcoholic liver disease, hepatitis B and C, PBC, AIH, Wilson’s disease, α1-antitrypsin deficiency or PSC) and HCC (when 1 nodule <5cm or 2-3 nodules <3cm).
• Contraindications – extra-hepatic malignancy, multiple primary or secondary tumours, severe cardiorespiratory disease, systemic sepsis, HIV infection or non-compliance with drug therapy.

Question 33

Liver transplantation - post-op care

Answer 33

12-24 hours on ITU with enteral feeding starting as soon as possible and close monitoring of LFTs.

Immunosuppression regimes usually involve a combination of ciclosporin or tacrolimus with azathioprine or mycophenolate mofetil and prednisolone.

Question 34

Liver transplantation - problems

Answer 34

• Rejection – hyperacute – due to ABO incompatibility or acute – due to T cell mediated reaction – occurs in about 50% at 5-10 days – patient feels unwell and develops pyrexia and tender hepatomegaly. It can be managed by increasing or altering the immunosuppression regime.
• Complications – sepsis (usually caused by Gram negative bacteria), hepatic artery thrombosis, CMV infection, chronic rejection (at 6-9 months), disease reoccurrence or graft vs host disease.

Question 35

Liver transplantation - prognosis

Answer 35

The average survival is 80% at 1 year and 60-90% at 5 years – poor pre-operative renal function has been identified as a risk factor for a poor outcome following surgery.