Block 5: decompensated liver disease

Question 1

Decompensated cirrhosis: imaging and special tests

Answer 1

• MRI
• CT head
• Abdominal ultrasound
• Ascitic tap for culture and cell count

Question 2

SAAG (serum to ascites albumin gradient)

Answer 2

• Identifies portal hypertension and is more accurate then protein based exudate
• You subtract the ascitic fluid albumin value from the serum albumin value, which should be obtained the same day. Don’t repeat after initial measurement
• ≥11g/l means there’s portal hypertension
• This is due to increased hydrostatic pressure within the blood vessels of the hepatic portal system, which in turn forces water into the peritoneal cavity but leaves proteins such as albumin within the vasculature.

Question 3

Score for GI bleed

Answer 3

Glasgow-Blatchford score: assesses likelihood that you need endoscopy or a blood transfusion after an upper GI bleed

Question 4

cirrhosis: Screening after a decompensation event

Answer 4

• Hepatocellular carcinoma: screening ultrasound and AFP every 6 months
• Ongoing review with addiction services to help maintain abstinence from alcohol and illicit drugs.
• Osteoporosis: Screen & treat
• Ascites & SBP: Monitor regularly for evidence of ascites & treat
• Variceal Haemorrhage: OGD at diagnosis of cirrhosis and every 2 years

Question 5

Treatment follow decompensation event (cirrhosis)

Answer 5

• Beta-blocker (non-cardio-selective; carvedilol or propranol) as primary prevention of bleedingrebleed
• Viral Superinfection: Immunise for HAV and HBV (although this patient has already been exposed to HBV therefore would not require additional vaccination)
• Vitamin deficiencies: Treat (Vit B Co-strong & Thiamine)

Question 6

Stages of alcohol related liver disease

Answer 6

• Steatosis: imbalance in triglyceride metabolism causing accumulation within hepatocytes
• Alcoholic hepatitis: inflammatory response causing neutrophilic infiltration and cytokine release. Jaundice, coagulopathy and encephalopathy
• Fibrosis and cirrhosis: chronic injury and inflammation activate hepatic stellate cells causing collagen deposition and fibrosis. Cirrhosis is causes by extensive fibrosis and formation of regenerative nodules

Question 7

Symptoms of alcoholic liver disease

Answer 7

fatigue, malaise, abdominal pain, anorexia, weakness, nausea and/or vomiting

Question 8

Clinical features of alcoholic hepatitis

Answer 8

• Jaundice (common)
• Right upper quadrant pain (common)
• Hepatomegaly: Generally an enlarged and smooth edge, but rarely tender to palpation
• Palmar erythema
• Peripheral oedema
• Clubbing
• Dupuytren’s contracture (present in 30% of patients with alcoholic liver disease)
• Pruritis: If there is cholestasis leading to bile salt deposition in skin
• Xanthomas
• Spider angioma: multiple increase disease severity

Question 9

Oestrogenic effects of alcoholic hepatitis

Answer 9

• Gynaecomastiaand testicular atrophy (in males)
• Loss of body hair
• Amenorrhoea (in females)
• Loss of libido

Question 10

Management of acute alcoholic hepatitis

Answer 10

• Glucocorticoids i.e. prednisolone
• Use Maddrey’s discriminant function (DF) to identify patients with severe acute alcoholic hepatitis: score above >32 indicates liver biopsy and corticosteroids
• Pentoxifylline can be used as an alternative to glucocorticoids if they are contraindicated (e.g. hepatitis B viral infection, tuberculosis, other serious infection)

Question 11

Main causes of ALT >1000

Answer 11

drugs, ischaemia, viruses

Question 12

Liver function

Answer 12

• Synthesis: proteins (including albumin), clotting factors, bile, lipids
• Metabolism: Bilirubin, carbohydrate drugs, waste products and toxin

Question 13

Bilirubin

Answer 13

• Heme from haemoglobin breaks down into unconjugated bilirubin which is water insoluble, so travels around combines with albumin
• In the liver its combined glucoronic acid to make conjugated bilirubin which is water soluble
• Conjugated acid is excreted as bile acid, soted in the gallbladder and released in the small intestine causing lipid breakdown
• Most bile acid is reabsorbed in the Enterohepatic circulation
• Total serum bilirubin is usually <21

Question 14

Unconjugated bilirubin: causes

Answer 14

• Elevated due to increased bilirubin production or decreased hepatic uptake/conjugation
• Causes of raised unconjugated bilirubin: Gilbert’s syndrome, haemolysis and drug relates (i.e. Rifampicicn)

Question 15

Gilbert’s syndrome

Answer 15

• A genetic disorder where less of the enzyme that breaks down Bilirubin (UDP-glucuronyltransferase) is produced. It affects 5% of the population. There is an increase in the bilirubin often with fasting or concurrent illness.
• Confirmation of just a predominant unconjugated hyperbilirubinaemia makes the diagnosis of Gilbert’s syndrome virtually certain. This does not require any treatment and the patient can be completely reassured.
• Rarely does it cause a bilirubin above 68umol/L

Question 16

Conjugated bilirubin

Answer 16

• Raised is usually a sign of liver disease which is acute or chronic in nature. Only increase when the liver has lost half of its excretory capacity
• Causes: obstruction in the common bile duct (gallstones, malignancy i.e. cholangiocarcinoma or Pancreatic cancer), Drugs (i.e. Penicillin), Primary sclerosing cholangitis, Primary biliary cirrhosis, hepatitis, cirrhosis

Question 17

Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST)

Answer 17

• ALT is more specific to liver. AST is found in cardiac, skeletal and renal tissue and red blood cells
• Raised with anabolic steroids, EBV, A fib causing low blood pressure, metabolic iron, acute/chronic Hepatitis, Excess iron (Haemochromatosis)
• Normal is <40. Its mild if the rise is <5, moderate if rise of 5-10, marked if >10

Question 18

Common causes of acute and chronic hepatitis

Answer 18

• Alcohol – including chronic alcohol abuse and Alcoholic hepatitis
• Non-alcoholic fatty liver disease (NAFLD)
• Viral Hepatitis – both acute and chronic
• Autoimmune Hepatitis
• Drug toxicity
• Ischaemia – this can be due to anything which suddenly causes a patient’s blood pressure to drop
• Metabolic liver disease (Wilson’s / Haemochromatosis)

Question 19

AST/ALT ratio indicating liver disease

Answer 19

An AST/ALT ratio of >2 in alcoholic liver disease; whilst an AST/ALT ratio of <1.0 would be more suggestive of non-alcoholic liver disease.

Question 20

ALP (alkaline phosphatase)

Answer 20

• Present in biliary tract, bones, placenta
• Normal ALP <130
• Physiological causes of raised ALP: 3rd trimester of pregnancy, increased bone turnover (puberty
• Hepatic causes: bile duct obstruction (stones, malignancy), PSC, PBC, drug induced cholestasis (antibiotics, anabolic steroids)
• Extra-hepatic causes: bone disease (fractures, Pagets disease, bone metastasis)

Question 21

GGT and isolated ALP rise

Answer 21

GGT: when raised with ALP suggests hepatobiliary source. Normal is <70.

Isolated ALP rises can occur in PSC and PBC. However could be other sources, in particular bone metastasis. Isolated GGT is seen in alcohol abuse, as well as COPD and renal failure.

Question 22

Hepatic or biliary cause bloods

Answer 22

• Where Transferases (ALT/AST)&raquo_space; ALP and GGT= Consider a Hepatic cause
• Where ALP and GGT&raquo_space; Transferases (ALT/AST)= Consider a Biliary/obstructive cause

Question 23

Prothrombin time (PT)

Answer 23

• Measure of extrinsic and common coagulation pathway. Time in seconds for blood to clot
• INR standardises PT across different labs
• Measures synthetic function as clotting factors II, V, VII, IX and X are produced in the liver
• Useful in acute liver injury but only prolonged in chronic liver disease when 80% of liver function is reduced. Useful in advanced liver disease particularly decompensated cirrhosis
• Causes: liver synthetic dysfunction, deficiency in vitamin K (can be caused by obstructive jaundice)

Question 24

Albumin

Answer 24

• Roles: maintains intravascular colloid osmotic pressure, transporter
• In chronic liver disease hypoalbuminaemia suggests advanced liver disease
• Causes of low albumin: Malnutrition, Nephrotic syndrome, Sepsis, Burns, IBD
• Normal range >30g

Question 25

Consequences of portal hypertension include

Answer 25

• Oesophageal and Gastric Varices
• Abdominal Ascites
• Peripheral oedema
• Hepatic Encephalopathy
• Low Platelets (due to hypersplenism)

Question 26

Investigations in liver failure: ultrasound and CT

Answer 26

• Ultrasound: good at assessing dilation of biliary tree, stones in gallbladder, size and flow of hepatic and portal veins, space occupying lesions. Hard to tell degree of fibrosis/cirrhosis
• CT: good at assessing hepatocellular carcinoma (HCC), liver metastases and liver abscesses. It is good at identifying vascular problems, including bleeding, hepatic artery thrombosis or portal vein thrombosis. Sensitive for detecting biliary ductal dilatation, intra-hepatic bile duct tumours, pancreatic tumours and the level of biliary obstruction. Visualise whole abdomen

Question 27

Investigations in liver failure: MRI/MRCP

Answer 27

• MRI: good at visualising blood vessels, ducts and hepatic tissue. It is good at diffuse liver disorders (fatty liver, Haemochromatosis) and assessing focal lesions (haemangiomas, HCC, metastasis). However, more expensive and contraindications. Cant see beyond liver
• MRCP: detects hepatobiliary and pancreatic systems. Can view biliary dilation, strictures and intra-ductal stones

Question 28

Investigations in liver failure: ERCP, Liver biopsy and fibroscan

Answer 28

• ERCP: endoscopic camera used in tissue sampling and therapy i.e. stone removal from CBD, duct dilation and stent placement. Risk of causing pancreatitis, perforation and bleeding. MRCP tends to be used instead of ERCP for diagnosis
• Fibroscan: specialist US
• Liver biopsy: can establish a diagnosis or assess disease severity i.e. staging or grading. Usually done with US guidance, if high risk of bleeding do transjugular

Question 29

Haemochromatosis

Answer 29

• A disorder of iron overload which can affect other organs. Is primary or secondary.
• Causes iron deposition in the liver, skin, pituitary, heart and pancreas.
• Progressive iron deposition and organ damage leads to a clinical spectrum beginning with non-specific symptoms of fatigue, arthralgias, hypogonadism and skin bronzing.
• Development of further organ dysfunction can lead to complications such as cirrhosis andhepatocellular carcinoma,diabetes mellitus,cardiomyopathyand heart failure.

Question 30

Primary Haemochromatosis

Answer 30

Inherited disorder, most common is being autosomal recessive due to a defect in the HFE gene, called HFE Haemochromatosis.

Question 31

Causes of secondary haemochromatosis

Answer 31

• Frequent blood transfusions: each new transfusion introduces new iron which is recycled and stored
• Iron supplementation: over-supplementing, particularly with concurrent vitamin C.
• Diseases of erythropoiesis: ineffective erythropoiesis leads to iron accumulation
• Haematological disorders i.e. myelodysplastic syndrome

Question 32

Clinical manifestations of haemochromatosis

Answer 32

• Early: fatigue, arthralgia, impaired sexual function, abdominal pain, mood disturbance
• Late: skin hyperpigmentation (bronzed, grey), hepatomegaly and cirrhosis, diabetes mellitus, cardiac death, arthroplasty of the 2ndand 3rd metacarpophalangeal joint, Hypogonadism
• Symptoms appear 40-60 in males and post menopausal in females

Question 33

Mutations in Haemochromatosis

Answer 33

• The two mutations of HFE are C282Y and H63D. Affected by gene expression (penetrance)
• C282Y/C282Y Homozygous gives a 95% risk of iron overload
• C282Y/H63D compound heterozygotes gives around 4% risk (increased risk with increased alcohol intake, viral hepatitis)
• H63D/H63D Homozygous is least likely to cause iron overload

Question 34

Blood results in Haemochromatosis

Answer 34

• Serum ferritin: raised >674 picomols/L in men, >449 picomols/L in women. Often in 1000’s. Can also be raised in chronic alcohol abuse and NAFLD
• Transferrin saturation: >45%
• LFT: raised AST and ALT, likely not more than 2x normal
• FBC: normal

Question 35

Diagnosis of Haemochromatosis

Answer 35

• Patients with elevated SF and T/S should undergo genetic screening; those with a ferritin greater than 1000 µg/l should be referred urgently to secondary care to exclude Cirrhosis.
• Liver function tests, ultrasound and/or fibroscan should be used to assess degree of liver damage.
• Diagnosis of HFE Haemochromatosis should not be based on genes it requires increased iron stores.
• Those with HFE genotype, but not gene expression, e.g. normal SF and TS should have annual iron studies

Question 36

Haemochromatosis: phases of treatment

Answer 36

• Acute iron removal– this is done via venesection (approx. 450ml of blood is removed). This will reduce the SF by approx. 20-25 µg/l. This is continued until SF are 50-100 µg/l.. Treatment may be required for 12 to 18months, weekly to 2 weekly.
• Maintenance phase– 2-4 venesections a year to keep SF 50-100 µg/l

Question 37

Haemochromatosis: management

Answer 37

• Management involves: venesection (regularly removing blood to remove excess iron- initially weekly). Monitoring serum ferritin, monitoring and treating complications
• Avoid iron, vitamin C tablets and alcohol
• Can use iron chelatin therapy if venesection is contraindicated
• Avoid food with high iron and vitamin C

Question 38

Haemochromatosis: screening

Answer 38

Every 6 months with ultrasound and serum AFP for HCC. Anyone with genetic haemochromatosis should be offered genetic counselling and screening for first degree relatives. A C282Y mutation on the HFE gene (chromosome 6) is the most common cause of hereditary haemochromatosis.

Question 39

Complications and investigations of Haemochromatosis

Answer 39

• Secondary diabetes(iron affects the functioning of the pancreas). Fasting blood sugar
• Liver cirrhosis
• Endocrine and sexual problems(hypogonadism, erectile dysfunction, amenorrhea and reduced fertility). Testosterone, FSH, LH
• Cardiomyopathy(iron deposits in the heart). ECG and Echocardiogram
• Hepatocellular carcinoma
• Hypothyroidism(iron deposits in the thyroid)
• Chondrocalcinosis(calcium pyrophosphate deposits in joints) causes arthritis

Question 40

Wilsons disease definition

Answer 40

Rare progressive genetic disorder causing accumulation of copper in body tissue. Affects the brain, liver and cornea of the eyes. Untreated can cause liver fibrosis and cirrhosis with central nervous system dysfunction

Question 41

Wilsons disease: pathophysiology

Answer 41

Gene mutation results in dysfunction in Wilson’s ATPase, which usually moves copper from along intracellular membranes in the liver. The defective ATPase results in accumulation of copper in the liver, resulting in damage. Over time as the liver becomes damaged the copper is released into the blood and causes other end organ damage. Damage may occur but doesnt become evident till a teenager range 5-35.

Question 42

Wilsons disease: patients may present with

Answer 42

• Liver dysfunction (most common presentation): decompensated liver cirrhosis, acute liver failure (with renal failure and haemolytic anaemia)
• Central nervous system (usually have establishes liver disease): asymmetrical tremor, poor co-ordination and clumsiness, speech and language problems, Neuropsychiatric illness- commonly severe depression or neurotic behaviour
• Opththamology: Kayser-Fleischer ring seen on slit lamp, almost always seen in neurological disease and half of other presentation. Sun-flower cataracts – seen on slit lamp. Do not impair vision

Question 43

Wilsons disease: diagnosis

Answer 43

• Presence of Kayser-Felischer ring (dark circles made of copper with circle the cornea) and low serum caeruloplasmin (<0.1g/L) is enough to establish diagnosis. Ceruloplasmin is a protein that stores and carries copper around the blood
• Other markers of disease: reduced 24 hour urinary copper, serum free copper and hepatic copper (liver biopsy)

Question 44

Wilsons disease: treatment and genetics

Answer 44

Treatment: D-penicillamine

Wilson’s disease is caused by a defect in the ATP7B gene located on chromosome 13. Causes increased copper absorption from the small intestine and decreased hepatic copper excretion

Question 45

Wilsons disease: features

Answer 45

• liver: hepatitis, cirrhosis
• neurological: basal ganglia degeneration, speech, behavioural and psychiatric problems are often the first manifestations. Also: asterixis,chorea,parkinsonism,dementia
• Kayser-Fleischer rings
• renal tubular acidosis (esp. Fanconi syndrome)
• haemolysis
• blue nails

Question 46

Aortic stenosis findings

Answer 46

• Regular small volume, slow rising pulse
• Narrow pulse pressure
• Heaving undisplaced apex beat
• Harsh ejection systolic (crescendo-descendo) murmur heard at left sternal edge: loudest leaning forward on expiration, may radiate to carotids
• Thrill or heave in aortic region

Question 47

Aortic regurgitation findings

Answer 47

• Large volume radial pulse which is collapsing
• Wide pulse pressure: difference between systolic and diastolic
• Thrusting apex beat
• Displaced apex beat
• High pitched early diastolic murmur: loudest leaning forward on expiration

Question 48

Mitral stenosis

Answer 48

• Irregularly irregular pulse
• Jugular vein distension
• Tapping apex beat
• Left parasternal heave
• Loud first heart sound
• Mid diastolic rumbling murmur
• Malar flush

Question 49

Mitral regurgitation findings

Answer 49

• Pulse and BP normal
• Apex thrusting and displaced
• Systolic thrill over apex
• Wide splitting of second heart sound
• Loud pansytolic murmur at the apex radiating to the axilla