Hepatobiliary Flashcards

Question

Explain gallbladder anatomy and physiology

Answer 1

The gallbladder is a small organ with a capacity, in an adult, of about 50ml. A diverticulum, the gallbladder is continuous with the cystic duct and thus common hepatic duct. It measures between 7-10 cm in an adult. It receives a blood supply from the cystic artery. This vessel has variable origin but most commonly arises from the right hepatic artery. **Note:** *Hartmanns pouch refers to dilatation or outpouching at the neck of the gallbladder. Stones may impact here causing extrinsic compression of the extrahepatic bile duct leading to Mirrizi's syndrome.* The biliary tree is a ductal system that transmits bile produced by hepatocytes to the second part of the duodenum (via the ampulla of Vater). By convention it is divided into intrahepatic and extrahepatic ducts. The right and left hepatic duct converge to form the common hepatic duct. The gallbladder meanwhile is drained by the cystic duct. The cystic duct and common hepatic duct converge to form the common bile duct. The common bile duct forms a common channel with the pancreatic duct just proximal to the ampulla of Vater. The ampulla of Vater is an orifice that allows bile to drain into the second part of the duodenum.

Answer 2

Cholelithiasis (gallstones) refers to the development of a solid deposit or ‘stone’ within the gallbladder.

Answer 3

- Gallstones affect up to 20% of the population. - F>M - Prevalence increases with age, before levelling off in the sixth - seventh decade of life. - More common in caucasians, Native American's and Hispanics. - The vast majority of people with gallstones will remain asymptomatic (80%).

Answer 4

Bile is secreted by hepatocytes into the biliary circulation. It is stored in the gallbladder. Bile is composed of bile acids (or salts), phospholipid, bilirubin, cholesterol and water. Imbalance in composition and stasis leads to stone formation. - **Cholesterol stones** Cholesterol stones are the most common type found in western populations, estimated to account for up to 75-85% stones. They occur due to crystallisation of cholesterol in bile (along with other compounds) due to supersaturation of cholesterol and crystillisation promoting factors. Disturbances in gallbladder motility may also contribute. - **Black pigment stones** These are dark stones composed primarily of calcium bilirubinate, accounting for around 10-20% of stones. They occur in people with increased amounts of bilirubin in their bile - hyperbilirubinbilia. This occurs in patients with increased haemolysis (i.e. haemolytic anaemias). - **Brown pigment stones** These stones are a mix of calcium bilirubinate and a calcium salts of fatty acids, accounting for around 5% of stones. They mostly occur in association with infection (bacterial or parasitic) and may develop de novo in the bile duct after cholecystectomy.

Answer 5

The classic risk factors for gallstone disease are described as the ‘**4 F’s**’: - **Female**: 2-3 times more likely to develop gallstones than men - **Fat**: a BMI > 30 is a key risk factor - **Forties**: the risk increases significantly from approximately 40 years old - **Fertile**: pregnancy is an important risk factor Other risk factors: - **Genetic predisposition/ family history** - **Rapid weight loss / prolonged fasting** - **Diabetes** - **Medications** - particularly the combined oral contraceptive pill and hormone replacement therapy due to the presence of oestrogen; fibrates also increase the risk - **Crohn's disease -** bile acid malabsorption due to a diseased or resected ileum leads to cholesterol supersaturated bile - **Haemolytic conditions:** haemolysis (e.g. sickle cell disease) causes excess circulating bilirubin resulting in pigment gallstones - **Diet** (high in triglycerides, refined carbohydrates) Risk factors for becoming symptomatic: - **Smoking** - **Parity**

Answer 6

Gallstones are normally asymptomatic. However in a proportion of patients they may cause pathology. A range of conditions may be caused: - **Biliary Colic:** This is an acute, severe, RUQ/epigastric pain that tends to be self-limiting. It is the most common complication of gallstones. - **Acute cholecystitis:** Impaction of a stone within the cystic duct leads to acute cholecystitis, inflammation of the gallbladder. It presents with signs of infection, RUQ pain and tenderness. - **Acute cholangitis** Gallstones are the most common cause of acute cholangitis. ****Impaction of a stone in the common bile duct impairs drainage leading to infection affecting the biliary tree. Results in ‘Charcot’s triad’ (right upper quadrant pain, fever and jaundice) - **Acute pancreatitis:** Gallstones are the most common cause of pancreatitis in the UK, they occur when stones get impacted distally in the biliopancreatic duct causing disruption to flow of pancreatic enzymes. - **Mucocoele/empyema:** obstructed gallbladder fills with mucus/pus. - **Mirizzi's Syndrome:** Stone in gallbladder presses on bile duct, causing jaundice. - **Obstructive jaundice:** due to ****a stone that obstructs the common bile duct; presents with jaundice, pale stools and dark urine - **Gallstone ileus:** stone erodes through the gallbladder into the duodenum and may obstruct the ileum - **Gallbladder cancer:** gallstones are thought to increase the risk by up to 5-fold

Answer 7

Biliary colic: Symptoms - intermittent, self limiting RUQ pain Observations - normal Examination - normal or mild tenderness Blood tests - Normal Ultrasound - gallstones Acute cholecystitis: Symptoms - RUQ pain, fevers, malaise Observations - Fever, Haemodynamic instability may occur Exam - Tenderness, maybe localised guarding Blood test - Rised WCC/CRP, Normal/mild LFT increase Ultrasound - Gallstones, inflamed thickened GB, pericholecystic fluid Acute cholangitis: Symptoms - RUQ pain, fevers, malaise, confusion Observations - fevers, haemodynamic instability more likely to occur Exam - Tenderness, clinical jaundice may be apparent Blood tests - Raised WCC/CRP, Raised bilirubin, ALP, ALT Ultrasound - CBD stone, duct dilation Acute pancreatitis: Symptoms - Epigastric pain, radiates to back Observations - fever and tachycardia Exam - Epigastric tenderness Blood test - raised amylase, WCC, CRP normally raised Ultrasound - Not imaging of choice, may show gallstone

Answer 8

The majority of patients with gallstones will be asymptomatic. 1-4% of patients develop gallstone-related complications, the most common being biliary colic. 10-20% of those who have had an attack of biliary colic will go on to develop a more serious complication, such as acute cholecystitis

Answer 9

Biliary colic refers to a pain in the RUQ/epigastrium caused by gallstones. Though termed a 'colic' the pain is normally constant lasting from 30 minutes to 6 hours.

Answer 10

- It is the most common symptomatic manifestation of cholelithiasis (gallstones) affecting around 10-20% of patients. - Prevalence increases with age - F>M - More common in caucasians, Native American's and Hispanics.

Answer 11

Risk factors of cholelithiasis: The classic risk factors for gallstone disease are described as the ‘**4 F’s**’: - **Female**: 2-3 times more likely to develop gallstones than men - **Fat**: a BMI > 30 is a key risk factor - **Forties**: the risk increases significantly from approximately 40 years old - **Fertile**: pregnancy is an important risk factor Other risk factors: - **Genetic predisposition/ family history** - **Rapid weight loss / prolonged fasting** - **Diabetes** - **Medications** - particularly the combined oral contraceptive pill and hormone replacement therapy due to the presence of oestrogen; fibrates also increase the risk - **Crohn's disease -** bile acid malabsorption due to a diseased or resected ileum leads to cholesterol supersaturated bile - **Haemolytic conditions:** haemolysis (e.g. sickle cell disease) causes excess circulating bilirubin resulting in pigment gallstones - **Diet** (high in triglycerides, refined carbohydrates)

Answer 12

The pain occurs when a stone impacts against the cystic duct during contraction of the gallbladder with increased pressures in the gallbladder itself.

Answer 13

- Nausea and vomiting - Right upper quadrant pain - Epigastric pain - Pain may radiate to right shoulder or interscapular region Episodes typically last 30 minutes - 6 hours. Often worse after ingestion of fatty foods. Note: there are no signs on abdominal examination. Murphy's sign negative.

Answer 14

- 1st line Abdominal ultrasound - can identify gallstones as well as looking for dilation of the CBD and presence of stones in CBD. LFTs - may show derangement of LFTs - indicative of stones within the biliary system (which can be asymptomatic). It is essential to identify patients with CBD stones prior to any cholecystectomy. - Other Many other investigations may be ordered depending on the presentation and co-morbidities. Alternative diagnoses should be considered and appropriately investigated. - **FBC and CRP**: neutrophilia and raised CRP may suggest cholecystitis - **Amylase level**: if suspecting pancreatitis secondary to suspected gallstone disease - **Magnetic resonance cholangiopancreatography (MRCP)**: if no common bile duct stones are seen on abdominal ultrasound, but: - The **common bile duct is dilated** on abdominal ultrasound **and/or** - **Liver function tests** are abnormal - **Endoscopic ultrasound (EUS)**: if MRCP does not allow a diagnosis to be made

Answer 15

- Cholecystitis - Ascending cholangitis - Common bile duct stone - Gastritis - Peptic ulcer disease - IBS - Carcinoma on right side of colon - Renal colic - Pancreatitis

Answer 16

- **Analgesia:** Simple pain relief with paracetamol and NSAIDs (in the absence of contra-indications). Occasionally opioid analgesia may be required in cases of severe pain. - **Diet:** A low-fat diet may be trialled with some patients - Surgical management - Prior to cholecystectomy it is key that CBD stones are excluded: ultrasound and LFTs. If CBD is suspected, there are two options: - **MRCP +/- ERCP:** MRCP allows for confirmation of stones in the biliary tree. If present ERCP allows for therapeutic intervention with stone retrieval, sphincterotomy and stent placement prior to cholecystectomy. - **On-table cholangiogram:** Less commonly available and technically challenging. During the laparoscopic cholecystectomy the bile duct is intubated to allow the injection of dye with fluoroscopy in-theatre to diagnose stones in the biliary tree. Various techniques may then be used to retrieve/expel stones. - **Elective laparoscopic cholecystectomy**

Answer 17

- **Obstructive jaundice:** due to ****a stone that obstructs the common bile duct; presents with jaundice, pale stools and dark urine - **Cholecystitis:** inflammation of the gallbladder results in **fever**, r**ight** **upper** **quadrant** **pain** (usually > 6 hours) and positive **Murphy’s sign** - **Ascending cholangitis:** infection of the biliary tree results in ‘Charcot’s triad’ (**right** **upper** **quadrant** **pain**, **fever** and **jaundice)** - **Acute pancreatitis:** gallstones are the most common cause - **Gallbladder empyema** - **Gallstone ileus:** a rare form of small bowel obstruction due to impaction of a gallstone within the lumen of the small intestine via a cholecysto-duodenal fistula - **Gallbladder cancer**: gallstones are thought to increase the risk by up to 5-fold

Answer 18

Acute cholecystitis refers to inflammation of the gallbladder most commonly occurring due to impacted gallstones (calculous cholecystitis) Relatively rarely acute cholecystitis occurs in the absence of gallstones (acalculous cholecystitis)

Answer 19

Acute cholecystitis occurs in 10% of patients with symptomatic gallstones

Answer 20

The initial event is the obstruction of gallbladder emptying. Obstruction results in an increase of gall bladder glandular secretion leading to progressive distension that, in turn, may compromise the vascular supply to the gall bladder. There is also an inflammatory response (this differentiates acute cholecystitis from biliary colic) secondary to retained bile within the gallbladder - infection is a secondary phenomenon following vascular and inflammatory events. - **Acute calculous cholecystitis** Inflammation and infection occur when a stone becomes impacted in the cystic duct. The exact pathogenesis is still not understood and it is thought the presence of additional mediators is required for cholecystitis to occur. An impacted stone leads to impaired drainage of gallbladder contents and the release of inflammatory mediators. This leads to bacterial overgrowth, usually involving gram-negative rods or anaerobes. Though patients with acute cholecystitis are always treated with antibiotics it is thought that a significant proportion of patients have a sterile inflammation. - **Acute acalculous cholecystitis** Acute acalculous cholecystitis refers to gallbladder inflammation in the absence of gallstones. Acalculous cholecystitis is far less common than calculous cholecystitis and is normally seen in patients with significant systemic upset or following major surgery. Risk factors include: - Diabetes - Age - Recent major surgery (e.g. Cardiac surgery) - Myocardial infarction - Sepsis - Major burn - Major trauma - Cancer - Cryptosporidium or cytomegalovirus infection may be the cause in immunocompromised patients - Vasculitis - CKD Again the pathogenesis is not fully understood but is thought to relate to biliary stasis and/or gallbladder ischaemia. In a proportion of cases infection is the primary cause but it is thought infection is normally secondary to established inflammation.

Answer 21

- RUQ abdominal tenderness - **Murphy’s sign positive:** palpating the RUQ whilst the patient breathes in deeply causes pain - Abdominal mass - Due to distended gallbladder (present in 30-40%) - Pyrexia - Tachycardia - Hypotension (in severe cases)

Answer 22

- Nausea and vomiting - Fever - Right upper quadrant abdominal pain - Severe and lasting >30 minutes - Preceding history of biliary colic - Referred right shoulder tip pain Note: jaundice should not be present. If jaundiced, this may suggest Mirizzi syndrome, CBD stone or ascending cholangitis.

Answer 23

Abdominal ultrasound

Answer 24

- **FBC:** leukocytosis with neutrophilia - **LFTs:** usually normal in uncomplicated disease; derangement suggests Mirizzi syndrome, obstructing CBD stone, or cholangitis - **U&Es**: may be deranged with an acute kidney injury secondary to infection - **Coagulation profile**: assess the synthetic function of the liver and required prior to surgical intervention - **Venous blood gas**: assess for degree of lactic acidosis - **Inflammatory markers**: an elevated CRP would be expected - **Transabdominal ultrasound**: **first-line** imaging modality of choice - Positive Murphy’s sign on palpation with the probe - Thickened gallbladder wall (≥3mm) - Distended gallbladder with the presence of gallstones - Pericholecystic fluid

Answer 25

- **CT abdomen:** if ultrasound is inconclusive, CT may be conducted. Traditionally considered less sensitive than ultrasound, but this is debated. Has the advantage of being able to assess for other pathology. - **MRCP:** NICE advise performing an MRCP when suspecting a **CBD** stone in cases where ultrasound has **not** detected gallstones but shows a **dilated** CBD, and/or **LFTs** are abnormal. - **ERCP** may be performed for extraction of CBD stone, if found. - **Cholescintigraphy (HIDA) scan**: not routinely performed, but consider if ultrasound is inconclusive. IV technetium-labelled HIDA is taken up by hepatocytes and excreted into bile. Cholecystitis is associated with cystic duct obstruction so the gallbladder will **not** be visualised.

Answer 26

- Pancreatitis - Peptic ulcer disease - Cholangitis - Appendicitis - Basal pneumonia

Answer 27

Initial management should follow an ABC approach in those who are acutely unwell. The sepsis 6 protocol should be implemented when indicated. - **Nil by mouth** - **IV fluids** **and analgesia** - **Intravenous antibiotics**: requires broad-spectrum antibiotics with gram-negative and anaerobic cover, such as cefuroxime and metronidazole *Note: before cholecystectomy, CBD stones should be checked for: MRCP or on-table cholangiogram.* - **Early laparoscopic cholecystectomy** - Perform **within 1 week of diagnosis**, but often performed within 72 hours (‘hot laparoscopic cholecystectomy’) - Delayed procedure (> 6 weeks from admission) if hot cholecystectomy not available or appropriate ('interval laparoscopic cholecystectomy') - Early cholecystectomy is associated with: lower complications, shorter hospital stay, improved quality of life and better patient satisfaction

Answer 28

**Urgent cholecystostomy** - Performed if early cholecystectomy is inappropriate due to suspected sepsis/gangrene/perforation - Surgical insertion of a percutaneous cholecystostomy tube with a delayed elective cholecystectomy 2-3 months after admission

Answer 29

- **Gallbladder empyema:** acute inflammation results in the gallbladder filling with pus and can lead to perforation - **Gallstone ileus:** when a gallstone passes from the biliary tract into the intestine via a fistula resulting in small bowel obstruction - **Acute cholangitis:** infection of the biliary tree commonly caused by gallstones which move into the common bile duct - **Obstructive jaundice:** if stone moves to CBD - **Procedure-related**: bile duct injury

Answer 30

Prompt medical management with intravenous antibiotics and identification of sepsis alongside an early laparoscopic cholecystectomy is associated with a very good prognosis. In patients with biliary colic without cholecystitis, early laparoscopic cholecystectomy reduces the risk of future episodes and the risk of cholecystitis. Gallbladder perforation has a mortality of over 30%, whilst untreated acute acalculous cholecystitis has a mortality of up to 50%

Answer 31

Murphy's sign is indicative of cholecystitis. As the patient breathes out, place your hand below the right costal margin. As the patient breathes in an inflamed gallbladder moves inferiorly, the patient catches their breath. To be considered positive, it should be absent on the left side.

Answer 32

Chronic inflammation of the gallbladder +/- colic

Answer 33

- Repeated lodging and dislodging of gallstone in CBD, causing inflammation and fibrosis of the gallbladder - In some cases, there may not be lodging and dislodging of gallstones. Instead, gallstones within the gallbladder can cause irritation to the gallbladder and causes damage this way. - Overtime, this leads to inflammtion, fibrosis and maybe even calcification. This is known as porcelain gallbladder. This makes the gallbladder visible on x-ray

Answer 34

- Flatulent dyspepsia - Abdominal discomfort - RUQ pain (esp after meal) - Distension - Nausea - Fat intolerance (fat stimulates cholecystokinin release and gallbladder contraction)

Answer 35

- **Ultrasound** - to image stone and assess CBD diameter - **MRCP** - used to find CBD stones - **X-ray -** may show porcelain gallbladder

Answer 36

- If symptoms persist post-treatment, consider: - Hiatus hernia - IBS - Peptic ulcer - Chronic pancreatitis - Tumour

Answer 37

- Cholecystectomy - ERCP + sphincterectomy prior to surgery

Answer 38

Increased risk of gallbladder cancer

Answer 39

Acute cholangitis refers to infection of the biliary tree characteristically resulting in pain, jaundice and fevers.

Answer 40

- Acute cholangitis is relatively uncommon and presents as a complication of gallstones in about 1% of patients. - Age > 50 years - Affects men and women equally - There appears to be greater incidence in caucasians, hispanics and Native Americans - following the distribution of gallstones. - It occurs following ERCP in around 0.5 - 3%. - Recurrent pyogenic cholangitis is seen in southeast Asian populations.

Answer 41

- **Choledocholithiasis**, stones in the bile duct, is the most common cause of acute cholangitis. Acute cholangitis occurs due to impaired drainage and bacterial overgrowth. - **Benign stricture:** leading to obstruction, may occur in the biliary tree for numerous reasons: - Chronic pancreatitis - Iatrogenic injury (during cholecystectomy) - Radio / chemo-therapy - Idiopathic e.g. primary sclerosing cholangitis is a chronic, progressive condition associated with ulcerative colitis. It is characterised by inflammation and stricturing of bile ducts. - **Malignant stricture:** e.g. cholangiocarcinoma, pancreatic cancer and gallbladder cancer. - **Other:** - **Post-ERCP** (normally related to inadequate drainage) - **Blocked biliary stent** - **Extrinsic compression** - **Blood clots** - **Parasites** (e.g. *Ascaris lumbricoides*) can cause blockage

Answer 42

- **Gallstones:** the most common predisposing factor - **Stricture of the biliary tree:** benign or malignant - **Post-procedure injury** of the bile ducts e.g. post-ERCP

Answer 43

Acute cholangitis almost always occurs due to bacterial infection secondary to biliary obstruction. Biliary obstruction is often secondary to choledocholithiasis (gallstones in the biliary tree) or biliary strictures (both benign and malignant). Obstruction causes cholestasis and promotes the growth of bacteria, most commonly gram-negative, which then cause an ascending infection. E. coli is the most common pathogen.

Answer 44

Right upper quadrant (RUQ) abdominal pain, jaundice, and fever is known as **Charcot’s triad** and suggests a diagnosis of ascending cholangitis. It is seen in 20-50% of patients. The addition of hypotension and change in mental state/ confusion (shock) is known as **Reynolds’ pentad** and is associated with biliary sepsis.

Answer 45

- RUQ tenderness - Scleral icterus - Pyrexia - Hypotension: part of Reynold’s pentad

Answer 46

- RUQ abdominal pain - Jaundice - Fever: the most common feature - Nausea and vomiting - Malaise - Pruritis - Dark urine and pale stool (cholestasis) - Confusion: part of Reynold’s pentad

Answer 47

- **FBC:** leukocytosis with neutrophilia - **LFTs:** obstructive jaundice with raised ALP > ALT, and bilirubin - **U&Es**: pre-renal acute kidney injury in sepsis - **CRP**: acute-phase protein and marker of inflammation - **VBG**: assess for acidosis and lactate if suspecting sepsis - **Blood cultures**: ideally taken prior to commencing IV antibiotics - **Transabdominal ultrasound**: first-line imaging modality to detect common bile duct dilatation and the presence of gallstones Other: - **CT abdomen with IV contrast:** if ultrasound is negative and there is a high suspicion of cholangitis - **MRCP:** gold-standard for diagnosis and used for pre-intervention planning and has the highest sensitivity. However, not as readily available so CT tends to be performed first - **ERCP:** endoscopic investigation and intervention. Usually preceded by imaging (e.g. ultrasound and CT); many gastroenterologists ask for an MRCP prior to ERCP.

Answer 48

- Acute cholecystitis - Peptic ulcer disease - Pancreatitis - Hepatic abscess - Appendicitis - Biliary colic

Answer 49

Initial management should follow an ABC approach in those who are acutely unwell. The sepsis 6 protocol should be implemented when indicated - **Intravenous antibiotics**: broad-spectrum antibiotics with gram-negative and anaerobic cover e.g. cefotaxime and metronidazole for 4-7 days - **IV fluids**: patients are often septic and require rehydration - **Analgesia:** if needed, and tailored to patients' needs.

Answer 50

- **Biliary decompression:** - **ERCP**: first-line procedure usually performed within 24-48 hours. Allows for endoscopic exploration of the biliary tract with the removal of gallstones to facilitate drainage. Sphincterotomy may be performed to reduce the risk of future blockage. - **Percutaneous trans-hepatic cholangiography (PTC)**: if ERCP fails, PTC is an alternative measure which allows access to the biliary tract via the liver. - **Surgical drainage** may be carried out in patients where minimally invasive techniques described above are not possible. This involves a choledochotomy (incision into the common bile duct) and T tube insertion **OR** laparoscopic cholecystectomy with bile duct exploration - **Elective cholecystectomy:** following successful biliary decompression, NICE recommends patients have a laparoscopic cholecystectomy to reduce future gallstone-related complications - Those with strictures need the cause identified (if not already) and may require further surgery/endoscopic management. Malignancies are managed via appropriate MDTs.

Answer 51

- **Biliary sepsis:** the commonest complication and typically presents with Reynolds’ pentad - **Acute pancreatitis:** CBD stones can obstruct the pancreatic duct - **Hepatic abscess** - **Risks of ERCP**: duodenal perforation, pancreatitis, biliary sepsis, intra-abdominal bleeding

Answer 52

The majority of patients recover quickly with effective resuscitation, initiation of antibiotics and adequate biliary drainage. The prognosis is worse if decompression is delayed or emergency surgical drainage is required (rather than non-surgical). Factors that predict a poor prognosis include high fever, hyperbilirubinaemia, hypoalbuminaemia, and older age.

Answer 53

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune condition characterised by granulomatous destruction of the intrahepatic biliary ducts, leading to cholestasis and subsequent leakage of bile into the circulation.

Answer 54

- Rare disease with a **prevalence of < 0.05%** - **Middle-aged:** peak incidence between 45 and 60 years old - **Female gender**: ten times more common in females

Answer 55

Cause is unknown but its thought to be immunological and serum anti- mitochondrial antibodies (AMA) are found in almost all patients. This allows T-cells to target the cells in the intrahepatic ducts and destroy them. - Environmental trigger and genetic predisposition seem to play a part in loss of immune tolerance to self-mitochondrial proteins.

Answer 56

- **Female gender** - **Autoimmune conditions** - **Family history** - **Past pregnancy** - **Smoking** - **Excessive use of nail polish and hair dye** - **Chronic urinary tract infection**

Answer 57

The inflammatory process coupled with trapping of bile acids in the liver leads to progressive fibrosis, cirrhosis, and eventually liver failure. The presence of **anti-mitochondrial antibodies (AMAs)** has been observed in almost all patients with PBC, further reinforcing the likely autoimmune nature of the condition. Up to 50% of PBC patients have at least one **associated autoimmune condition**, such as: - Sjögren's syndrome (25%) - Raynaud’s phenomenon (25%) - Autoimmune thyroid disease (25%) - Rheumatoid arthritis (20%) - Systemic sclerosis(10%)

Answer 58

The classic presentation of PBC is with significant itching in a middle-aged female. Some patients may be asymptomatic and be simply diagnosed on a routine blood test demonstrating abnormal LFTs (e.g. raised ALP).

Answer 59

- Skin hyperpigmentation: due to increased melanin - Clubbing - Mild hepatosplenomegaly - Xanthelasma and xanthomata (late sign) - due to leakage of cholesterol - Scleral icterus (late sign)

Answer 60

- Pruritis (itchy skin) - leakage of bile salts - Fatigue and weight loss - Dry eyes and dry mouth - Sjögren's syndrome - Obstructive jaundice (late sign) - due to leakage of bile and conjugated bilirubin - Icteric - Pale stool and dark urine

Answer 61

- **Antimitochondrial antibodies (AMA):** present in 95% of patients (highly specific) - **Antinuclear antibodies (ANA):** present in 50% of patients - **Smooth muscle antibodies**: 30% of patients; most associated with autoimmune hepatitis - **Raised serum cholesterol** - **LFTs:** an obstructive picture is seen with a raised ALP, GGT and bilirubin. AST and ALT may be mildly raised - ***Bloods in later disease:** High bilirubin, low albumin and higher prothrombin time* - **Coagulation profile**: assess the synthetic function of the liver. Deranged in advanced disease - **Serum immunoglobulin:** elevated IgM - **Transabdominal ultrasound**: excludes other extrahepatic causes of cholestasis e.g. gallstones

Answer 62

- **MRCP:** if the above tests are inconclusive, an MRCP should be conducted to look for intrahepatic biliary duct stenosis - **Liver biopsy**: was previously used to diagnose all patients but non-invasive tests have largely replaced it. Must be performed if there is diagnostic uncertainty - look for granulomas around bile duct +/- cirrhosis

Answer 63

- Primary sclerosing cholangitis - AMA would not found - Obstructive bile duct lesion - Drug induced cholestasis - can do liver biopsy

Answer 64

- **Ursodeoxycholic acid** - First-line agent in all patients - A bile acid analogue which dampens the inflammatory response, acts as an anti-apoptotic agent, and improves cholestasis - May be combined with obeticholic acid in those who do not respond to monotherapy - **Fat-soluble vitamin supplementation**: cholestasis impairs fat absorption; vitamins A, D, E and K must be supplemented - **Cholestyramine**: bile acid sequestrant for symptomatic relief of **pruritus** - **Codeine phosphate:** for diarrhoea - **Biphosphonates:** for osteoporosis - 2nd line **Liver transplantation:** indicated in end-stage disease with liver cirrhosis; considered if complications of cirrhosis have occurred, based on disease severity (e.g. MELD score ≥15 ), if bilirubin values rising progressively >50–85 µmol/L and in some patients with intractable pruritus. Recurrence can occur in the graft but is not usually significant

Answer 65

Regular LFT; ultrasound +/- AFP if cirrhotic (with chronic liver diseases, such as hepatitis and cirrhosis, AFP may be chronically elevated).

Answer 66

- **Malabsorption** of fat-soluble vitamins A, D, E and K due to cholestasis; may result in coagulopathy due to decreased bilirubin in gut lumen - **Hypercholesterolaemia:** cholestasis is associated with hypercholesterolaemia - **Liver cirrhosis:** end-stage disease results in fibrosis and eventual cirrhosis, whilst portal hypertension may cause ascites and variceal bleeding - **Hepatocellular carcinoma**: 20-fold increased risk - **Metabolic bone disease:** osteoporosis and osteomalacia

Answer 67

Portal hypertension, advanced histological stage, and failure to respond to ursodeoxycholic acid are poor prognostic factors. Median survival is approximately 9 years, however, in patients diagnosed at an asymptomatic stage, survival is twice as high compared to those diagnosed at a symptomatic stage.

Answer 68

Primary sclerosing cholangitis (PSC) is an immune-mediated chronic liver disease that is characterised by inflammation, fibrosis and destruction of intrahepatic and/or extrahepatic bile ducts.

Answer 69

- PSC has a prevalence of **6.3 per 100,000** of the population, making it less common than primary biliary cholangitis (35 per 100,000). - It is more common in **Northern Europe and North America.** - **Male sex:** two-fold more common in males than females - **Age 40-50 years:** the mean age of diagnosis is 40 years; it can occur at any age, including children

Answer 70

- **Male** - **History of inflammatory bowel disease:** usually ulcerative colitis (UC); 4% of patients with UC have PSC, 80% of patients with PSC have UC - **Family history** - Some association with **HLA-A1, B8 and DR3**

Answer 71

It is believed that the condition arises due to a complex interplay between **predisposing genetic element**s and (undetermined) **environmental exposures**. A leading hypothesis for an environmental trigger is the **host gut microbiome**. Irrespective of cause, the damage to bile ducts leads to: - **Cholestasis** - **Bile and toxin build up in the liver** - **Bile duct strictures** All of the above contribute to **liver fibrosis, cirrhosis** and progression to **end-stage liver disease.**

Answer 72

PSC is often asymptomatic in the early stages and detected on routine blood tests. - Signs - Jaundice - Signs of complications: - **Ascending Cholangitis:** Charcot’s triad - **Chronic liver disease:** rare at first presentation, e.g. ascites or encephalopathy

Answer 73

- Pruritis - Fatigue - RUQ/ epigastric abdominal pain - Symptoms of underlying bowel disease: bloody stools, tenesmus, diarrhoea, steatorrhoea

Answer 74

- **LFTs -** raised ALP and raised bilirubin, raised GGT, raised ALT and AST if liver damage present, decreased albumin. - **Viral hepatitis screen:** screen for HBsAg and anti-HCV in all patients - **Antibodies screening:** - **pANCA Anti-neutrophil cytoplasmic antibodies**: positive in 33-88% of PSC patients, however is not specific - **Anti****mitochondrial antibodies**: positive in patients with PBC, **not** PSC - **ANA**: as part of a liver screen, as often elevated in autoimmune hepatitis and specific subtypes raised in PBC - **Anticardiolipin antibodies** - may be elevated - **MRCP:** preferred diagnostic imaging modality showing multiple biliary strictures giving a **'beaded' appearance**; has largely replaced ERCP - **Abdominal ultrasound:** rarely useful in diagnosis but useful to exclude alternative causes (e.g. choledocholithiasis)

Answer 75

ERCP - but has been replaced by MRCP as MRCP is less invasive.

Answer 76

- **ERCP**: mainly requested if biopsies are required or for therapeutic reasons, e.g. relief of biliary strictures - **Liver biopsy:** reserved for when the diagnosis is unclear, if there is a suspected overlap variant (e.g. PSC with autoimmune hepatitis) or in small duct PSC; biopsy may show fibrous, obliterative cholangitis often described as 'onion skin'

Answer 77

- 1st line - **Observation and lifestyle optimisation:** encourage a healthy lifestyle, such as alcohol cessation and exercise - **Cholestyramine:** a bile acid sequestrant that is the first-line treatment for relief of pruritus; rifampicin is considered second-line - **Fat-soluble vitamin supplementation:** cholestasis leads to impaired fat absorption; to ensure the absorption of fat-soluble vitamins (ADEK), supplementation is required - Other - **Ursodeoxycholic acid** - may improve LFTs - **Antibiotics** - for bacterial cholangitis **End-stage liver disease:** - **Liver transplantation:** indicated when expected survival after transplantation exceeds that predicted without transplantation

Answer 78

The UK-PSC recommends an annual gallbladder ultrasound scan and colonoscopy to detect pre-cancerous gallbladder cancer polyps, due to the increased risk of cholangiocarcinoma in patients with PSC. Consider cholecystectomy for gallbaladder polyps.

Answer 79

- **Cholangitis:** inflammation of the biliary tree secondary to infection is common in patients with PSC - **Biliary strictures**: narrowing of the extra-hepatic biliary tree occurs in 40-50% of patients - **Choledocholithiasis**: an increased risk of gallstones - **Metabolic bone disease**: increased risk of developing osteopaenia and osteoporosis due to disturbed vitamin D and calcium metabolism - **End-stage liver disease:** cirrhosis, portal hypertension and liver failure are a common outcome - **Cholangiocarcinoma:** cancer of the biliary tree is the commonest cause of death in patients with PSC, with a lifetime risk of 20% - **Hepatocellular carcinoma:** liver cancer has a reported prevalence of 2-4% - **Colorectal carcinoma:** an increased risk of colorectal cancer in patients with UC who also have PSC compared to those with UC only

Answer 80

The average survival of patients newly diagnosed with PSC is 9.3 to 18 years. Despite the rare nature of this disease, PSC is the 5th leading indication for liver transplantation in the USA. For those who receive a liver transplantation, the 5-year survival rate is approximately 85%.

Answer 81

Epidemiology: PBC - More common in middle aged women PSC - More common in middle aged men (can affect any age) Pathophysiology: PBC - Progressive destruction of only intrahepatic small and medium sized bile ducts PSC - Progressive chronic inflammation or intrahepatic and/or extrahepatic bile ducts Associated conditions: PBC - Sjogrens, Raynauds, Autoimmune thyroid PSC - IBD (particularly UC) Presentation: PBC - Often asymptomatic, fatigue and pruritis, jaundice, hepatomegaly PSC - Similar to PBC, symptoms of IBD, features of ascending cholangitis Serum tests: PBC: Increased ALP + GGT, +/- conjugated bilirubin, Anti-mitochondrial antibodies PSC: Increased ALP + GGT, +/- conjugated bilirubin, pANCA Diagnosis: PBC: Cholestatic LFT's + history + examination + abdo USS PSC: Cholestatic LFT's + history + examination + MRCP Management: PBC: Ursodeoxycholic acid, Colestyramine, Fat soluble vitamins, End stage: liver transplant PSC: Observation and lifestyle change, Colestyramine, fat soluble vitamins, End stage liver transplant Median survival: PBC: 7.5 years if symptomatic and 16 years if asymptomatic PSC: 7-14 years Complications: PBC: Osteoporosis, Fat-soluble vitamin deficiences, end stage liver disease and hepatocellular carcinoma, hypercholesterolaemia PSC: Osteoporosis, Fat-soluble vitamin deficiences, end stage liver disease and hepatocellular carcinoma, Cholangiocarcinoma, Ascending cholangitis, choledocholithiasis, colorectal cancel: relationship with UC

Answer 82

Acute pancreatitis refers to an acute inflammatory process involving the pancreas. The 2 main causes of acute pancreatitis are gallstones and alcohol

Answer 83

- In the UK there are an estimated 30 per 100,000 cases each year and the incidence is increasing globally - The overall mortality rate in the UK is reported as around 5%, rising to 25% for patients with severe disease. - In the UK, around 50% of cases are caused by gallstones, 25% by alcohol, and 25% by other factors. - Increases with advancing age - Afro-Caribbean ethnicity: risk is 2-3 fold higher in black populations than white - Sex: alcohol-related pancreatitis is more common in males, whilst gallstone-related pancreatitis is more common in females - Gallstone pancreatitis is more common in white women >60 years of age, especially among patients with microlithiasis.

Answer 84

I GET SMASHED: I - Iatrogenic G - Gallstones E - Ethanol abuse T - Trauma S - Scorpion and spider bites M - Mumps virus A - Autoimmune S - Steroids H - Hypercalcaemia, hyperlipidaemia E - ERCP D - Drugs (valproate, azathioprine, thiazide diuretics, tetracyclines, mesalazine, oestrogen, sitagliptin, vidagliptin) **Gallstones** Gallstones are the most common cause of acute pancreatitis, they are **responsible for around 40-50% of cases**. Gallstones migrate from the gallbladder to the biliary tree where they may cause obstruction of the ampulla. It is thought that **biliary reflux** and **raised pressures** are responsible for the resultant pancreatitis. Intracellular Ca2+ increases and causes the early activation of trypsinogen. In this situation, trypsinogen is cleaved (by cathepsin B) to trypsin, and trypsin degradation (by chymotrypsin C) is impaired and overwhelmed leading to a buildup of trypsin and thus increased enzymatic digestion of the pancreas and inflammation leading to extensive acinar damage **Alcohol** **Alcohol has toxic effects on the pancreas and is implicated in around 25-35% of cases**. Though it is known to increase the production of digestive enzymes, the exact mechanism by which it causes pancreatitis remains unclear. Other causes include pregnancy or neoplasia.

Answer 85

- **Diet:** intake of high glycaemic foods is associated with non-gallstone-related pancreatitis - **Obesity** - **T2DM** - **Family history**: 65-80% of patients with hereditary pancreatitis have a mutation in the PRSS1 gene, whilst mutated SPINK1 is also implicated in some cases - **Gallstones** - **Alcohol** - **ERCP (endoscopic retrograde cholangiopancreatography)** - use of contrast during ERCP has been linked to pancreatic inflammation.

Answer 86

Pancreatitis is caused by the release of enzymes, which causes autodigestion of pancreatic tissue. The pancreas has both **endocrine and exocrine function**. Endocrine function is governed by the islets of Langerhans and the hormones produced include insulin and glucagon. The pancreatic ductal cells are responsible for its exocrine function. They produce the **‘pancreatic juice’ composed of bicarbonate and digestive enzymes**. One of these enzymes, trypsin, is key to the development of pancreatitis. Under normal circumstances the pancreas releases zymogens - inactive enzyme precursors (trypsinogen in the case of trypsin). In pancreatitis, normal zymogen transport fails and trypsinogen is converted to trypsin within the pancreas leading to a cascade of zymogen activation. This triggers the recruitment of inflammatory cells and the release of inflammatory mediators. This inflammation causes changes in the vascular bed, which leads to increased permeability and resultant oedema. The condition may be worsened by the release of inflammatory mediators and enzymes into the systemic circulation. This can result in a systemic inflammatory response (SIRS), sepsis and adult respiratory distress syndrome (ARDS). Enzymes include proteases (causing further destruction), amylases (which can be used for diagnosis of pancreatitis) and lipases (which may result in fatty necrosis, and may also be used as a diagnostic feature) Furthermore, destruction of blood vessels by enzymes causes haemorrhage. Destruction of the adjacent islets of Langerhans can result in hyperglycaemia as beta cells will be destroyed resulting in less insulin.

Answer 87

**Acute pancreatitis** should be suspected in any person with: - Acute upper or generalised abdominal pain, particularly if they have a history or clinical features of gallstones or **alcohol misuse**

Answer 88

- Abdominal tenderness and guarding - Abdominal distension - common, mainly due to leakage of fluid into the retroperitoneum - Tachycardic and/or hypotensive - pt may be in shock - Jaundice - Cullen's sign - periumbilical bleeding, secondary to intraperitoneal haemorrhage - Grey Turner's syndrome - flank bleeding secondary to retroperitoneal haemorrhage - Fox’s sign: bleeding over the inguinal ligament secondary to retroperitoneal haemorrhage

Answer 89

- Severe upper abdominal pain: epigastric, RUQ or LUQ pain which may radiate to the back - Nausea, vomiting and anorexia: common features - Steatorrhoea: excess fat in faeces in acute-on-chronic pancreatitis - Poor urinary output: due to insensible fluid losses, third-spacing (movement of fluid from intravascular to interstitial spaces), and vomiting

Answer 90

- Diagnostic - **Serum amylase**: amylase rises faster than lipase but also levels fall faster within 24-48hrs; less specific than lipase; is **not** of prognostic value. Serum amylase may be raised in other conditions such as renal failure, so is non-specific - **Serum lipase**: more specific for acute pancreatitis; levels rise slower than amylase but have a longer half-life. Amylase is tested more frequently in the UK

Answer 91

- **FBC:** white blood cell count is required for severity scoring - **U&Es:** renal function is required for severity scoring - **LFTs:** required for severity scoring; an ALT of >150 U/L has an 95% positive predictive value for **gallstone-related pancreatitis** - **Arterial blood gas:** arterial pO2 and lactate are required for severity scoring - **Serum glucose:** glucose levels are required for severity scoring - **Serum LDH:** required for severity scoring (if AST is not available- raised AST/LDH is a sign of cell damage/pancreatitis ) - **Serum calcium:** calcium levels are required for severity scoring and identifying significant hypocalcaemia - **CRP:** C-reactive protein is a predictor of severe pancreatitis

Answer 92

- **Chest X-ray:** to assess for the development of ARDS, as well as pleural effusions - **Erect chest X-ray**: to exclude perforation - which also raises serum amylase - **Abdominal X-ray:** to exclude bowel obstruction, as the clinical picture can overlap - **Abdominal ultrasound:** to identify gallstones as an underlying cause or evidence of duct dilatation - **MRCP:** type of MRI scan most commonly indicated in suspected gallstone pancreatitis to help evaluate for CBD stones. - **CT abdomen:** a contrast-enhanced CT is **not** ordered routinely for diagnosis - Features include **local oedema** and **swelling**, whilst **non-enhancing areas** suggest **pancreatic necrosis** - A CT scan to assess for complications or severity should only be performed after **6-10 days of admission**

Answer 93

The mainstay of acute pancreatitis management is supportive: - **IV fluid resuscitation**: aggressive fluid replacement is required to compensate for insensible fluid losses, third-spacing, and vomiting - **Catheterisation**: monitoring urine output is required to ensure appropriate rehydration - **Oxygen supplementation**: if SpO2 <94%, supplementary oxygen is required - **Opiate analgesia**: the dosage of analgesia is titrated according to pain severity - **Early nutritional support**: ‘resting’ the pancreas is **not** evidence-based - Commence **oral feeding** in people with mild pancreatitis if there is no nausea, vomiting, or abdominal pain - **Enteral feeding** (e.g. nasogastric feeding) is otherwise preferable - **Parenteral feeding** (e.g. total parenteral nutrition; TPN) is reserved for a small subset of people in whom enteral nutrition is not possible - **Antibiotics:** not routinely indicated in acute pancreatitis and they should not be used prophylactically. Antibiotics should be commenced in patients with suspected/confirmed infected pancreatic necrosis, cholangitis or other infective source.

Answer 94

- **ERCP**: ****for those with gallstone related pancreatitis and cholangitis, removal of gallstones is required to relieve the obstruction within 72 hours - **Cholecystectomy**: performed during the same admission for gallstone related pancreatitis; may be delayed in protracted, severe cases - **Alcohol cessation and withdrawal management**: in alcohol-related pancreatitis, preventative measures are offered to prevent further episodes

Answer 95

During management: - Hourly pulse, BP, urine output. - Daily FBC, U&E, Ca2+, glucose, amylase and ABG. Long-term monitoring is not necessary. Patients usually resolve after their acute attack. If they modify their risk factors, another episode may not recur later in life.

Answer 96

Local complications - **Peripancreatic fluid collection:** occurs **<4 weeks** after initial presentation - **Pancreatic pseudocyst**: occurs **>4 weeks** after initial presentation - **Pancreatic abscess**: usually due to infection of pseudocysts by *E. coli* - **Haemorrhage**: infected necrosis may involve vascular structures → bleeding (may result in Grey-Turner’s sign) - **Necrotising pancreatitis** : a severe, life-threatening subtype of acute pancreatitis - **Chronic pancreatitis**: due to recurrent episodes of acute pancreatitis - **Local vascular complications:** pseudo-aneurysm and venous thrombosis - **Fistula:** resulting from inflammation surrounding the pancreas

Answer 97

- **Acute respiratory distress syndrome:** spread of inflammation to the lungs ****has a high mortality rate (approximately 20%) - **Pleural effusions**: exudative pleural effusion. Build-up of fluids between layers of pleura - **Aspiration pneumonia**: in the event of excessive emesis, it is possible for aspiration of the vomitus - **Hypovolaemic shock**: due to insensible fluid losses, third-spacing, and vomiting - **Renal failure:** often due to pre-renal acute kidney injury secondary to significant intravascular depletion - **Paralytic ileus**: the collection of pancreatic fluid in the retroperitoneum can obstruct the proximal intestine, resulting in ileus - **Hypocalcaemia:** excessive pancreatic enzyme release causes fat necrosis, which increases **free fatty acid** (FFA) levels. The FFAs **chelate calcium salts** in the pancreas, resulting in calcium deposition in the **retroperitoneum** (fat saponification) → reduced calcium levels - **Hyperglycaemia**: the destruction of the islets of Langerhans causes disrupted insulin release → raised glucose levels

Answer 98

25% of acute pancreatitis cases are severe and associated with complications. Severe cases often require critical care input, and are associated with prolonged hospital stay and an increased mortality rate (25%), compared to the overall mortality rate (5%).

Answer 99

A severe subtype of acute pancreatitis - Necrosis presents within the **first 24-48 hours** resulting in the death of portions of the pancreas - It should be suspected in those who continue to have **abdominal pain, nausea and fever** despite supportive management of acute pancreatitis - The **key diagnostic factor** is non-enhancing low attenuating pancreatic tissue on **CT imaging**, which signifies necrosis - Some hospitals perform **fine-needle aspiration** to determine if necrotic tissue is infected, but false negatives are possible - **Walled-off necrosis** (WON) occurs after 4 weeks, at which point percutaneous drainage or open necrosectomy may be indicated; **early** necrosectomy has a **high mortality rate** - Despite the above, the presence of sepsis and multi-organ dysfunction may warrant **early surgery** - It carries a **poor prognosis** and has a high risk of becoming infected

Answer 100

Chronic pancreatitis refers to inflammation of the pancreas. Unlike acute pancreatitis, chronic pancreatitis is irreversible. It is characterised by structural changes e.g. fibrosis, calcification and atrophy which leads to a decline in function of the pancreas.

Answer 101

- Alcohol is the primary risk factor accounting for 80% of cases, whilst 20% of cases have an unknown cause - The age at presentation varies with aetiology. Hereditary pancreatitis has a peak age at 10 to 14 years, juvenile idiopathic chronic pancreatitis at 19 to 23 years, alcoholic chronic pancreatitis at 36 to 44 years, and senile idiopathic chronic pancreatitis at 56 to 62 years. - M>F - Worldwide prevalence is around 4-5%

Answer 102

- Recurrent bouts of acute pancreatitis - Ductal dilatation and damage to pancreatic tissue - Healing process involves laying down fibrotic tissue, causing stenosis and atrophy - Alcohol - Increases digestive enzyme secretion while decreasing fluid and bicarbonate in the ducts. This can lead to blockage of duct as pancreatic juices become thick and viscous. This increases pressure in the duct and may cause distension. As well as this, it may cause early activation of digestive enzymes and therefore, autogestion. - Alcohol also stimulates release of cytokines, leading to an immune response which worsens the issue. - Calcium may also deposits on protein plugs - Cystic fibrosis (main cause of chronic pancreatitis in children) - Mutations in ion transporter cause pancreatic secretions to become thick and sticky, leading to obstruction. - Pancreatic tumours - Trauma to pancreas - Autoimmune pancreatitis - raised IgG4 (seen in many autoimmune disorders) trigger pancreatitis - Congenital - Pancreas divisum - single pancreatic duct is not formed, but rather remains as two distinct dorsal and ventral ducts.

Answer 103

- Alcohol excess - Smoking - Family history - Ductal obstruction e.g. gallstones, tumours, structural abnormalities - Genetic - cystic fibrosis and haemochromatosis

Answer 104

Chronic pancreatitis describes irreversible inflammation and/or fibrosis of the pancreas characterised by epigastric pain and progressive decline in endocrine and exocrine function. It often occurs secondary to repeated episodes of acute pancreatitis. Alcohol is responsible for up to 80% of cases. Other causes include ductal obstruction (e.g. gallstones), autoimmune pancreatitis, and cystic fibrosis. The exact pathogenesis is poorly understood, but the initial insult is thought to occur in the pancreatic duct (e.g. gallstone), or to the acinar cells (e.g. alcohol). The outcome is an inflammatory reaction with autodigestion of pancreatic tissue due to inappropriate activation of trypsinogen to trypsin, with the end result of fibrosis and loss of function.

Answer 105

- Epigastric tenderness - Signs of liver disease due to alcohol excess e.g. jaundice and ascites - Skin nodules (rare) - pancreatic lipase leaks into circulation and causes fat necrosis in soft tissue

Answer 106

- **Epigastric pain** - Dull and radiating to the back - Improved by leaning forwards - Occurs 15 to 30 minutes after eating - **Steatorrhea and diarrhoea** - Foul-smelling stools which are hard to flush. Stool contains fat as pancreatic function declines and food isn't digested properly - **Nausea and vomiting** - **Weight loss and fatigue** - Features of **diabetes e**.g. polyuria and polydipsia

Answer 107

- **Transabdominal ultrasound**: advised by NICE as the **first-line** imaging modality. The pancreas may appear atrophic, calcified, or fibrotic - **CT abdomen:** if ultrasound is suggestive, CT should be conducted and may demonstrate: - Pancreatic calcifications (80% sensitivity and 85% specificity) - Pancreatic atrophy - Duct dilatation

Answer 108

- **MRCP:** usually performed if CT imaging is inconclusive; shows a ‘chain of lakes’ appearance due to alternating dilation and stenosis of pancreatic ducts - **Faecal elastase:** used to assess exocrine function ****and ****is ****reduced in severe disease, but may be normal in mild disease; useful if imaging is inconclusive - **LFTs**: abnormal if co-existent liver disease; AST>ALT suggests alcoholic liver disease - **HbA1c:** islet cell destruction results in reduced endocrine function - **IgG4:** associated with autoimmune chronic pancreatitis - **ERCP:** again, may be performed if first-line investigations are inconclusive; has the added benefit as treatment of ductal pathology can also be conducted, e.g. gallstone removal

Answer 109

- **Lifestyle modification:** alcohol and smoking cessation - **Diet:** low fat, high-calorie diet with fat-soluble vitamin supplementation (vitamin A, D, E, K) - **Analgesia**: start with paracetamol and NSAIDs - **Pancreatic enzyme replacement**: pancreatin (Creon) contains lipase, amylase and protease. Often given with a proton pump inhibitor as this increases the activity of the enzymes. - Pt may also require insulin replacement - 2nd line **Interventional procedures:** - **Endoscopic stenting** (fibrosis can lead to duct blockage and pain) - **Coeliac plexus nerve blocks**: may be considered in patients with intractable pain - **Drainage of pseudocysts/ pancreaticojejunostomy** - **Pancreatectomy**

Answer 110

Patients are recommended to be seen yearly for non-invasive testing, to include laboratory blood work and perhaps stool tests to monitor for specific complications, including: - Cholestasis and biliary obstruction (LFTs) - Malnutrition - Baseline bone densitometry in high-risk patients - Steatorrhoea (qualitative faecal fat) - Diabetes (glucose).

Answer 111

- **Pancreatic complications** - **Malabsorption:** reduced exocrine function leads to malabsorption - **Duct obstruction:** chronic inflammation and fibrosis leads to pancreatic duct obstruction which can contribute to pain - **Pseudocysts:** disruption of pancreatic duct architecture leads to pseudocysts; small cysts are observed, whilst larger ones may cause pain and rupture - **Diabetes:** islet cell destruction leads to reduced insulin production - **Pancreatic cancer** - **Local vascular complications:** venous thrombosis and aneurysms - **Gastric varices:** dilated submucosal veins in the lining of the stomach, which can be a life-threatening cause of bleeding - **Metabolic bone disease:** increased risk of osteoporosis, likely due to malabsorption

Answer 112

Almost all patients will develop exocrine insufficiency, and up to 75% will develop endocrine insufficiency. Survival is dependent upon the underlying cause, with a life expectancy of 55-72% in chronic pancreatitis due to alcohol excess.

Answer 113

Alcoholic liver disease (ALD) has 3 stages of liver damage: fatty liver (steatosis), alcoholic hepatitis (inflammation and necrosis), and alcoholic liver cirrhosis. All are caused by chronic heavy alcohol ingestion. *Typically, alcohol consumption >100 g per day for 15-20 years increases the risk of alcoholic hepatitis. Approximately 8 g of pure ethanol is equal to 1 unit.*

Answer 114

- The prevalence of alcohol-use disorders among men and women in the European region was 14.8% and 3.5%, respectively, in 2016. In the UK, it is estimated that 24% to 28% of adults drink in a hazardous or harmful way. - M>F prevalence - ArLD is the foremost health risk in developing countries and ranks third in developed countries. - The mortality related to liver cirrhosis increases with age. - Rising numbers of people are dying from liver disease associated with alcohol, particularly in young age groups. Mortality from ArLD is estimated at 9.0 per 100,000 people under 75 years old.

Answer 115

- Prolonged and heavy alcohol consumption - Hepatitis C - increased risk of cirrhosis - Female sex - ALD develops more rapidly and occurs at lower drinking levels in women than in men. However, most patients with ALD are male. - Genetic predisposition - genes encoding enzymes that metabolise both alcohol and acetaldehyde, and pro-inflammatory (tumour necrosis factor [TNF]-alpha) and anti-inflammatory cytokines (interleukins 6 and 10), may influence the predisposition to ALD and cirrhosis. - Increasing age >65 - Obesity

Answer 116

Alcohol is metabolised mainly in the liver, through 2 main pathways: alcohol dehydrogenase and cytochrome P450 2E1. Alcohol dehydrogenase is a hepatic enzyme that converts alcohol to acetaldehyde, which is subsequently metabolised to acetate by the mitochondrial enzyme acetaldehyde dehydrogenase. Alcohol dehydrogenase and acetaldehyde dehydrogenase reduce nicotinamide adenine dinucleotide (NAD) to NADH (reduced form of NAD). Excessive NADH in relation to NAD inhibits gluconeogenesis and increases fatty acid oxidation, which in turn promotes fatty infiltration in the liver. The cytochrome P450 2E1 pathway generates free radicals through the oxidation of NADPH to NADP. Chronic alcohol use upregulates cytochrome P450 2E1 and produces more free radicals. Chronic alcohol exposure also activates a third site of metabolism: hepatic macrophages, which produce tumour necrosis factor (TNF)-alpha and induce the production of reactive oxygen species in the mitochondria. People with alcohol-use disorder are usually deficient in antioxidants, such as glutathione and vitamin E. Therefore, oxidative stress promotes hepatocyte necrosis and apoptosis in these patients. Free radicals can also induce lipid peroxidation, which can cause inflammation and fibrosis. The alcohol metabolite acetaldehyde, when bound to cellular protein, produces antigenic adducts and induces inflammation. Alcohol also affects the barrier function of intestinal mucosa, producing endotoxaemia, which leads to hepatic inflammation. As the immune system attacks the hepatocytes, patients develop alcoholic hepatitis. If alcohol consumption continues, this may progress to cirrhosis.

Answer 117

The acetaldehyde formed from metabolism of alcohol can react with molecules in the liver, forming acetaldehyde adducts. These are recognised as foreign and can be attacked by the immune system, causing further damage. At this point, the patient develops hepatitis. This inflammatory response can also lead to the activation of stellate cells, which causes deposition of extracellular matrix proteins, generation of portal hypertension and fibrosis.

Answer 118

- Often, no symptoms or signs - Vague abdominal symptoms of nausea, vomiting, diarrhoea are due to the more general effects of alcohol on the GI tract - Hepatomegaly, sometimes huge, can occur together with other features of chronic liver disease

Answer 119

- Patient may be well, with few symptoms, the hepatitis only being apparent on the liver biopsy in addition to fatty change. - Mild to moderate symptoms of ill-health - Mild jaundice may occur - Signs of chronic liver disease (ascites, bruising, clubbing, Dupuytren’s contracture) - Anorexia - Asterixis - Diarrhoea and vomiting - High temperature, pulse and respiration - In the severe cases - Abdominal pain is frequently present and a high fever is associated with the liver necrosis. - On examination there is deep jaundice, hepatomegaly and ascites with ankle oedema

Answer 120

- Patients can be very well with few symptoms - On examination there are usually signs of chronic liver disease - ascites, bruising, clubbing and Dupuytren’s contracture - There are features of alcohol dependency

Answer 121

May not always be present: - Hepatomegaly - Abdominal pain - Haematemesis - Venous collaterals - engorged para-umbilical veins (caput medusae), present in advanced alcoholic liver disease. - Splenomegaly - Jaundice - Palmar erythema - Asterixis - Ascites - Weight loss - Fatigue - Confusion - Pruritis - Fever - Nausea and vomiting - Finger clubbing - Dupuytren's contracture - Bruising - coagulopathy - Withdrawal symptoms - high pulse, low BP, tremor, confusion, fits, hallucinations

Answer 122

A combination of clinical features and laboratory findings are used to make a diagnosis. A liver biopsy is usually reserved for severe case. It helps to assess severity, look for underlying cirrhosis and exclude alternative causes of liver disease. - Screening tools e.g. CAGE - have they thought about **c**utting down on drink, have they felt **a**nnoyed at comments about their drinking, **g**uilt about drinking, **e**ye-opener in the morning? - Baseline investigations: - **Full blood count** - **Urea & electrolytes** - **Liver function tests** - **Bone profile** - **C-reactive protein** - **Magnesium** - **Coagulation** (INR) - **Non-invasive liver screen** - **Liver ultrasound** - **+/- septic screen** (e.g. blood cultures, urines, ascitic cultures, chest x-ray) - *Findings - Elevated MCV, leukocytosis, raised AST and ALT (2:1 ratio), raised ALP and GGT, raised bilirubin, reduced platelets, raised prothrombin time.* - **Ultrasound or CT** - will show fatty infiltration - **Biopsy** - may show mallary bodies, large mitochondria, neutrophil infiltrate, hepatocyte ballooning, fibrosis, cholestasis

Answer 123

- Maddrey discriminant function (DF) - used to assess the severity of alcoholic hepatitis. It is based on serum bilirubin and prothrombin time. - Model for End-stage liver disease (MELD) - assesses severity - Glasgow alcoholic hepatitis score (GAH) - predicts mortality among patients with alcoholic hepatitis. It is a slightly more complex score based on age, white blood cell count, urea, bilirubin and prothrombin time.

Answer 124

- **Alcohol cessation - alcoholics anonymous, disufiram can be used in chronic alcohol dependence (causes negative effects for patients due to acetaldehyde buildup - aversion therapy)** - Manage alcohol withdrawal - - **Diazepam** - **IV Thiamine** to prevent Wernicke-Korsakoff encephalopathy (presents with ataxia, confusion and nystagmus) which occurs from alcohol withdrawal, occurs 6-24 hours after last drink and lasts up to a week - Hydration - Nutrition - diet high in vitamins and proteins

Answer 125

- Nutrition must be maintained with enteral feeding (high protein diet) and if necessary vitamin supplementation e.g. Vit K - Steroids show short-term benefit e.g. prednisolone. Given to patients who score high on Maddrey Discriminant Factor scoring system. - Screen for infections (ascitic fluid tap) and treat spontaneous bacterial peritonitis

Answer 126

- Reduce salt intake - Avoid aspirin and NSAIDs - Liver transplantation

Answer 127

Monitoring for alcoholic hepatitis - daily: LFTs, weight, U&Es, INR

Answer 128

- Liver cirrhosis and related complications e.g. liver failure, hepatocellular carcinoma - CNS - self neglect, low memory and cognition, cortical atrophy, retrobulbar neuropathy, fits, falls, neuropathy, hepatic encephalopathy - Gut - obesity, diarrhoea and vomiting, gastric erosions, peptic ulcers, varices, pancreatitis, cancer, oesophageal rupture - Blood - coagulopathy, thrombocytopenia, anaemia from: marrow depression, GI bleeding, alcoholism related folate deficiency, haemolysis, sideroblastic anaemia - Heart - arrhythmias, high BP, cardiomyopathy, sudden death - Reproduction - testicular atrophy, low testosterone and progesterone, high oestrogen, fetal alcohol syndrome

Answer 129

- Fatty liver is reversible, but may progress to cirrhosis with continued drinking. - 80% of people with alcoholic hepatitis progress to cirrhosis. Mild episodes of alcoholic hepatitis do not affect mortality but severe episodes associated with 50% mortality at 30 days. 1 yr after admission for alcoholic hepatitis, 40% mortality. - 5 yr survival is 48% with cirrhosis, if drinking continues.

Answer 130

NAFLD refers to a fatty liver that cannot be attributed to alcohol or viral causes Spectrum of disease - steatosis, steatohepatitis, fibrosis, cirrhosis (least to most severe)

Answer 131

- Commonest liver disorder in industrialised western countries - Affects around 3/4's of all obese individuals

Answer 132

Results from fat deposition in the liver and usually affects individuals with metabolic syndrome: - Obesity - Hypertension - Diabetes - Hypertriglyceridemia - Hyperlipidemia

Answer 133

- Older age - Obesity - Hypertension - Diabetes - Hypertriglyceridemia - Hyperlipidemia

Answer 134

Insulin resistance plays a role. Overtime, insulin receptors are less responsive to insulin so liver increases fat storage and decreases fatty acid oxidation. This means there is less secretion of fatty acids into the blood stream. There is also increased synthesis and uptake of free fatty acids from the blood (known as steatosis). This causes fat droplets to form within hepatocytes and this may cause hepatocytes to swell up with fat and push nuclei to edge of cell. Liver appears large, soft, yellow and greasy. Overtime, the fat is vulnerable to degradation. Unsaturated fatty acids are especially vulnerable to things like ROS. This reacts to form a fatty acids radicals which can then react further with non-radicals such as oxygen and non-radical fatty acids. This carries on until one radical reacts with another radical to terminate the reaction. This ultimately damages lipid membrane, leading to mitochondrial dysfunction and cell death. This generates inflammation. Inflammation + steatosis = steatohepatitis. Damage also attracts neutrophils to the liver. Chronic steatoheptitis can trigger stellate cells to lay down fibrotic tissue (fibrosis). The architecture then changes to the point where disease is now classed as cirrhosis

Answer 135

May be asymptomatic even at advanced stages Sometimes symptoms are vague: - Fatigue - Malaise Sufficient damage presents with: - Hepatomegaly - Pain in RUQ - Jaundice - Ascites - Bruising - Pruritis etc

Answer 136

**Serum AST and ALT:** Increase in ALT and sometimes AST. (Different to alcoholic liver disease where AST>ALT) **LFT:** raised bilirubin, ALP, GGT, prothrombin time, low serum albumin **FBC:** anemia and thrombocytopenia due to hypersplenism **Imaging:** US, CT, MRI to look for fatty infiltrates **Biopsy:** used to diagnose and assess severity

Answer 137

- Alcoholic liver disease - Autoimmune hepatitis - Hepatitis B and C - Hemochromatosis - DILI - Primary biliary cholangitis - Primary sclerosing cholangitis - Wilson's disease - Alpha-1 antitrypsin deficiency

Answer 138

*Steatosis and steatohepatitis is reversible if underlying cause is addressed. Cirrhosis is not reversible.* - Avoid alcohol consumption - Reverse factors that contribute to insulin resistance - Healthy diet - Active lifestyle - Medication to control blood glucose - Control risk factors e.g. bariatric surgery for obesity - Address cardiovascular risk (commonest cause of death) - Vitamin E may improve histology of fibrosis

Answer 139

- Monitor for complications and progression (NASH, cirrhosis, DM) - If cirrhotic, screen for hepatocellular carcinoma with ultrasound +/- alpha fetoprotein tumour marker test twice-yearly.

Answer 140

- Ascites - Varices and variceal haemorrhage - Encephalopathy - Hepatocellular carcinoma - Hepatorenal syndrome - renal disease secondary to liver failure - Hepatopulmonary syndrome - shortness of breath and hypoxemia caused by vasodilation in the lungs of patients with liver disease.

Answer 141

The overall prognosis in patients with steatosis (fatty liver without evidence of active inflammation) is considered to be good and a majority of patients will remain stable throughout their lifetime. The same cannot be said of non-alcoholic steatohepatitis (NASH), which is considered the progressive form of NAFLD. Patients who have NASH progress to cirrhosis 9% to 20% of the time. Up to one third of these patients will die from complications from liver failure or require liver transplantation. Recurrent NAFLD following liver transplantation is now a well-recognised phenomenon. The incidence of the development of post-liver transplantation steatosis ranges anywhere from 25% to 100%, and the incidence of NASH ranges from a low of 10% to as high as 37.5%. Hepatic steatosis affects up to 80% of patients with chronic hepatitis C infection. Concurrent fatty liver disease with hepatitis C includes increased disease progression, elevated risk of primary liver cancer, and a decreased response to antiviral therapy.

Answer 142

Cirrhosis is a diffuse pathological process, characterised by fibrosis and conversion of normal liver architecture to structurally abnormal nodules known as regenerative nodules, surrounded by fibrotic tissue. It can arise from a variety of causes (chronic alcohol use or viral attack) and is the final stage of any chronic liver disease. It can lead to portal hypertension, liver failure, and hepatocellular carcinoma. In general, it is considered to be irreversible in its advanced stages, although there can be significant recovery if the underlying cause is treated.

Answer 143

- Liver disease is the third biggest cause of premature mortality in the UK with 62,000 working life years lost. - In Europe, cirrhosis related to either viral infection (21% with 13% of HCV infection and 7% of hepatitis B virus infection), or alcohol abuse (19%) are the main indications of liver transplant.

Answer 144

- Common: - Chronic alcohol abuse (most common cause in the West) - Non-alcoholic fatty liver disease - Hepatitis B +/- D - Hepatitis C - Others: - Hepatic vein events e.g. Budd-Chiari syndrome - Autoimmunity - primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis - Genetic disorders - hereditary haemochromatosis (iron overload), Wilson’s disease, Alpha1-Antitrypsin deficiency - Drugs e.g. amiodarone and methotrexate

Answer 145

- Alcohol misuse - IV drug use - Obesity

Answer 146

- Chronic liver injury results in inflammation, matrix deposition, necrosis and angiogenesis all of which lead to FIBROSIS - Liver injury causes necrosis and apoptosis, releasing cell contents and reactive oxygen species (ROS) - This activates hepatic stellate cells and tissue macrophages (Kupffer cells) - Stellate cells release cytokines that attract neutrophils and macrophages to the liver which results in further inflammation and thus necrosis and eventual fibrosis - Kupffer cells phagocytose necrotic and apoptotic cells and secrete pro- inflammatory mediators: - Transforming growth factor-beta (TGF-beta) which leads to the transdifferentiation of stellate cells to myofibroblasts - Platelet derived growth factor (PDGF) which stimulates myofibroblast proliferation - Increased myofibroblasts leads to progressive collagen matrix deposition resulting in fibrosis and scar accumulation in the liver - This results in severe reduction in liver function as fibrosis is non- functioning - This process is usually progressive and perturbs blood flow through the liver, thereby leading to increased pressure within the portal venous system, as well as shunting blood away from the liver. - If the cause of fibrosis is eliminated e.g. treatment of viral hepatitis then resolution (complete reversal to near-normal architecture) of early fibrosis can occur - In cirrhosis, regression (improvement, not reversal) occurs, which improves clinical outcomes - The characteristic features of cirrhosis are regenerating nodules separated by fibrous septa and loss of lobular architecture within the nodules - Two types: - Micronodular cirrhosis: - Regenerating nodules are usually < 3mm in size with uniform involvement of the liver - Often caused by alcohol or biliary tract disease - Macronodular cirrhosis: - These nodules are of varying size and normal acini (functioning unit of liver) may be seen within the larger nodules - Often caused by chronic viral hepatitis

Answer 147

- Leuconychia - white discolourations on nails due to hypoalbuminaemia - Clubbing - Palmar erythema - Dupuytren’s contracture - Spider naevi - Xanthelasma - yellow fat deposits under skin usually around eyelids - Gynaecomastia - Loss of body hair - Hepatomegaly - Splenomegaly - Bruising - Ankle swelling and oedema - Abdominal pain due to ascites

Answer 148

- **Liver biopsy -** GOLD STANDARD - confirms diagnosis and type and severity. Will see regenerative nodules and fibrotic tissue - **Bloods and LFTs** - low albumin, raised prothrombin time, high AST, ALT, ALP, GGT, bilirubin, low platelets, low WCC, raised serum creatinine - Find cause e.g. alpha-fetoprotein may suggest hepatocellular carcinoma, hepatitis serology, auto-antibodies, alpha-1-antitrypsin - **Ultrasound and duplex**- - Can show hepatomegaly (small liver in severe disease) - Splenomegaly - Hepatic vein thrombus - Ascites - Reverse flow in portal vein - **MRI** - Increased claudate lobe size, smaller islands of regenerative nodules and presence of right posterior hepatic notch is more likely in alcoholic cirrhosis rather than viral cirrhosis. - Can detect tumours - **Ascitic tap** - Sent for microscopy, culture and sensitivity (MC&S) - high neutrophils indicate spontaneous bacterial peritonitis.

Answer 149

- Constrictive pericarditis - Budd-Chiari syndrome - Portal vein thrombosis - Splenic vein thrombosis - Schistosomiasis - Sarcoidosis - Inferior vena cava obstruction

Answer 150

- Good nutrition is vital - Alcohol abstinence - Avoid NSAIDs, sedatives and opiates as these may precipitate gastro-intestinal bleeding or renal impairment - Treatment of the underlying causes may arrest or reverse the cirrhosis - e.g. treatment for hepatitis, Wilson's etc - Those at risk should have Hep A & B vaccination - Pruritus - Colestyramine - Acites - fluid restriction and reduced salt intake, spironolactone - Spontaneous bacterial peritonitis - antibiotics - Encephaloathy - prophylactic lactulose and rifaximin for reduction in episodes - If very advanced and no longer responsive to therapy then liver transplantation

Answer 151

Patients should undergo 6 monthly ultrasound screening for early development of hepatocellular carcinoma

Answer 152

- Coagulopathy; fall in clotting factors II,VII, IX & X - Encephalopathy - asterixis (flapping tremor with wrist extended) & confusion/coma - Hypoalbuminaemia resulting in oedema - Hepatocellular carcinoma - Spontaneous bacterial peritonitis - Acute kidney injury, secondary to liver failure due to portosystemic shunt - Portal hypertension: - Ascites - Oesophageal varices

Answer 153

Overall 5 year survival is roughly 50% Poor prognostic indicators = encephalopathy, low serum Na+, low serum albumin, high prothrombin time.

Answer 154

Normal portal vein pressures range from 5–10 mm Hg. The term portal hypertension refers to elevated pressures in the portal venous system. Venous pressure more than 5 mm Hg greater than the inferior vena cava pressure is defined as portal hypertension. Portal vein is formed by the union of the superior mesenteric and splenic veins

Answer 155

**Pre-hepatic:** - Portal vein thrombosis - Splenic vein thrombosis **Intra-hepatic:** - Cirrhosis (80% UK) - Schistosomiasis (commonest worldwide) - Sarcoidosis - Myeloproliferative disease - Congenital hepatic fibrosis **Post-hepatic:** - Right heart failure (rare) - Budd-Chiari syndrome - obstruction of hepatic venous outflow - Constrictive pericarditis - Veno-occlusive disease

Answer 156

- Cirrhosis - Alcohol - Congestive heart failure - Hyper-coagulable state

Answer 157

- Following liver injury and fibrogenesis e.g. due to cirrhosis, the contraction of activated myofibroblasts and activation of stellate cells contributes to increased resistance to blood flow. There may also be increased resistance due to various mechanical causes as well as increased blood flow into the portal vein. - This leads to portal hypertension → splanchnic vasodilation → drop in BP → increased cardiac output to compensate for BP → salt and water retention to increase blood volume and compensate → hyperdynamic circulation (high circulatory volume)/increased portal flow → formation of collaterals between the portal and systemic systems e.g. in the lower oesophagus and gastric cardia → gastro-oesophageal varices - Venous collaterals/ varices can occur in many places: - Gastro-oesophageal junction - superficial varices that tend to rupture - Anterior abdominal wall - Rectum (30%) - Left renal vein - Diaphragm - Retroperitoneum

Answer 158

*Patients are often asymptomatic* **Features of chronic liver disease** - Leukonychia (white discolouration on nails) - Palmar erythema - Spider telangiectasia - Gynecomastia **Features of decompensated liver disease** - Encephalopathy - Jaundice - Ascites **Splenomegaly due to portal hypertension** **Variceal bleeding**

Answer 159

- Abdominal ultrasound - dilated portal vein - Doppler ultrasound - slow velocity and dilated portal vein - Endoscopy - for presence of oesophageal varices

Answer 160

- Treat underlying cause - Salt reduction and diuretics - Beta-blockers and nitrate to reduce blood pressure

Answer 161

- Varices and variceal haemorrhage - Ascites - Hepatopulmonary syndrome - Liver failure - Hepatic encephalopathy - Cirrhotic cardiomyopathy

Answer 162

Oesophageal varices are abnormal, dilated veins that occur at the lower end of the oesophagus; they account for 10-20% of upper GI bleeds. They develop as a consequence of portal hypertension.

Answer 163

- Oesophageal varices are present in almost half of patients at the time of the diagnosis of cirrhosis - Varices tend to develop in the lower oesophagus and gastric cardia - The 1-year incidence of bleeding is 5% with small varices, and 15% with large varices.

Answer 164

- **Secondary to portal hypertension:** - Increased resistance: causes include pre hepatic (portal vein or splenic vein thrombus), hepatic (cirrhosis, schistosomiasis, sarcoid, myeloproliferative disease, congenital hepatic fibrosis) and post hepatic (e.g. right heart failure, constrictive pericarditis, Budd-Chiari syndrome - hepatic vein obstruction by tumour or thrombosis) - Increased flow - **Secondary to chronic liver disease/ cirrhosis**

Answer 165

- **Portal hypertension** - **Cirrhosis** - **Alcoholism** - **Schistosomiasis infection** Risk factor for bleeding: - **Large varices:** the single most important factor in determining bleeding risk - **Decompensated liver cirrhosis:** a higher Child-Pugh class is associated with a greater bleeding risk

Answer 166

- Following liver injury and fibrogenesis e.g due to cirrhosis, the contraction of activated myofibroblasts contributes to increased resistance to blood flow. - This leads to portal hypertension → splanchnic vasodilation → drop in BP → increased cardiac output to compensate for BP → salt and water retention to increase blood volume and compensate → hyperdynamic circulation (high circulatory volume)/increased portal flow → formation of collaterals between the portal and systemic systems e.g. in the lower oesophagus and gastric cardia → gastro-oesophageal varices The lower one-third of the oesophagus drains into the portal vein via the left gastric vein. In portal hypertension, there is backpressure and these veins become engorged and dilated. There is also pooling of blood in these veins. If varices rupture, they can cause a life-threatening upper gastrointestinal (GI) bleed. In contrast, the upper oesophagus drains directly into the azygos vein and then into the superior vena cava, so is not involved in the development of varices.

Answer 167

Patients can be asymptomatic if varices aren't bleeding - Signs **Features of chronic liver disease** - Leukonychia (white discolouration on nails) - Palmar erythema - Spider telangiectasia - Gynecomastia **Features of decompensated liver disease** - Encephalopathy - Jaundice - Ascites **Splenomegaly due to portal hypertension** **Hypotension** **Tachycardia** **Pallor** - Symptoms - **Haematemesis and malaena (dark sticky faeces)** - **Abdominal pain** - **Symptoms of blood loss (shock)** - Light-headedness - Dyspnoea - Chest pain - Syncope

Answer 168

- **Upper GI endoscopy**: diagnostic and therapeutic - **FBC:** anaemia - **LFTs and coagulation profile:** assess the severity of liver disease and bleeding risk - **U&Es**: urea is raised in an upper GI bleed (protein in RBCs is digested into urea in the GI tract) - **Venous blood gas**: can be analysed within minutes and provides an estimate of the Hb. Also, a raised lactate suggests poor tissue perfusion and is associated with a significant bleed - **Crossmatch/group and save**: ensures blood is ready to be transfused if needed - Other investigations to consider - **Erect CXR:** if history and examination are unclear and a perforated ulcer is a possibility, an erect CXR should be performed for pneumoperitoneum (presence of air or gas in the abdominal (peritoneal) cavity); oesophageal rupture may demonstrate pneumomediastinum (abnormal presence of air or another gas in the mediastinum)

Answer 169

- Gastric varices - Mallory-weiss tear - Peptic ulcer disease - Hiatal hernia

Answer 170

It is recommended patients undergo endoscopic surveillance and are commenced on a beta-blocker

Answer 171

- Resuscitation - **ABCDE approach**: patients should ideally be resuscitated prior to endoscopy - **IV fluids:** useful if the patient is in shock, but important not to overhydrate as this can cause haemodilution - **Blood products:** blood transfusion; platelet transfusion if PLTs < 50 x10^9/L; fresh frozen plasma (FFP) if clotting is deranged or vitamin K - **Terlipressin:** ADH analogue and causes splanchnic vasoconstriction, reducing blood flow into the portal vein and thereby reducing portal pressure. Improves initial haemostasis and prevents rebleed. Octreotride is an alternative but is less effective - **Prophylactic antibiotics:** patients with variceal bleed and cirrhosis are at increased risk of bacterial infection. NICE recommend all patients should receive antibiotics; quinolones are usually used - **Balloon tamponade:** conducted in an emergency for uncontrolled bleeding as a temporary measure until definitive management can be performed - A **Sengstaken-Blakemore tube** can be inserted through the mouth/nose and lowered into the stomach where a balloon can be inflated to compress bleeding vessels

Answer 172

- **Oesophageal varices:** endoscopic variceal **band ligation** is first line and is superior to sclerotherapy - **Gastric varices:** endoscopic **sclerotherapy** with N-butyl-2-cyanoacrylate is first line. Sclerotherapy is a form of treatment where a doctor injects medicine into blood vessels or lymph vessels that causes them to shrink - **Transjugular intrahepatic portosystemic shunt** (TIPS): for a variceal bleed (gastric or oesophageal) if endoscopic treatment fails

Answer 173

- **Beta-blocker:** all patients should be commenced on a non-selective beta-blocker e.g. propranolol, as long term **secondary prevention** to reduce portal pressure. This reduces rebleeding and mortality - **Endoscopic variceal band ligation** (EVL): used as **primary prevention** for people with cirrhosis who have medium to large oesophageal varices. Performed at two-weekly intervals until all varices are eradicated, alongside a proton pump inhibitor to prevent EVL-induced ulceration

Answer 174

- **Rebleed**: there is a risk of rebleed in the future; the risk is reduced with a beta-blocker - **Encephalopathy**: patients who have a variceal bleed and liver disease often develop encephalopathy - **Infection**: patients with variceal bleeds are at risk of infection, e.g. spontaneous bacterial peritonitis, and require prophylactic antibiotics

Answer 175

Patients who have had a variceal bleed have a 1-year mortality of up to 40%. Prognosis can be improved by avoiding alcohol, losing weight (in fatty liver disease) and the use of prophylactic beta-blockers (e.g. propranolol). Prophylactic beta-blockers can reduce the risk of bleeding by 45-50%.

Answer 176

Haematemesis is simply defined as “vomiting blood”. It is caused by bleeding from part of the upper portion of the gastrointestinal tract. It may be bright red or look like coffee grounds. (Upper GI tract bleeds may also present as malaena - dark sticky poo)

Answer 177

It has a wide range of possible causes, depending on the site of blood loss and the tissue that is actively bleeding. **Common causes:** - Peptic ulcers - ulceration can result in erosion into the blood vessels and can result in significant haemorrhage. - Mallory-Weiss tear - typified by episodes of severe or recurrent vomiting, then followed by minor haematemesis. Such forceful vomiting causes a tear in the epithelial lining of the oesophagus, resulting in a small bleed. - Oesophageal varices - caused by portal hypertension - Gastritis/ gastric erosions - Drugs - NSAIDs, aspirin, steroids, thrombolytics, anticoagulants - Oesophagitis - inflammation of the intraluminal epithelial layer of the oesophagus, most often due to either gastric acid reflux (GORD) or less commonly from infections (typically Candida Albicans), medication (such as bisphosphonates), radiotherapy, ingestions of toxic substances, or Crohn’s disease. - Duodenitis - Malignancy **Rare causes** - Bleeding disorders - Portal hypertensive gastropathy - refers to changes in the mucosa of the stomach in patients with portal hypertension - Aorto-enteric fistula - pathologic communications between the aorta (or aortoiliac tree) and the gastrointestinal tract - Angiodysplasia - abnormality with the blood vessels in the gastrointestinal (GI) tract. - Haemobilia - bleeding into the biliary tree. - Dieulafoy lesion - large arteriole most commonly in the stomach wall (submucosal) that erodes and bleeds - Meckel's diverticulum - outpouching or bulge in the lower part of the small intestine (congenital defect) - Peutz-Jegher's syndrome - benign hamartomatous polyps in the gastrointestinal tract - Osler-Weber-Rendu syndrome - leads to abnormal blood vessel formation

Answer 178

- History and examination The key facts to ascertain from a history of haematemesis are: - Timing, frequency, and the volume of bleeding - History of dyspepsia, dysphagia, or odynophagia - Past medical history: varices? liver disease? past GI bleeds? - Smoking, drug and alcohol status - Use of steroids, NSAIDs, anticoagulants, or bisphosphonates - Co-morbidities: cardiovascular? respiratory? renal? malignancy? - Signs of chronic liver disease? On examination, it is important to assess specifically for epigastric tenderness or peritonism (inflammation of peritoneum), as well as features suggestive of a potential underlying cause, such as evidence of varices or liver stigmata. PR check for malaena.

Answer 179

- FBCs - acute bleeds may not show anaemia - LFTs - may be deranged and show liver damage as potential cause - U&Es - high urea out of proportion to creatinine, indicative of massive blood meal. - All patients with haematemesis should have a Group and Save; those with significant haematemesis (especially suspected variceal bleed) should have at least 4 units of blood cross-matched. - Oesophagogastroduodenoscopy (OGD) - definitive investigation and should be performed within 12hrs in most cases of acute haematemesis or as soon as possible if the patient is unstable. - Erect chest X-ray - may also be required if a perforated peptic ulcer is suspected as the underlying cause. - CT abdomen - can be useful in assessing any active bleeding in an unstable patient Use GBS (Glasgow-Blatchford bleeding score) scoring system to risk stratify patients

Answer 180

**Acute management** Patients with haematemesis can be extremely unstable. - Rapid **ABCDE assessment** - **High flow O2** - Insert 2 large bore IV cannulae and take blood for **FBC, LFT, U&E, clotting and crossmatch.** - Start **fluid resuscitation** if needed - **Insert urinary catheter** to monitor and guide fluid replacement. Consider **CVP line** for monitoring fluid replacement - **Transfuse** if significant Hb drop - Correct clotting abnormalities - **Vit K, fresh frozen plasma, platelets** Most cases will warrant an **upper GI endoscopy.** If endoscopic control fails, surgery or emergency **mesenteric angiography/embolisation** may be needed **Suspected varices** - **Terlipressin +** **IV antibiotics** - For uncontrolled variceal bleeding, a **Sengstaken-Blakemore tube** may be needed, before definitive management. **Peptic ulcer bleeds** - High risk: achieve **endoscopic haemostasis. Start IV PPI. Treat if positive for H.Pylori.** - Low risk: endoscopic haemostasis not required. Consider **early discharge and oral PPI. Treat if positive for H.Pylori.**

Answer 181

Hepatitis is inflammation of the liver Acute hepatitis is defined as hepatitis within 6 months of onset Chronic hepatitis is defined as any hepatitis lasting for 6 months or longer

Answer 182

- Can be symptomatic: - General malaise - Myalgia (muscle pain) - GI upset - Abdominal pain - particularly in right upper quadrant - With/without cholestatic jaundice (pale stools, dark urine) - Tender hepatomegaly - Raised AST, ALP +/- bilirubin

Answer 183

- Infective: - Viral: - Hepatitis A and E - Herpes viruses e.g. EBV (Epstein Barr Virus), CMV (Cytomegalovirus), VZV (Varicella Zoster Virus) - Non-viral: - Leptospirosis - Toxoplasmosis - Coxiella (Q fever) - Non-infective: - Alcohol - Drugs - Toxins/poisoning - Pregnancy - Autoimmune - Hereditary metabolic

Answer 184

**Presentation:** - Can be asymptomatic e.g. hepatitis C infection - +/- signs of chronic liver disease: - Clubbing - Palmar erythema - Dupuytren’s contracture (one or more fingers bending into palm of hand) - Spider naevi - LFTs e.g. AST and ALT can be normal - Compensated liver function can be maintained with cirrhosis - If scarring is too severe then decompensated function: - Jaundice, ascites, low albumin, coagulopathy (clotting issues) and encephalopathy (confusion)

Answer 185

- Hepatocellular carcinoma (HCC) - Portal hypertension - varices and bleeding

Answer 186

- Infection: - Hepatitis B (+/- D) - Hepatitis C - Non-infective: - Alcohol - Drugs - Autoimmune - Hereditary metabolic

Answer 187

The Hepatitis A virus is a non-enveloped single-stranded RNA virus.

Answer 188

Spread via the faeco-oral route (contaminated food and water), hepatitis A belongs to the ***Hepatovirus* genus of the *Picornaviridae* family.** Hand washing and good hand hygiene are key to reducing transmission. It causes a **viral hepatitis**, and is frequently seen in travellers to endemic areas and those engaging in higher-risk sexual activities. Endemic in Africa and South America. It is uncommon in the UK. The majority of adults infected experience symptoms (approx 70-95%). Commonly a **mild self-limiting illness** manifesting with flu like symptoms, abdominal discomfort and nausea. Children under the age of 5 are frequently asymptomatic. Most infection is in childhood. Hep A is only acute, not chronic.

Answer 189

- **Travel**: those travelling to endemic areas - **Sexual**: ****high risk activities (e.g analingus, digital-rectal contact, chemsex), multiple partners - **Haematological disorders**: factor VIII and factor IX concentrates have been implicated in transmission - **Occupational risks**: for example laboratory or sewage workers - **IV drug users**: ****known to be at increased risk

Answer 190

- Hep A is a picornavirus - Replicates in the liver, is excreted in bile and then excreted in the faeces for about 2 weeks before the onset of clinical illness and for up to 7 days after - Disease is maximally infectious JUST BEFORE the onset of jaundice - Short incubation period of 2-6 weeks - Causes ACUTE HEPATITIS ONLY - 100% immunity after infection **Phases** Hepatitis A is said to follow four clinical phases (though significant variation exists). 1. **Incubation**: ****Hepatitis A has a relatively long incubation period that may last from 2 - 6 weeks (mean 28-30 days). 2. **Prodromal**: Early part of the disease, characterised by fever, joint pain and rash. Flu-like symptoms may be present 3. **Icteric**: ****In addition to jaundice, the icteric phase is characterised by anorexia, abdominal pain and change in bowel habit. 4. **Convalescent**: ****Recovery phase as the body returns to normal and symptoms subside. Symptoms like malaise may last months.

Answer 191

Hepatitis A tends to cause a mild illness characterised by a flu-like illness and GI upset.

Answer 192

- **Jaundice** - **RUQ tenderness** - **Hepatomegaly (85%)** - **Splenomegaly (15%)** - **Lymphadenopathy (5%)**

Answer 193

- **Abdominal discomfort** - **Nausea** - **Arthralgia** - **Anorexia** - **Diarrhoea** - **Flu-like illness** - **Pruritus** - **Dark urine, pale stool** - **Rash**

Answer 194

**Serology** HAV-IgM is positive soon after symptoms develop and tends to remain detectable for a few months. This signifies active infection. HAV-IgG becomes positive 5-10 days after symptoms develop and remains lifelong. This signifies either recovery or evidence of vaccination. - **+ve HAV-IgM, +ve HAV-IgG**: ****Likely acute hepatitis A infection - **+ve HAV-IgM, -ve HAV-IgG**: ****May indicate acute infection or false positive IgM - -**ve HAV-IgM, +ve HAV-IgG**: ****Indicates previous infection or vaccine based immunity - -**ve HAV-IgM, -ve HAV-IgG**: ****No evidence of infection, may be very early or still in the incubation phase

Answer 195

**Liver enzymes** - **ALT/AST**: ****Tends to be significantly elevated, between 500 and 10,000 IU/L - **Bilirubin**: Tends to be moderately elevated, between 50 and 200 micromols/L - **Prothrombin time**: ****Tends to be normal, may be elevated in complicated disease

Answer 196

Management tends to be supportive except in the most severe cases. The majority of patients do not need hospital admission. However any patient who is unwell or has significant liver impairment should be admitted and referred to hepatology. **Supportive management:** - **General points**: advise good oral hydration and rest. Alcohol should be avoided. - **Nausea**: metoclopramide (max. 5 days) or cyclizine can be given if there is no significant liver impairment. In the presence of liver impairment discuss with specialists. - **Pruritus**: chlorphenamine can be prescribed in the absence of liver impairment. In the presence of liver impairment discuss with specialists. - **Fulminant liver failure:** rarely, interferon alfa given. - **Reduce transmission**: ****stay at home, good hygiene, avoid unnecessary contact and unprotected sex for 7 days after jaundice appears or symptoms began. **Notification and protection:** Clinicians should contact their local Health Protection Unit to allow contact tracing and monitoring of outbreaks. In England hepatitis A is a ‘notifiable disease’, meaning you must notify a Proper Officer of the local authority. At risk contacts should be reviewed, if they have not been vaccinated, immunoglobulin should be considered. Typically the hepatitis vaccine will be offered.

Answer 197

Patients should be reviewed on a weekly basis for clinical review and repeat LFTs. Refer to specialist services if clinically worsening or persistently abnormal LFTs.

Answer 198

Rarely hepatitis A leads to more serious illness and complications needing specialist care: - **Relapsing hepatitis** (may occur in 5-15%) - **Fulminant liver failure** - **Prolonged cholestasis** - **Others** (interstitial nephritis, acute pancreatitis, red cell aplasia, Guillian-Barre syndrome)

Answer 199

Usually self-limiting. Fulminant hepatitis is rare. Chronicity doesn't occur (only acute)

Answer 200

Hepatitis A vaccine is recommended to those at risk of infection and at risk of complications of infection. Individuals who should be offered vaccination include: - **Travel** (to endemic areas) - **Chronic liver disease** - **Sexual** (MSM, high risk activities e.g analingus, digital-rectal contact, chemsex) - **Occupational risks** - **IV drug users** Inactivated viral vaccine. It is available as a monovalent vaccine or in combination with hepatitis B or typhoid. The contents of each vaccine and the patients allergy status must be checked. The first dose should be given at least 2-3 weeks prior to travel. Extra doses may be recommended if long term protection is needed.

Answer 201

Hepatitis B is caused by the hepatitis B virus (HBV). It is an enveloped DNA virus that belongs to the Hepadnaviridae family and can cause acute or chronic hepatitis: - **Acute**: can occur at any age. Majority of patients have a subclinical or anicteric (no evidence of jaundice) illness. In adults and older children, usually a self-limiting illness. In young children, more likely to develop chronic infection. - **Chronic**: failure to clear the virus after acute infection. Defined as persistence of hepatitis B surface antigen (HBsAg) for >6 months. HBsAg is a viral protein that can be measured in the blood. Chronic hepatitis B (CHB) can lead to cirrhosis and hepatocellular carcinoma (HCC). Incubation period of 1-6 months

Answer 202

It is a DNA virus that contains a nucleocapsid and outer envelope. Its small DNA genome is contained within the nucleocapsid. **Genome** Based on the nucleotide sequence of the 3200 base pairs, HBV is classified into eight separate genotypes termed A-H. These genotypes are distributed differently throughout the world. The predominant genotype in the UK is A. There are four major genes within the HBV genome. - **Surface (S) gene**: encodes the small surface protein HBsAg - **Core (C) gene**: encodes the hepatitis B core antigen (HBcAg), which also helps form the e antigen (HBeAg) - **Polymerase (P) gene**: encodes DNA polymerase/reverse transcriptase - **X gene**: encodes the hepatitis B x (HBx) protein **Protein products** - **HBsAg**: needed for construction of the outer HBV envelope - **HBcAg**: composed within the nucleocapsid that contains the viral DNA. - **HBeAg**: acts as an immune decoy to promote viral persistence. Presence is a marker of viral replication and infectivity. - **DNA polymerase**: involved in the synthesis of DNA molecules. Has reverse transcriptase activity, which means it can form DNA from RNA. - **X protein**: a transcriptional regulator that promotes cell cycle progression.

Answer 203

- HBV can be transmitted **perinatally, parenterally (e.g. infected needles), percutaneously or though sexual contact.** - The overall prevalence of HBV in the UK is estimated at **0.3%** - Worldwide, hepatitis B is a major health problem. An **estimated 240 million** people have chronic hepatitis B - High prevalence countries are generally defined by a prevalence > 8%. These include **Southeast Asia, China, Pacific islands and Sub-Saharan Africa.**

Answer 204

- IV drug users - Healthcare workers - Haemophiliacs - Men who have sex with men - Sexually promiscuous - Haemodialysis

Answer 205

Once infected, HBV enters hepatocytes within the liver. Within hepatocytes the viral particle removes its outer envelope and forms covalently closed circular DNA (cccDNA). This DNA forms a template for transcription of the HBV proteins. cccDNA enters the nucleus of the cell where transcription takes place. Once transcribed, core proteins, polymerase proteins and pregenomic RNA are packaged into core particles. Pregenomic RNA is then reverse transcribed into HBV DNA whilst surface proteins are attached to create the outer envelope. The full viral particle may then be secreted to infect other hepatocytes.

Answer 206

HBV is not directly cytopathic. Liver injury is due to the interaction between virus and host immune response. HBV leads to an acute infection, which is most commonly subclinical. Persistent infection leads to chronic hepatitis B, which is characterised by five phases. - **Acute infection** The majority (~70%) of patients have a subclinical or anicteric hepatitis. The remaining 30% present acutely with jaundice (icteric hepatitis). Fulminant hepatic failure is uncommon, occurring in 0.1-0.5 % of cases. Spontaneous clearance of hepatitis B is characterised by loss of HBsAg. This is usually accompanied by development of Hepatitis B surface antibodies (HBsAb or Anti-HBs), Hepatitis B core antibodies (HBcAb) and undetectable HBV DNA levels. - **Acute to chronic** Risk of progression to chronic infection has an inverse relationship with age. - **Perinatal transmission**: 90% risk of chronic infection - **Early childhood transmission**: 25-50% risk of chronic infection - **Adult transmission**: < 5% risk of chronic infection - **Chronic infection** These phases are not necessarily sequential. The five phases include: - **Phase 1 - HBeAg +ve chronic infection** (previously ‘immune tolerant’) - **Phase 2 - HBeAg +ve chronic hepatitis** (previously ‘immune reactive/clearance’) - **Phase 3 - HBeAg -ve chronic infection** (previously ‘inactive carrier’) - **Phase 4 - HBeAg -ve chronic hepatitis** (previously ‘reactivation phase’) - **Phase 5 - HBsAg negative phase** (previously ‘occult hepatitis B infection’) - recovery.

Answer 207

- Acute infection - **Subclinical** - no symptoms - **Anicteric** - non specific illness and no jaundice - Malaise, anorexia, nausea, fever, right upper quadrant pain, vomiting, arthralgia, urticarial rash - **Icteric** - presents same as anicteric, with jaundice - **Fulminant hepatitis failure** - rare, presents with jaundice, confusion and coagulopathy

Answer 208

- Chronic infection - **Asymptomatic carrier state** - **Chronic hepatitis** - wide range of symptoms depending on the severity of hepatitis and underlying liver impairment. May mimic acute hepatitis B symptoms. - **Cirrhosis** - hepatomegaly, splenomegaly, portal hypertension - **Decompensated cirrhosis** - ascites, encephalopathy, jaundice, coagulopathy and GI bleeding. - **Extra-hepatic manifestations** - polyarteritis nodosa (PAN), glomerulonephritis, mixed cryoglobulinaemia, papular acrodermatitis

Answer 209

Serology - antigens, antibodies and HBV DNA levels HBV DNA- used as markers of infectivity and also reflects hepatitis B viraemia. HBV DNA levels fluctuate during chronic infection. They are used to determine the phase of chronic hepatitis B and form part of treatment indications. HBsAg: HBV infection - acute or chronic HBeAg: High levels of HBV replication & infectivity Anti-HBe: Low levels of HBV replication and infectivity Anti-HBc (IgM): Recent HBV infection Anti-HBc (IgG): Recovered or chronic HBV infection Anti-HBs: Immunity to HBV infection (natural or vaccination) Anti-HBc (IgG) + Anti-HBs: Past HBV infection Anti-HBc (IgG) + HBsAg: Chronic HBV infection

Answer 210

- Acute infection - The majority of cases of acute hepatitis B are self-limiting so management is supportive. - Manage complications, if any - rarely, acute hepatitis B may cause a profound acute hepatitis or even fulminant hepatic failure. - Manage close contacts - HBIG and vaccine

Answer 211

- **Avoid alcohol** - **Antiviral therapy** - **Nucleos(t)ide analogues**: act primarily by inhibition of reverse transcription of pregenomic HBV RNA into HBV DNA within hepatocytes. e.g. lamivudine, entecavir, and tenofovir among others. Entecavir and tenofovir have a high barrier to resistance. Good safety profile and well-tolerated. Given orally for long-term viral suppression. May be stopped in selected cases. - **Pegylated Interferon**: PegIFN has both antiviral and immunomodulatory activity. Exact mechanism is unclear. Thought to induce specific genes that interrupt with HBV replication cycle. Given weekly as subcutaneous injection for 48 weeks. Poor tolerability due to side-effects (flu-like illness, fatigue, weight loss, psychiatric disturbance, bone marrow suppression). Contraindicated in decompensated cirrhosis. High variability in response. - **Management of cirrhosis** - **Liver transplantation** if needed

Answer 212

Patients with cirrhosis need to be screened for HCC every 6 months. In those without cirrhosis, screening is less clear cut, but should be completed in high risk patients.

Answer 213

Cirrhosis Fulminant liver failure Decompensated liver disease Hepatocellular carcinoma

Answer 214

Without treatment, the estimated 5-year incidence of cirrhosis in adults with chronic hepatitis B is up to 20%. Globally, up to 1 million patients die from hepatitis B each year. Patients who are HBeAg-negative due to seroconversion (i.e. development of Anti-HBe) with low or undetectable HBV DNA levels have better outcomes due to the slower rate of disease progression and less development of cirrhosis and HCC. Five-year survival rates among people with untreated decompensated cirrhosis can be as low as 15%.

Answer 215

- **HBV Vaccination** Within the UK, hepatitis B vaccination now forms part of the universal vaccination programme for children. The vaccine is usually given as a combination vaccine (6 in 1) at 8, 12 and 16 weeks of age. The two most widely used HBV vaccines are recombinant vaccines. **Indications for HBV vaccine** - All newborns - All children and adolescents not vaccinated at both - High risk adults (e.g. healthcare workers, intravenous drug users, haemodialysis patients, etc) **Hepatitis B immune globulin** Hepatitis B immune globulin (HBIG) is a substance that contains high levels of hepatitis B surface antibody. It can be given within hours of exposure to prevent infection. It should be given alongside the HBV vaccine.

Answer 216

Hepatitis C virus (HCV) is an infectious, hepatotropic virus belonging to the Flavivirus family. Infection may be acute and chronic.

Answer 217

- UK prevalence >20,000 - Spread via blood transfusions, IV drug abuse, sexual contact. Vertical transmission is rare.

Answer 218

- IV drug abuse - Transfusions Risk factors for progression: - Male - Older - High viral load - Use of alcohol - HIV - HBV

Answer 219

- RNA flavivirus - 7 genotypes; genotype 1a and 1b account for 70% cases in USA and 50% in Europe - Rapid mutations so envelope proteins change rapidly so its hard to develop a vaccine - Early infection is usually mild and asymptomatic. 85% develop silent chronic infection. 25% get cirrhosis in 20 years and of these, 4% get hepatocellular carcinoma

Answer 220

- Most patients are asymptomatic - 10% have mild influenza-like illness with jaundice and a rise in serum aminotransferases (ALT and AST)

Answer 221

Signs of cirrhosis, liver failure and hepatocellular carcinoma

Answer 222

- **Serology -** HCV antibody, HCV RNA (indicates current active infection, decreasing levels indicate recovery) - Other - Check for liver damage: - **LFTs** - raised AST and ALT - **Liver biopsy** - **Non-invasive elastography**

Answer 223

- Stop alcohol consumption - Acute HCV - If viral load is falling then no treatment may be required - Monitor patient to confirm viral clearance - *SC pegylated interferon-alfa 2A/B + oral Ribavirin no longer considered* - *Pegylated interferon increases risk of mental health side effects* - *Ribavirin causes haemolytic anaemia and anxiety* - Ribavirin may still be used for some harder to treat genotypes - Due to side effects and compliance issues, antiviral treatment that is interferon free is first line: - Triple therapy with direct acting antivirals (DAAs) - treatment is usually a once daily, oral tablet regimen for either 8 or 12 weeks - NS5A (initiates viral replication) inhibitor end in ASVIR e.g. ledipasvir, ombitasvir, ritonasvir - NS5B (needed for viral replication) inhibitors end in BUVIR e.g. sofosbuvir, dasabuvir

Answer 224

- Glomerulonephritis - Cryoglobulinaemia - abnormal proteins in blood - Thyroiditis - Autoimmune hepatitis - Polyarteritis nodosa (PAN) - systemic necrotising inflammation of blood vessels - Polymyositis - inflammatory disease that causes muscle weakness affecting both sides of the body - Porphyria cutanea tarda - porphyrin build up in skin

Answer 225

- **Hepatitis C prevention** - No vaccination for Hep C - Previous infection does not confer immunity - Must screen blood products prior to transfusions - Precaution when handling bodily fluids

Answer 226

Hepatitis D is caused by the defective hepatitis D RNA virus (delta virus) that needs hepatitis B for replication. Hepatitis D virus (HDV) is a unique RNA virus that can only establish infection in the human liver with the help of Hepatitis B virus (HBV). HDV has an outer envelope that contains the HBV surface antigen (HBsAg). Therefore, it can only establish infection in HBsAg-positive patients. There are two key terms to recognise with HDV infection: - **Coinfection**: acute hepatitis D infection acquired at the same time of hepatitis B infection. Typically indistinguishable from acute hepatitis B alone. - **Superinfection**: development of acute hepatitis D infection in a patient with pre-existing hepatitis B infection. Usually more severe illness and higher risk of chronic infection (>90% of cases).

Answer 227

- HDV spread through sexual contact, close household contact (e.g. abrasions, cuts, sharing toothbrushes), perinatally (although vertical transmission rare) or parenterally (e.g. contaminated needles). - Hepatitis D has a worldwide distribution with 15-20 million carriers of HBsAg infected with HDV. - Individuals with hepatitis D are always dually infected with hepatitis B. - Endemic regions include Mediterranean areas, Middle East, Central and Northern Asia, East Africa, the Amazon Basin and Pacific islands. - The UK has a low prevalence of hepatitis D (0-5%) and it is usually confined to high risk groups (e.g. intravenous drug users, historical recipients of multiple blood transfusions).

Answer 228

IV drug users

Answer 229

Like other hepatotropic viruses, HDV is not directly cytopathic and liver injury occurs due to host immune-mediated injury. Hepatitis D may lead to either acute or chronic infection - **Acute infection** - **Coinfection**: variable clinical presentation ranging from mild to fulminant hepatitis. Usually a self-limited infection as HDV will not outlive the transient HBsAg positive status. Usually indistinguishable from acute hepatitis B. As with acute hepatitis B in adults, it usually results in complete recovery and rarely causes chronic infection (<2%). - **Superinfection**: more commonly there is an overt, severe hepatitis that is occasionally fulminant (i.e. acute liver failure). May present as an exacerbation of chronic hepatitis B, or new presentation of hepatitis in a previously unknown HBsAg carrier. Likely to become chronic hepatitis D in >90% of cases. - **Chronic infection** The natural history of chronic hepatitis D is highly variable from asymptomatic to presentation with features of decompensated cirrhosis. The majority of liver damage that occurs in patients with hepatitis D and B coinfection is from HDV. This is because hepatitis D suppresses viral replication of HBV. Chronic hepatitis D is a severe disease with persistently abnormal liver biochemistry (i.e. liver function tests) and increased risk of progression to cirrhosis. Up to 80% of chronically infected patients develop cirrhosis within 5-10 years. A high proportion will subsequently die from liver-related complications (e.g. hepatocellular carcinoma, decompensated cirrhosis).

Answer 230

- **Asymptomatic carrier** Patients will be asymptomatic and usually have evidence of subclinical hepatitis (e.g. deranged liver function tests). Usually seen in patients with chronic hepatitis D. - **Hepatitis** In coinfection, symptoms are indistinguishable from acute hepatitis B. Clinical hepatitis ranges in severity and may be anicteric (without jaundice). In Superinfection there is usually a more severe hepatitis with onset of jaundice. - **Nausea** - **Vomiting** - **Anorexia** - **Malaise** - **Right upper quadrant pain** - **Fever** - **Jaundice** - **Cirrhosis** Patients who progress to chronic hepatitis D may have features of underlying cirrhosis (e.g. hepatomegaly, splenomegaly, portal hypertension). Stigmata of chronic liver disease (e.g. spider naevi) may be present - **Decompensated cirrhosis** Decompensated cirrhosis refers to an inability of the liver to carry out normal function. It is characterised by the development of ascites, encephalopathy, jaundice, coagulopathy and GI bleeding.

Answer 231

Serology - hepatitis D and B serological markers and viral levels are important to distinguish between both acute and chronic infection, as well as coinfection and superinfection. - Assessment of liver injury - - FBCs, U&Es, bone profile, CRP, coagulation tests and LFTs - Imaging - CT, US - Liver biopsy

Answer 232

- Chronic hepatitis D - Interferon alfa - usually given for a course over one year - Liver transplant indicated in some patients. Can use hepatitis B immunoglobulin and antiviral therapy to prevent reinfection after liver transplant.

Answer 233

- Cirrhosis - Decompensated cirrhosis - Hepatocellular carcinoma

Answer 234

Adult patients who develop coinfection with hepatitis D and B have a good prognosis. This is because the infection is usually self-limiting and there is a low chance of chronicity. However, superinfection is associated with a significant increase in morbidity and mortality with a very high chance of chronicity and associated complications.

Answer 235

**Hepatitis E is a small, non-enveloped RNA virus that can lead to acute and chronic hepatitis.** Now recognised as the **most common cause of acute viral hepatitis** in many countries. HEV is spread via the **faeco-oral route.** The spectrum of HEV is wide and depends on the underlying **genotype**, **patient co-morbidities** (e.g. immunosuppressed or immunocompetent) and **pregnancy status**. It can cause: - **Asymptomatic infections** - **Acute viral hepatitis** - **Chronic viral hepatitis** - **Extra-hepatic manifestations**

Answer 236

HEV belongs to the genus **Orthohepevirus** within the family **Hepeviridae**. There are four genotypes of mammalian HEV that are known to affect humans: **HEV1 and HEV2** These genotypes are **waterborne obligate human pathogens**. They usually cause epidemics of hepatitis E in developing countries and are most commonly seen in travellers returning from endemic areas. HEV1 is mostly found in Asia, while HEV2 is more commonly seen in Africa and Mexico. **HEV3 and HEV4** These genotypes are responsible for sporadic cases in developed and developing countries. In the UK, autochthonous (locally-acquired) HEV3 is the **most common cause of hepatitis E** and the genotype is widespread in Europe. HEV4 is largely restricted to Southeast Asia, but an increasing number of cases are being identified in Europe. HEV3 and HEV4 are considered a **porcine zoonotic infection**, although they have been identified in other mammalian species including rats, wild boar and rabbits. The primary host is pigs, but it is apathogenic in these animals. Eating contaminated pig meat or water can transmit the virus.

Answer 237

- There is an estimated two million locally acquired HEV infections in Europe every year. - Across Europe, there are areas of **hyperendemic HEV** (predominantly genotype 3). These include Southwest France, Netherlands, Scotland, western Germany, Czech Republic, Abruzzo, central Italy and western/central Poland. - Genotypes 1 and 2 are more prevalent in developing countries. - Commoner in men - Commoner than HAV in UK - Can be harmful in pregnancy, causing death.

Answer 238

HEV is transmitted via the faeco-oral route. HEV1 and HEV2 are generally transmitted through **contaminated water**, whereas HEV3 and HEV4 are considered **zoonotic infections**, acquired from infected animals (usually contaminated meat or infected water from the run off of slurry). Once acquired, the incubation period is 2-6 weeks. This describes the **period between exposure to the virus and development of clinical symptoms**. HEV viraemia reaches its peak during the early infectious period, which is associated with a transient rise in IgM (acute antibody response) followed by a more sustained IgG response. During this acute infection, viral RNA may be detected in the blood or stool. It disappears from the blood within 3 weeks. The narrow viraemic window means the absence of viral RNA does not exclude acute infection. The vast majority have a **subclinical infection**. In fact, < 5% of patients with HEV3 will develop clinical hepatitis. Patients who do develop a clinically apparent acute infection usually have a self-limiting illness. However, the condition is associated with several extrahepatic manifestations. In patients with pre-existing liver disease, there is an increased risk of decompensated cirrhosis or acute on chronic liver failure (ACLF). Patients who are immunosuppressed are at risk of chronic infection (presence of HEV for > 3 months) and accelerated liver disease.

Answer 239

The majority of patients with acute hepatitis E will have a subclinical (asymptomatic) illness. - Acute hepatitis - **Jaundice** - **Fatigue** - **Nausea & vomiting** - **Abdominal pain** - **Pruritus** - **Flu-like illness** - **Hepatomegaly**

Answer 240

- **Commonly asymptomatic** - **Fatigue** - **Rarely jaundiced**

Answer 241

- Primary investigations - **Serology -** IgM shows active infection; IgG shows recovery - **Presence of HEV RNA -** detected using PCR. Due to viraemic window, this may be negative but a negative result doesn't exclude HEV. - **LFTs -** elevated AST and ALT - Other - **HEV antigen assay -** check for presence of HEV antigen - **Non-invasive liver screen if LFT's deranged**

Answer 242

- **Supportive treatment** In the majority of patients, acute hepatitis E will **clear spontaneously**. Advice consists of good oral hydration and rest. Alcohol should be avoided. - **Management of complications, if any:** e.g. acute liver failure or chronic liver disease - Other - **Anti-viral therapy** **Ribaviron is the anti-viral therapy of choice** and usually reserved for patients with chronic hepatitis E that has failed to clear spontaneously. Chronic hepatitis E most commonly occurs in immunosuppressed patients so the first management strategy is reduction in immunosuppression if possible. If this fails to clear the virus, ribaviron can be considered. - **Liver transplantation** Chronic hepatitis E may lead to progressive fibrosis/cirrhosis. Liver transplantation is a potential option in these patients.

Answer 243

**Hepatic complications** - **Fulminant hepatitis in pregnancy** (20% mortality) - **Decompensated cirrhosis or ACLF** - **Acute liver failure** - **Rapidly progressive fibrosis** (chronic hepatitis E) **Extrahepatic complications** - **Neurological**: wide variety of neurological problems associated with hepatitis E (e.g. Guillain-Barré syndrome, brachial neuritis, mononeuritis multiplex, meningoencephalitis). - **Haematological**: thrombocytopaenia, MGUS, cryoglobulinemia - **Renal**: glomerulonephritis - **Other**: pancreatitis, autoimmune thyroiditis, polyarthritis, among others.

Answer 244

Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver of unknown aetiology. It is characterised by the presence of circulating auto-antibodies with a high serum globulin concentration, inflammatory changes on liver histology, and a favourable response to immunosuppressive treatment.

Answer 245

- A rare condition, with a prevalence of 1 in 10,000 individuals in the UK - **Gender:** affects females more often than males (4:1) - **Age:** type 1 AIH mainly affects adults whereas type 2 AIH affects children

Answer 246

- Associated with other autoimmune conditions such as, Hashimoto's thyroiditis and primary biliary cholangitis - HLA-DR3 and HLA-DR4 association

Answer 247

Autoimmune Hepatitis (AIH) is a rare, **chronic autoimmune liver disease** which can progress to cirrhosis. The aetiology is unclear and seems to be due to an interplay between **environmental** and **genetic** factors. Some HLA haplotypes (HLA-DR3 and -DR4) are associated with the disease as shown in the table below. Most cases present with **no identifiable precipitant** although viral infection (e.g. hepatitis A) or medication (e.g. nitrofurantoin) have been proposed as possible triggers in some cases. Associated antibodies include antinuclear antibody **(ANA)**, anti-smooth muscle antibody **(ASMA)**, anti-soluble liver antigen/liver-pancreas antibody **(anti-SLA/LP)**, anti-liver kidney microsome antibody **(anti-LKM1)** and anti-liver cytosol 1 antibody **(anti-LC1)**. Upto 25% of cases may not have detectable antibodies. There are two different types of autoimmune hepatitis, as seen below. Both produce different antibodies. Essentially, these antibodies attack self-antigens and cause hepatitis.

Answer 248

25% of cases are asymptomatic and patients may be asymptomatic even if their disease has progressed to cirrhosis. If symptoms are present, most cases present with non-specific symptoms. - Signs **Evidence of chronic liver disease:** - Jaundice - Spider telangiectasia - Gynaecomastia - Splenomegaly **Evidence of acute liver failure (less common):** - Jaundice - Ascites - Variceal bleed - Encephalopathy - Symptoms **Generalised symptoms:** - Fatigue - Fever - Malaise - Urticarial rash - Arthralgia - Weight loss - Nausea - Amenorrhoea

Answer 249

- Primary investigations - **LFTs:** elevated ALT and AST with normal or mildly elevated ALP. Bilirubin may also be raised - **FBCs:** anaemia, low WCC, low platelets - **Immunoglobulins:** IgG is raised in 85% of patients - **Liver biopsy:** performed on all patients. Interface hepatitis (inflammation of hepatocytes at the junction of the portal tract and hepatic parenchyma), also known as piecemeal necrosis, is seen in up to 98% of patients. - **Viral** **screen:** exclude a viral cause for the hepatitis (e.g. EBV, CMV, and hepatitis A, B, C, E) - **Autoimmune** **screen:** ANA, anti-SMA, Anti-SLA/LP, anti-LKM1, Anti-LC1 - **Hereditary** **Screen:** exclude metabolic causes e.g. hereditary hemochromatosis and Wilson’s disease - Other investigations to consider - **Liver ultrasound:** exclude biliary disease and can identify features consistent with chronic liver disease and cirrhosis - **MRCP:** helps exclude primary sclerosing cholangitis, if ALP disproportionately high.

Answer 250

- 1st line - **Immunosuppression:** prednisolone **and** azathioprine are given together as first-line therapy to induce remission. Upon biochemical and histological remission, patients may stop treatment or go onto long term azathioprine maintenance therapy. - Prednisolone (suppresses immune response) and azathioprine (inhibits DNA synthesis - targets the rapidly proliferating B and T cells) - Alternate regimes are possible which involve budesonide or mycophenolate, for example - **Hepatitis A and B vaccines**: recommended in all patients - 2nd line - **Transplantation:** may be needed in refractory cases where biochemical or histological remission is not achieved

Answer 251

- **Cirrhosis:** approximately 30% of patients already have cirrhosis at presentation - **Hepatocellular carcinoma:** 4-6% risk and some patients may be screened regularly with AFP and liver ultrasounds - **Iatrogenic:** - **Osteoporosis:** steroids increase the risk of osteoporosis along with chronic liver disease. DEXA scans should be conducted 1-2 yearly whilst on steroids - **Cushing's syndrome:** associated with long-term steroid use

Answer 252

Relapses are common and within 12 months of stopping treatment, following biological and histological remission, 50-90% of patients experience a relapse. 10-20% of patients will require a transplant. Nevertheless, the overall prognosis is good with a 10-year survival in excess of 90%

Answer 253

Gastroenteritis is inflammation all the way from the stomach to the intestines and presents with nausea, vomiting and diarrhoea.

Answer 254

- 2nd leading cause of death in children under 5 globally - after Pneumonia - Highest prevalence in South Asia and Africa

Answer 255

- **Viral causes** (most common) - **Rotavirus** - leading cause of diarrhoea illness in young children, affects nearly all children by the age of 4 - **Norovirus** - most common among adults. Associated with; cruise ships, hospitals, restaurants - close proximity of people - **Adenovirus:** a less common cause and presents with a more subacute diarrhoea - **Astrovirus** - **Bacterial causes** - **Campylobacter jejuni** (most common, associated with poultry) - Most common bacterial cause of gastroenteritis worldwide. - Common cause of travellers diarrhoea. - Spread by raw or improperly cooked poultry, untreated water, unpasteurised milk - **E.coli -** more common in children - Spread through contact with infected faeces, unwashed salads or water. - **Enterotoxigenic E.coli** main cause of travellers diarrhoea - E. coli 0157 produces the **Shiga toxin.** This causes abdominal cramps, bloody diarrhoea and vomiting. The Shiga toxin destroys blood cells and leads to **haemolytic uraemic syndrome** - **Salmonella** - more common in children - Spread by eating raw eggs or poultry and food contaminated with infected faeces of small animals - **Shigella spp.** - more common in children - Spread by faeces contaminating drinking water, swimming pools and food. - Shigella can produce the **Shiga toxin** and cause **haemolytic uraemic syndrome.** - **Bacillus cereus** - Spread through inadequately cooked food, typically fried rice left out. - Produces a toxin called **cereulide** that causes abdominal cramping and vomiting - When it arrives in the intestines it produces different toxins that cause a watery diarrhoea. - **Yersinia enterocolitica** - Eating raw or undercooked pork can cause infection. - Also spread through contamination with the urine or faeces of other mammal such as rat and rabbits. - **Vibrio cholerae** - Spread via faecal-oral route - Produces rice water stools - **Antibiotic related** - in general, antibiotics beginning with C can give rise to antibiotic induced **Clostridium difficile** diarrhoea: e.g. clindamycin, ciprofloxacin (Quinolones), co-amoxiclav (Penicillins), cephalosporins - Clostridium difficile replaces normal gut flora (e.g. when normal gut flora die due to antibiotic use) and causes necrosis giving rise to pseudomembranous colitis. This results in diarrhoea - **Parasitic causes** - **Giardia lamblia** - most common - Spread via faecal-oral route - **Entamoeba histolytica** - **Cryptosporidium**

Answer 256

- Foreign travel - PPI or H2 antagonist use - Crowded area - Poor hygiene Risk factors for pseudomembranous colitis: - Elderly - Antibiotics - Long hospital admission - Immunocompromised i.e. HIV - Acid suppresion (e.g. with PPI or H2 antagonist)

Answer 257

- **Bloody diarrhoea** - associated with bacterial infection (salmonella, shigella, e.coli) - **Vomiting** - **Abdominal cramping** - Some causes (especially viral) present with: - **Fever, fatigue, headache, muscle pain**

Answer 258

- **Bloods -** - Low MCV and/or Fe deficiency e.g. in coeliac disease or colon cancer - High MCV if alcohol abuse or decreased B12 absorption e.g. coeliac disease or Crohn’s - Raised white cell count if parasites - Raised CRP, WCC and low albumin if C.diff - Raised ESR and CRP indicate infection, Crohn’s, UC or cancer - U&E: hypokalaemia in severe diarrhoea and vomiting - **Stool MCS** - establish the causative organism and antibiotic sensitivities - **Abdominal xray** - for toxic megacolon in case of C.diff - **Sigmoidoscopy with biopsy**

Answer 259

- Appendicitis - Volvulus - IBD - UTI - Diabetes mellitus - Pancreatic insufficiency - Short bowel syndrome - Coeliac disease - Laxative abuse

Answer 260

- Isolate patient - Good hygiene - Treat causes - IV fluids if severely dehydrated - Oral rehydration and avoid high-sugar drinks in children (increases diarrhoea) - Antibiotics, where appropriate - Anti-motility agents e.g Loperamide - Anti-emetics - treat vomiting e.g. Metoclopramide - C.diff management - Metronidazole - Oral vancomycin - Rifampicin/Rifaximin - Stop C antibiotic - Stool transplant - for recurrent disease - Urgent colectomy if toxic megacolon

Answer 261

Haemochromatosis is a multisystem disorder of dysregulated dietary iron absorption and increased iron release from macrophages.

Answer 262

- Type 1 (HFE-related) hereditary haemochromatosis most commonly occurs in individuals of northern European descent (1 in 10 people carry a mutation). - It affects 1 in 200 European people. - Middle age: most commonly presents at 40-50 years old. - Men present earlier than women, due to menstruation being a protective mechanism.

Answer 263

- HFE gene mutation on chromosome 6. Autosomal recessive gene. - High intake of iron and chelating agents e.g. ascorbic acid - Alcoholics may have iron overload - Chronic transfusions

Answer 264

- **Family history** - **Alcoholism** - **History of chronic transfusion**: only relevant in **acquired** haemochromatosis, for example in patients with thalassaemia

Answer 265

Hereditary haemochromatosis describes an **autosomal recessive** defect in iron absorption due to a mutation in the **HFE** gene on chromosome 6, resulting in **iron overload**. **C282Y** and **H63D** are the two main missense mutations associated with hereditary haemochromatosis. Acquired haemochromatosis, on the other hand, usually occurs due to frequent transfusions of red blood cells or excessive intake of iron. The HFE gene protein interacts with the transferrin receptor 1, which is a mediator in intestinal iron absorption. Iron is taken up by the mucosal cells of the small intestine inappropriately, exceeding the binding capacity of transferrin. Hepcidin, a protein synthesised in the liver, is central to the control of iron absorption; it is increased in iron deficiency states and decreased with iron overload. Hepatic expression of the hepcidin gene is decreased in HFE haemochromatosis thereby facilitating iron overload. In physiological states, the absorption of iron from the duodenum is tightly controlled. In haemochromatosis, this process is disrupted and there is **unregulated absorption of iron** from the gut resulting in iron overload. Iron deposition in multiple tissues and organs leads to disruption of function, most commonly affecting the **liver**, **pancreas**, and **heart**.

Answer 266

Patients are usually asymptomatic, especially in early stages. - Signs - Skin hyperpigmentation (bronze skin) - Arthritic joints - Testicular atrophy - Features of chronic liver disease e.g. hepatomegaly - Features of congestive cardiac failure e.g. peripheral oedema due to dilated cardiomyopathy - Signs of osteoporosis

Answer 267

- Early symptoms: lethargy, arthralgia (often in hands) and erectile dysfunction - Loss of libido: hypogonadism due to cirrhosis and pituitary dysfunction - Polyuria and polydipsia due to T1DM

Answer 268

- Check serum ferritin: will be high in patients with haemochromatosis. But, may also be high in other conditions so is non-specific - Check serum transferrin saturation: if this is also high, can confirm that high serum ferritin was due to haemochromatosis and not other causes. - Refer to secondary care

Answer 269

- First line **Blood tests**: - **Serum transferrin saturation**: elevated; see table below - **Serum ferritin**: elevated; often normal in early disease - **Serum** **iron**: elevated - **LFTs**: liver function may be deranged secondary to iron deposition - **HbA1c**: elevated due to damage to pancreatic beta cells - **Initial screening**: requires FBC, transferrin saturation, serum ferritin **and** serum iron - Other investigations **Genetic testing:** - Test for C282Y and H63D mutations associated with HFE gene; for testing **family members** or symptomatic north European patients with the abnormal iron studies above **Liver biopsy:** - This is the most specific test and will show evidence of iron accumulation using Prussian blue (Perls) staining, whilst also assessing for fibrosis and cirrhosis - No longer required for diagnosis **CT abdomen:** - Increased attenuation of liver **MRI:** - Gives detailed picture of iron deposition on liver and heart. **ECG and echocardiogram:** - Assess for evidence of cardiomyopathy and/or heart failure **Joint X-rays:** - Characteristically demonstrate **chondrocalcinosis (calcium deposits in joints)** **Family screening:** - All first degree relatives are screened with iron studies and, if deranged, should proceed to genetic testing

Answer 270

**Venesection:** first-line management - Involves draining a small amount of blood, usually around 500 ml - Initially offer weekly venesection until serum ferritin levels are **20–30 lg/l** and **transferrin saturations <50%** - Following this, offer **maintenance phlebotomy**, depending on the rate of iron re-accumulation - **Aims of maintenance phlebotomy:** normal FBC, serum ferritin <50 lg/l and transferrin saturations < 50% **Lifestyle:** - Patients should be advised to avoid alcohol and have a low iron diet **Iron chelation:** - Desferrioxamine can be used for patients with a contraindication to phlebotomy, such as severe anaemia

Answer 271

- Monitor serum ferritin - Monitor and treat complications

Answer 272

- **Liver** - **Cirrhosis** - **Hepatocellular carcinoma**: requires regular screening - **Endocrine** - **DM:** due to damage to pancreatic beta cells - **Hypogonadism**: secondary to liver cirrhosis (increased oestrogens) and pituitary dysfunction. Can result in loss of libido and erectile dysfunction - **Cardiac** - **Dilated cardiomyopathy** - **Congestive cardiac failure** - **Musculoskeletal** - **Pseudogout** - **Osteoporosis** - **Dermatological** - **Skin hyperpigmentation**

Answer 273

The prognosis associated with hereditary haemochromatosis depends on the degree of iron overload. The mean survival is approximately 20 years from diagnosis, whilst early diagnosis and intervention can significantly improve outcomes. Liver cirrhosis and subsequent hepatocellular carcinoma is the most common cause of death. Therefore, patients require regular liver function tests and, if deranged, serum AFP and a liver ultrasound should be arranged.

Answer 274

Wilson's disease is an autosomal-recessive disease of copper accumulation and copper toxicity caused by mutations in the ATP7B gene, which is part of the biliary excretion of copper pathway.

Answer 275

- Wilson’s disease has a worldwide incidence of 30 cases per million. - **Adolescence**: the mean age of onset is 17 years old, and the mean age of diagnosis is 20 years old.

Answer 276

- Family history: suggests inherited mutations in the ATP7B gene

Answer 277

Wilson’s disease is a rare, **autosomal recessive** disorder of **copper accumulation** and toxicity. It occurs due to mutations in the **ATP7B** gene on chromosome 13, resulting in **dysfunction in ATP-mediated hepatocyte copper transport**. The condition is characterised by **increased copper absorption from the small intestine** and **decreased hepatic copper excretion**. Dysfunction in ATP-mediated hepatocyte copper transport causes a lack of copper transport into the bile and a lack of incorporation into ceruloplasmin, resulting in reduced biliary excretion of copper. There is subsequent copper accumulation in **hepatocytes**, as well as leakage into serum causing raised free serum copper levels. The excess copper then accumulates in other tissues such as the **basal ganglia**, **kidney**, and **cornea**, causing oxidative damage.

Answer 278

3 main effects: - **Hepatic issues** - **Neurological issues** - **Psychiatric issues**

Answer 279

- **Neurological** - **Behavioural and psychiatric issues**: such as depression and delusions, often the first presentation. Also, loss of libido and bad memory. - **Parkinsonism**: half of patients present with a tremor - **Asterixis** - **Chorea** - **Dysarthria** - **Dystonia** - **Dementia** - **Hepatic** - **Hepatosplenomegaly** - **Hepatitis and cirrhosis** - **Jaundice** - **Ascites** - **Asterixis and encephalopathy** - **Renal** - **Renal tubular acidosis** - **Fanconi syndrome** - **Opthalmological** - **Kayser-Fleischer rings:** copper ring in iris. - **Haematological** - **Haemolytic anaemia** - **Other** - **Blue nails** - **Arthritis** - **Grey skin** - **Hypermobile joints**

Answer 280

- Primary investigations - **Copper studies:** - **Reduced** ceruloplasmin and **increased** 24 hour urinary copper excretion is highly suggestive of Wilson’s disease. - Ceruloplasmin may be raised in cancer or inflammation, so other investigations are needed for diagnosis. - **Increased free** serum copper but **reduced total** serum copper. Remember, copper is normally bound to ceruloplasmin. Reduced ceruloplasmin means there is more free copper but a total reduction in the amount of copper in the blood - **LFTs:** deranged liver function due to copper accumulation resulting in hepatitis, which particularly causes an increase in AST and ALT - **Genetic testing:** ATP7B mutation; perform for all patients to confirm the diagnosis and facilitate family testing

Answer 281

Liver biopsy to test for copper content.

Answer 282

- **Liver biopsy:** used to assess for hepatic copper accumulation, hepatitis and cirrhosis - Only required if the clinical signs and initial tests are inconclusive - **MRI brain:** structural abnormalities within the basal ganglia - **Slit lamp exam:** look for Kayser-Fleischer rings. - **Family screening:** first degree relatives should be screened with LFTs, copper studies, and genetic analysis

Answer 283

- 1st line **Copper chelation:** usually the first-line treatment. Chelators bind copper and facilitate renal excretion; **D-penicillamine** is most commonly used - **Trientine hydrochloride**: an alternative chelating agent - Other - **Lifestyle advice:** high copper content foods such as shellfish should be avoided. However, dietary restriction cannot be used as sole therapy. - **Liver transplantation:** indicated in acute liver failure or decompensated cirrhosis

Answer 284

Monitor FBC, urinary copper and protein excretion.

Answer 285

- **Liver failure:** patients can present with acute liver failure or decompensation of pre-existing chronic liver disease. This may necessitate transplantation - **Renal stones:** secondary to hypercalciuria - **Renal failure**: often due to D-penicillamine therapy, rather than the disease itself - **Side effects of medication:** nausea, rash, haematuria, nephrosis, lupus and reduced WCC, platelets and Hb.

Answer 286

If detected and treated early, many patients can live a normal life with a normal life expectancy. Chelation therapy can reverse symptoms related to early liver and some neurological damage.

Answer 287

Alpha-1 antitrypsin deficiency is a rare autosomal recessive disorder that causes liver and pulmonary disease. A1AT is a type of serine protease inhibitor. Deficiency is called serinopathy.

Answer 288

- A1AT deficiency is most common in people of European ancestry and is uncommon in people of Asian descent. - Worldwide, there are > 3 million people affected by AATD. - Equal sex prevalence. - There is a bimodal distribution in clinical presentation. In neonates, AATD may cause hepatitis and in children it can cause decompensated cirrhosis. In adults, it is most commonly seen in the fifth decade of life with features of liver and/or lung disease.

Answer 289

Family history: there may be a family history of early-onset COPD and/or AAT deficiency

Answer 290

Alpha-1 antitrypsin (A1AT) is a **protease inhibitor** made in the liver which predominantly acts to protect the lungs from neutrophil elastase. A1AT deficiency is a common inherited condition caused by a deficiency in A1AT, resulting in **protease-mediated damage**, particularly in the lungs. The mutation is located on chromosome 14 and is inherited in an **autosomal recessive/co-dominant** fashion. - **Genetics** The severity of the disease depends on the mutation of the protease inhibitor (Pi) allele. **PiM is the normal allele** with 2 copies expressed, giving the genotype PiMM. **A1AT deficiency** is associated with various abnormal alleles, of which the most clinically relevant are **PiS** and **PiZ**. The table below is a simplified summary, however, to complicate matters heterozygous genotypes such as PiMZ also exist. - **M**: normal - **S**: slow - **Z**: very slow - **Liver effects** Patients with the PiZZ genotype are particularly at risk of liver cirrhosis. The mutation causes a change in the structure of the A1AT protein, resulting in aggregation and accumulation within hepatocytes as the protein is misfolded and gets stuck in the endoplasmic reticulum. This causes cell death leading to liver damage with jaundice, hepatitis, cirrhosis, and hepatocellular carcinoma. - **Lung effects** Normally, neutrophil elastase (also induced by smoking) destroy harmful causes of infection and inflammation, but can also destroys the elastin in the alveoli. A-1 antitrypsin usually regulates the elastase, but with an A1AT deficiency the elastase is able to destruct the elastin in the lungs. The disease primarily affects the lungs due to dysregulation of proteases leading to parenchymal destruction and subsequent panacinar emphysema, most severe in the lower lobes. This is in contrast to smoking which causes centriacinar emphysema, most prominent in the upper lobes. Acinus is the functional unit of the lung consisting of a bronchiole and its alveolus. Panacinar means that the entire unit is affected, whereas centriacinar means only the central part is affected.

Answer 291

- Key Presentations Early onset of COPD symptoms - Symptoms - **Respiratory** - Dyspnoea and productive cough - Prolonged expiratory phase and wheeze with pursed-lip breathing - Weight loss - Barrel chested due to hyperexpanded lungs - **Liver** *(liver symptoms only occur with certain genotypes that cause a misfolded protein that gets stuck in the endoplasmic reticulum of hepatocytes)* - Jaundice - Hepatomegaly - Ascites - Inability to make coagulation factors - Buildup of toxins leading to hepatic encephalopathy - Portal hypertension and consequent complications

Answer 292

- **Serum A1AT levels:** reduced with levels < 20 micromol/L - **Chest X-ray:** hyperinflated lung fields - **Lung Function Tests:** obstructive pattern with FEV1/FVC < 0.7 - **LFTs:** deranged and must be monitored due to the risk of hepatocellular carcinoma - **Liver biopsy:** Stained with Periodic acid Schiff (PAS) which stains A1AT pink, and Diastase, which should destroy A1AT. If A1AT is mutant and stuck in ER, it will not respond to diastase = Periodic acid Shiff +ve and diastase resistant. - **CT chest:** panacinar emphysema, most significantly in the lower lobes - **Genetic tests:** allows identification of the mutated allele and the patient’s genotype, e.g. PiZZ

Answer 293

- Asthma - COPD - Bronchiectasis - Viral hepatitis - Alcoholic liver disease

Answer 294

- Respiratory - **Smoking cessation:** all patients should be advised regarding smoking cessation as this reduces the risk of respiratory disease - **COPD treatment:** if there is evidence of pulmonary disease, patients should be treated with short and long-acting bronchodilators, as well as inhaled corticosteroids, as per COPD guidelines. - **A1AT augmentation:** patients with markedly low A1AT levels with evidence of respiratory disease may be commenced on intravenous A1AT - **Surgery**: lung volume reduction surgery, or lung transplantation for end-stage, refractory lung disease - Liver - **Alcohol avoidance** - **Hepatitis A and B vaccinations** - **Liver transplantation**: for end-stage, refractory liver disease

Answer 295

- **Respiratory failure:** much like COPD, these patients are at risk of respiratory failure, particularly type 2 respiratory failure - **Cirrhosis and hepatocellular carcinoma:** patients should have their LFTs monitored and if there is any derangement, a serum AFP and CT abdomen should be performed to assess for malignancy - **Cholestasis**: usually in children

Answer 296

The vast majority of deaths secondary to A1AT deficiency are due to respiratory failure rather than liver failure. The median age of death is 40 years old in smokers and 65 years old in non-smokers, thus highlighting the importance of smoking cessation.

Answer 297

Liver tumours may be primary or secondary. Most commonly, liver tumours are a result of metastases (90%) Primary liver tumours are less common and may be benign or malignant, but most commonly are malignant.

Answer 298

Malignant: Hepatocellular carcinoma Cholangiocarcinoms Benign: Hemangiomas Adenomas

Answer 299

Primary hepatocyte neoplasia. Accounts for 90% of primary liver cancers.

Answer 300

- Common in China and Africa - 2% prevalence in UK - M>F

Answer 301

- HBV - leading cause worldwide especially, if high viral load - HCV - Autoimmune hepatitis - Cirrhosis - NAFLD - Aflatoxin - Clonorchis sinensis - Anabolic steroids

Answer 302

- HBV - HCV - Cirrhosis

Answer 303

- Tumour is either single or occurs as multiple nodules throughout the liver - Consists of cells resembling hepatocytes - It can metastasise via the hepatic or portal veins to the lymph nodes, bones and lungs

Answer 304

- Signs - Palpation - enlarged, irregular, tender liver may be felt - Signs of chronic liver disease - Signs of decompensation - jaundice (will appear late), ascites - Listen for bruit - murmur over the liver

Answer 305

- Symptoms - Fever - Malaise - Fatigue - Loss of appetite - Weight loss - RUQ pain - Jaundice - Ascites - Haemobilia - bleeding into biliary tree

Answer 306

- CT - to identify HCC but hard to confirm diagnosis if the lesion is less than 1cm. Usually used to confirm diagnosis if lesion is large enough - Ultrasound - to identify lesions - MRI - to distinguish between benign and malignant - Biopsy - used less now due to potential seeding of tumour along biopsy tract and since imaging is better - Blood: FBC, clotting, LFT, hepatitis serology, serum alpha-fetoprotein may be raised

Answer 307

- Resect solitary tumours - Liver transplant - Percutaneous ablation (radiowaves destroy tumour), tumour embolisation (TACE - to restrict tumours blood supply) and sorafenib (kinase inhibitor) are also treatment options

Answer 308

- HBV vaccination - Don't reuse needles - Screen blood - Reduce aflatoxin exposure - Monitoring Consider monitoring in high risk patients e.g. patients with cirrhosis, chronic HBV in Africans or older Asians - **AFP +/- ultrasound (6-monthly screen)**

Answer 309

Biliary tree cancer. Makes up 10% of the primary liver cancers.

Answer 310

- Associated with infestation with parasitic worms (flukes) e.g. *Clonorchis sinensis* - Primary sclerosing cholangitis - Biliary cysts - Caroli's disease - genetic condition that causes the bile ducts in the liver to be wider than usual - HBV - HCV - Diabetes mellitus - N-nitroso toxins (carcinogenic)

Answer 311

- Inflammatory bowel disease - HBV - HCV - Infection with parasitic worms (flukes)

Answer 312

Usually slow-growing cancers. Most are distal extrahepatic or perihilar

Answer 313

- Signs - Palpation - enlarged, irregular, tender liver may be felt - Signs of chronic liver disease - Signs of decompensation - jaundice, ascites - Listen for bruit - murmur over the liver - Symptoms - Fever - Weight loss - Abdominal pain +/- ascites - Malaise

Answer 314

- **CT and ultrasound** - to identify lesions - **MRI** - to distinguish between benign and malignant - **Biopsy** - may achieve histological diagnosis - **ERCP** - **Blood:** FBC, clotting, LFT, hepatitis serology, serum alpha-fetoprotein may be raised, raised bilirubin, raised ALP

Answer 315

- **Surgery (not possible in 70% of patients at presentation)** - e.g. major hepatectomy, extrahepatic bile duct excision and caudate lobe resection - **Purcutaneous stenting or ERCP** - stenting of obstructed extrahepatic bililary tree improves QOL - **Liver transplantation**

Answer 316

Post-op complications: - Liver failure - Bile leak - GI bleeding

Answer 317

70% are inoperable at presentation. Those that are operable, around 76% recur. 5-yr survival post-op = 30%

Answer 318

- Commonest benign tumour - Usually small and single but can be multiple and large - Often incidental finding on US or CT - Don't require treatment

Answer 319

- Common - Caused by anabolic steroids, oral contraceptive pill, pregnancy - Can present with abdominal pain or intraperitoneal bleeding - Only treat if symptomatic or >5cm

Answer 320

- Most common liver tumour is secondary (metastatic tumour) - Mainly from breast, bronchus and GI tract - Secondary liver tumours are usually multiple and they signify advanced disease

Answer 321

Primary cancer elsewhere

Answer 322

- Variable, depending on primary cancer - Generic features include: - Weight loss - Malaise - Upper abdominal pain - Hepatomegaly +/- jaundice

Answer 323

- Ultrasound is primary investigation - Use CT, MRI, marrow biopsy, CXR, mammography, colonoscopy etc to find primary cancer - Bloods: present similar to primary liver tumours

Answer 324

- Depends on site of the primary and the burden of liver metastases - Removal of primary tumour and hepatic resection - Small, solitary metastases may be amenable to resection - Chemotherapy may be used - e.g. in lymphomas and germ cell tumours - Palliative care

Answer 325

Varies with type and extent of primary tumour. Prognosis is often <6 months.

Answer 326

'Pancreatic cancer' refers to primary pancreatic ductal adenocarcinoma, which accounts for >85% of all pancreatic neoplasms. These adenocarcinomas usually affect the head of the pancreas, but sometimes the body and tail. Some are multifocal.

Answer 327

- In females in the UK, pancreatic cancer is the 9th most common cancer. In males in the UK, it is the 12th most common cancer. - The estimated incidence of pancreatic cancer is 10 per 100,000 individuals - 9000 deaths/ year in the UK. - Most common at 65-75 years of age

Answer 328

- **Male** - **Family history** - **Smoking** - **Alcohol** - **Obesity** - **Diet high in red meat** - **Diabetes**: a risk factor and a potential consequence of pancreatic cancer - **Chronic pancreatitis** - **Genetic:** hereditary non-polyposis colorectal carcinoma, BRCA1 and BRCA2 mutations, Peutz-Jeghers syndrome - **Multiple endocrine neoplasia**

Answer 329

Pancreatic cancer develops from pre-invasive pancreatic intraepithelial neoplasia, which can eventually become an invasive ductal adenocarcinoma. Other precursor lesions include mucinous cystic and papillary mucinous neoplasms. Over 90% of cases carry a faulty K-RAS gene (a proto-oncogene), while more invasive subtypes tend to also carry CDKN2A (p16), p53 and SMAD4. Most pancreatic cancers metastasise early and present late. 60% arise in pancreatic head, 25% in the body and 15% in tail.

Answer 330

- **Positive Courvoisier’s sign:** In the presence of painless obstructive jaundice, a palpable gallbladder is **unlikely** to be due to gallstones - **Trousseau sign of malignancy:** migratory thrombophlebitis (blood clots felt as small lumps under skin) - Symptoms - **Painless jaundice** - **Non-specific symptoms:** - Epigastric or atypical back pain, anorexia, weight loss; these features are common - **New-onset diabetes**: - Thirst, polyuria, nocturia, weight loss - Due to the loss of endocrine function - **Nausea and vomiting** - **Steatorrhoea:** due to loss of exocrine function fats are not digested - **Dark urine and pale stools:** due to obstructive jaundice - **Cancer related anorexia** - **Acute pancreatitis**

Answer 331

- **LFTs:** likely an obstructive picture with raised ALP, GGT and bilirubin - **Coagulation profile:** assess the synthetic function of the liver to determine the possibility of liver metastasis - **CA 19-9:** will be raised but is non specific - so can be used to monitor disease progression but is **not** diagnostic. - Serum lipase and serum amylase may also be raised, but this is non-specific - **Abdominal ultrasound:** first-line imaging (60-90% sensitivity) and if any suspicion proceed to CT. However, a normal ultrasound does **not** exclude cancer - **CT chest, abdomen and pelvis**: investigation of choice and also useful in staging; CT pancreatic protocol is 97% diagnostic - Other investigations to consider - **PET CT:** NICE recommend performing a PET scan if CT is inconclusive - **Endoscopic ultrasound**: used if CT is inconclusive and allows fine-needle aspiration. Useful at identifying small tumours - **ERCP**: used if CT is inconclusive and allows for biliary drainage at the same time as tissue sampling - **MRCP:** typically not required if the above tests are performed

Answer 332

- Localised tumour - **Surgical resection:** - Less than 20% are suitable for surgery at diagnosis - **Whipple’s resection**: pancreaticoduodenectomy for resectable lesions of the head of the pancreas. This removes the antrum of the stomach, proximal duodenum, head of the pancreas, common bile duct and gallbladder - **Laparoscopic excision:** easiest for tail lesions - **Adjuvant chemotherapy**: offered after surgery. - **Neoadjuvant chemotherapy** (before surgery to shrink tumour) may also be offered

Answer 333

- Locally advanced or metastatic **Palliative management:** - **ERCP with stenting**: for symptomatic relief of obstructive jaundice in patients with unresectable and metastatic tumours - **Chemotherapy/chemoradiotherapy**: offered if patients are able to tolerate it - **Management of pain:** opiates or radiotherapy

Answer 334

**Cancer-related:** - **Venous Thromboembolism (VTE):** pancreatic adenocarcinoma is thrombogenic and patients are at increased risk of DVT and PE - **New-onset diabetes mellitus:** reduced endocrine function due to cancer growth, as well as surgical resection - **Cholangitis:** obstruction of biliary drainage due to a head of pancreas cancer predisposes to biliary tree infection **Surgery-related:** - **Dumping syndrome**: occurs when sugar moves too quickly into the small bowel - **Early dumping syndrome:** occurs 30 mins after a meal as fluid moves into the intestine due to the high osmotic load, resulting in dizziness and palpitations - **Late dumping syndrome**: occurs 2 hours after a meal. As glucose is rapidly absorbed in the intestine, this causes reactive hyperinsulinaemia and subsequent hypoglycaemia - **Peptic ulcer disease**

Answer 335

The overall 5-year survival is 5%. Even for the minority of patients suitable for surgical resection, the median survival ranges from 15 to 19 months, with a 5-year survival rate of only 20%. Metastatic disease is associated with a survival of 3 to 6 months. Better prognosis if tumour <3cm, with no node involvement.

Answer 336

Ascites is the accumulation of free fluid within the peritoneal cavity. Physiologically, in men, no fluid should be present. In women, up to 20 mls may be considered normal depending on the timing of the menstrual cycle. Ascites, like pleural fluid, can be broadly divided into **transudates** or **exudates**: - **Transudate**: due to the ultrafiltration of plasma (i.e. removal of fluid). It does not contain large proteins and only few cells. - **Exudate**: due to leakage of whole contents of plasma (i.e. fluid, cells and proteins). Largely due to an inflammatory process. In ascites, rather than using the terms transudate and exudate, we refer to **raised portal pressure** or **normal portal pressure**

Answer 337

- Malignancy e.g. abdominal cancers - Infections, especially TB - Low albumin - less ability to pull fluid back into intravascular space - Pancreatitis - Bowel obstruction - Myxoedema With portal hypertension - Cirrhosis - Congestive cardiac failure, pericarditis - due to raised pressure in vessels causing fluid to leak out - Budd-Chiari syndrome - Inferior vena cava or portal vein thrombus - Risk Factors

Answer 338

- High sodium diet - Hepatocellular carcinoma - Splanchnic vein thrombosis resulting in portal hypertension

Answer 339

- Abdominal swelling - Distended abdomen - Fullness in the flank and shifting dullness - Mild abdominal pain and discomfort - Severe pain may signal towards bacterial peritonitis - Respiratory distress - Difficulty eating - Scratch marks on abdomen due to itching caused by jaundice - Many patients also have peripheral oedema

Answer 340

- How long has the swelling been there? - Drugs? - Weight loss? - Story suggestive of any underlying cause?

Answer 341

Percussion - demonstrating shifting dullness - percuss centrally to laterally until dull sound. Keep finger at dull spot and ask patient to lean to opposite side. If the dullness was fluid, it will have moved and the previously dull area will now be resonant

Answer 342

- Ascitic fluid tap - fluid sample for cytology, culture and albumin - Raised white cell count - indicative of bacterial peritonitis - Gram stain and culture - Cytology to find malignancy - Amylase to exclude pancreatic ascites - Protein levels - transudate (low protein, less bad), exudate (high protein, extremely bad) - refer to SAAG notes below - Ultrasound

Answer 343

The serum ascites-albumin gradient (SAAG) is used to determine the cause of liver disease. It is used to determine whether the aetiology of ascites is from raised portal pressure (transudate) or normal portal pressure (exudate). SAAG = serum albumin (g/dL or g/L) - ascitic fluid albumin (g/dL or g/L) - **High SAAG (>1.1 g/dL or >11 g/L)**: transudate - **Low SAAG (<1.1 g/dL or < 11g/L)**: exudate

Answer 344

- Treat underlying cause - e.g. antibiotics for SBP - Reduce sodium to help liver and reduce fluid retention - Increase renal sodium excretion. Diuretic of choice is spironolactone (potassium-sparing aldosterone antagonist) - Drain fluid (paracentesis) - can drain 5 litres at a time - Transjugular Intrahepatic Portosytemic Shunt (TIPS) - can be used for resistant ascites

Answer 345

- Severe hypovolemia due to reaccumulation of ascites post-drainage - Intravascular replenishment needed prior to drainage to avoid this complication.

Answer 346

10-20% survival 5 years from onset Poor prognosis

Answer 347

Consists of two parts: **Parietal:** - Covers the abdominal wall - Somatic innervation - Sensation is well localised **Visceral:** - On organs e.g. stomach, liver and colon - Autonomic innervation - Sensation is poorly localised Peritoneal cavity is a closed sac lined by mesothelial cells; these produce surfactant, which acts as a lubricant within the peritoneal cavity. The cavity contains < 100mL of serous fluid containing < 30g/L of protein (transudate) The mesothelial cells lining the diaphragm have gaps that allow communication between the peritoneum and the diaphragmatic lymphatics Around 1/3rd of fluid drains through these lymphatics, the remainder through the parietal peritoneum These mechanisms allow particulate matter to be removed rapidly from the peritoneal cavity

Answer 348

Inflammation of the peritoneum

Answer 349

- Primary peritonitis - inflammation caused by spontaneous bacterial peritonitis. This is the most common type of peritonitis - e.g. E.coli, klebsiella, staphylococcus aureus - Secondary peritonitis - caused by something else e.g. chemical such as, bile

Answer 350

SBP is theorised to occur by two mechanisms: - **Direct spread:** bacterial translocation across the bowel wall - **Haematogenous spread**: bacteria enter ascites via the blood stream in the context of an immunosuppressed state

Answer 351

- Perforation Causes SUDDEN ONSET with acute severe abdominal pain followed by general collapse and shock - When peritonitis is secondary to inflammatory disease, the onset is less rapid with the initial features being those of the underlying disease - Poorly localised (irritation of visceral peritoneum) then moving to one point on abdomen and becoming localised (when it begins to irritate the parietal peritoneum) - Rigid abdomen - Tenderness and guarding of abdomen - Pain relieved by resting hands on abdomen - thereby stopping movement of peritoneum and thus pain - Lying still - people with peritonitis want to stay still - Prostration - lying stretched out on the ground

Answer 352

- Blood test: - To monitor/confirm infection - raised white cell count and CRP - Serum amylase to exclude acute pancreatitis - Human Chorionic Gonadotrophin (HCG): - Hormone secreted in pregnancy - Obviously there is abdominal pain in pregnancy - This test is to exclude pregnancy as cause - Erect CXR - may see free air under diaphragm - Abdominal X-ray to exclude bowel obstruction and foreign body as cause of abdominal pain - CT abdomen to exclude ischaemia as cause of pain

Answer 353

- Ascitic tap - high white cell count - Blood cultures

Answer 354

- ABC (airways, breathing, circulation) - Insertion of nasogastric tube - IV fluids - Treat underlying cause and treat early - Broad spectrum antibiotics e.g. cephalosporin. Following an episode of SBP, patients require prophylactic oral antibiotics e.g. rifaximin. - Surgery for secondary peritonitis: - Laparotomy - perform a full exploration and lavage (clean) of the peritoneum. - Specific treatment of the underlying condition

Answer 355

- Delay in treatment can produce toxaemia and septicaemia which may lead to multi-organ failure - Local abscess formation can occur and should be suspected if a patient continues to remain unwell post-op, with a swinging fever, high white cell count and continuing pain - Abscesses are commonly pelvic or subphrenic and can be localised using ultrasound and CT - Kidney failure - Paralytic ileus: - Peristaltic waves in colon stop leading to fluid stagnation causing distended gut and bloating which puts pressure on stomach and interferes with diaphragm and thus breathing - causes patient to breathe less deeply which promotes infection as bacteria can remain deep in lungs as they are not exhaled

Answer 356

The one year survival following an episode of SBP is 30-50%

Answer 357

A hernia occurs when an internal part of the body pushes through a weakness in the muscle or surrounding tissue wall. A hernia usually develops between your chest and hips. In many cases, it causes no or very few symptoms, although you may notice a swelling or lump in your tummy (abdomen) or groin.

Answer 358

- Irreducible - contents cannot be pushed back into place - Obstructed - bowel contents cannot pass as the intestine is obstructed - Strangulated - ischaemia occurs as blood supply of the sac is cut off - this requires urgent surgery. - Incarceration - contents of the hernial sac are stuck inside by adhesions

Answer 359

Inguinal, Femoral, Umbilical, Incisional, Epigastric, Hiatal

Answer 360

The protrusion of abdominal contents through the inguinal canal

Answer 361

- Commonest type of hernia in both men and women. Account for 70% of all abdominal hernias - M>F - Most common in men >40 years

Answer 362

- Inherent or acquired weakness at site - Increased abdominal pressure

Answer 363

- Male - Chronic cough - Constipation - Urinary obstruction - Heavy lifting - Ascites - Past abdominal surgery

Answer 364

The inguinal canal is a passage that extended medially and inferiorly, through the inferior part of the abdominal wall. It acts as a pathway by which structures can pass from the abdominal wall to the external genatalia, and are a potential site of weakness, and so are prone to hernias. Inguinal hernias pass through the internal inguinal ring and, if large, out through the external ring. They present above and medial to the pubic tubercle. 2 types of inguinal hernia: direct and indirect (more common) **Direct hernia:** hernia protrudes through the posterior wall of the inguinal canal. - Less common (20%) - Direct inguinal hernias protrude through acquired defects in the posterior wall of the inguinal canal. This occurs in an area termed Hesselbach’s triangle. - Rarely strangulate - Reduce easily **Indirect hernia:** hernia protrudes through the deep inguinal ring and into the inguinal canal - More common (80%) - Indirect inguinal hernias exit the abdominal wall via the deep inguinal ring. They may pass through the entirety of the inguinal canal and protrude anywhere along its length or into the corresponding testicle. If large enough, they protrude out through the superficial inguinal ring - Lateral to the inferior epigastric artery - Can strangulate

Answer 365

- Bulging associated with coughing or straining (bowel movement, heavy lifting) - Appearance of lump - Rarely painful - If painful then indicates strangulation - Patient can usually reduce the hernia themselves

Answer 366

Look for lump and previous scars, check for cough impulse (swelling expands when coughing) - compare to the other side. Examine external genitalia

Answer 367

Femoral hernia Epididymitis Testicular torsion Groin abscess Aneurysm Hydrocele Undescended testes

Answer 368

- Medical: - Use of truss to contain and prevent further progression of hernia - Surgical: indicated if patient is very symptomatic - Pre-op: diet and stop smoking - Three types: - **Herniotomy:** contents reduced and hernial sac removed. Typically used in children with congenital patent processus vaginalis. - **Herniorrhaphy:** combines a herniotomy with repair of the posterior inguinal wall. - **Hernioplasty:** combines a herniotomy with the insertion of a mesh to reinforce the posterior inguinal wall - Can be open repair or laparoscopic (total extra-peritoneal (TEP) or transabdominal pre-peritoneal (TAPP) repair)

Answer 369

Bowel enters the femoral canal (presenting as a mass in upper medial thigh) or above the inguinal ligament (points down the leg) Likely to be irreducible and to strangulate due to the rigidity of the canal’s borders

Answer 370

- Occur more often in females - More common in middle-age and elderly

Answer 371

The neck of the hernia is felt inferior and lateral to the pubic tubercle

Answer 372

- Inguinal hernia - Saphena varix (dilation of saphenous vein at junction of femoral vein in groin) - Enlarged cloquet's node - Lipoma - Femoral artery aneurysm - Psoas abscess

Answer 373

- Surgical repair - Herniotomy - ligation and excision of the sac - Herniorrhaphy - repair of the hernial defect

Answer 374

A type of paediatric hernia affecting 3% of life births.

Answer 375

A result of a persistent defect in the transversalis fascia

Answer 376

Rarely needed, most resolve by the age of 3.

Answer 377

Occurs when tissue protrudes through a surgical scar that is weak They are a complication of abdominal surgery but can occur anywhere where there is an incision and follows a breakdown of muscle closure after surgery

Answer 378

- Emergency surgery - Wound infection post op - Persistent coughing and heavy lifting - Poor nutrition

Answer 379

- Repair is more difficult in those that are obese - Mesh repair - reduced recurrence but associated with high levels of infection

Answer 380

Pass through the linea alba above the umbilicus

Answer 381

A condition where part of the stomach pushes up into the lower chest through a weakness in the diaphragm. 2 subtypes: - Sliding hiatus hernia - Paraoesophageal hernia (rolling hiatus hernia)

Answer 382

30% of patients are above 50, especially obese women

Answer 383

Sliding hiatus hernia (80%) - the gastrooesophageal junction slides up into the chest. Acid reflux can occur as the lower oesophageal sphincter becomes less competent. Paraoesophageal hernia (20%) - the gastrooesophageal junction remains in the abdomen but the bulge of stomach herniates up into the chest alongside the oesophagus. GORD is less common as the gastrooesophageal junction remains intact

Answer 384

- Small hernias - asymptomatic - Large hernias - GORD

Answer 385

- Upper GI endoscopy - to visualise the mucosa, but cannot exclude hiatus hernia - Barium swallow to confirm diagnosis

Answer 386

- Weight loss - Treatment of GORD - Surgical treatment, if: - High risk of strangulation - Intractable symptoms despite medical therapy - Complications

Answer 387

A toxic overdose is defined as ingestion of paracetamol >75mg/kg. 12g/ 24 tablets or 150mg/kg in adults may be fatal

Answer 388

Paracetamol is the most common drug in overdose, associated with approximately 100 to 200 deaths per year in the UK

Answer 389

- **Depression or history of self-harm** - **Glutathione deficiency** - **Alcoholism**, **malnutrition and anorexia**: key risk factors for hepatotoxicity - **P450 inducers**: increased risk of hepatotoxicity due to facilitation of paracetamol metabolism and NAPQI production - Examples include rifampicin, carbamazepine, phenytoin, St John’s Wort and long-term alcohol excess - Surprisingly, acute alcohol intake may actually be protective against hepatoxicity

Answer 390

Paracetamol is converted to a number of metabolites, most of which are non-toxic. Predominantly metabolised via a Phase II reaction - conjugated with glucuronic acid & sulphate. A small proportion is metabolised by the P450 system to the toxic metabolite known as N-acetyl-p-benzoquinone imine (NAPQI), which is a mitochondrial poison. It is typically detoxified by conjugation with glutathione. In the case of a paracetamol overdose, as the production of NAPQI increases, glutathione stores become depleted, leaving NAPQI to remain unconjugated and resulting in hepatocellular damage. Acute liver failure is a feared complication of paracetamol overdose.

Answer 391

- Jaundice - Encephalopathy - reduced GCS - consciousness - Tachycardia/ hypotension - Evidence of self-harm

Answer 392

- Abdominal pain - Right upper quadrant pain - Nausea or vomiting - Confusion or coma

Answer 393

- **Date of ingestion**: is there a delay in presentation? - **Timing of ingestion**: single overdose or staggered - **Time since last ingestion** (even staggered) - **Weight**: if >110 kg, used 110 kg as the maximum weight for calculations. - **Pregnancy**: use pre-pregnancy weight to determine toxicity and current weight for treatment - **Total amount ingested** (mg/kg) - **Current suicidal risk**: consider a registered mental health nurse (RMN) to stay with the patient

Answer 394

- **Serum paracetamol:** levels should be measured at 4 hours post-ingestion. If presenting after 4 hours of ingestion, take levels immediately - **LFTs:** deranged liver function and rising INR - **Clotting screen:** PT and APTT prolonged in hepatocellular damage - **U&E:** severe toxicity results in renal failure - **Arterial blood gas:** severe toxicity results in a lactic acidosis

Answer 395

- **Activated charcoal:** reduces intestinal absorption - Administered if the patient presents **within 1 hour** of ingestion - **N-acetylcysteine (NAC)**: ****replenishes glutathione stores which bind NAPQI, the toxic metabolite - NAC is given in the following instances: - **Timed plasma paracetamol level on or above treatment line** (see nomogram) - **Doubt over ingestion time**: regardless of the paracetamol concentration - **Staggered overdose**: when all the tablets are **not** taken within 1 hour - NAC was previously infused over 15 minutes but is now infused over **1 hour** to avoid side effects. Second infusion is over 4 hours. - Next day do INR, U&E, LFT. If INR rising, continue NAC. - Side effect: rash. Give **chlorphenamine**

Answer 396

If the paracetamol concentration lies on or above the treatment line, NAC should be administered. When there is doubt regarding management, the National Poisons Information Service/TOXBASE should be consulted.

Answer 397

- **Liver transplantation**: ****indicated as per the King's College Criteria if arterial pH < 7.3 after 24 hours of ingestion **OR all three of the following** are present: - Prothrombin time > 100 seconds - Creatinine > 300 µmol/l - Grade III or IV encephalopathy - **Psychiatric input** for deliberate overdoses

Answer 398

- **Acute liver failure:** evidence of liver failure may warrant urgent liver transplantation, as per the King’s College Criteria - **Acute kidney injury -** due to acute tubular necrosis occurs in 25% of patients who have severe hepatic damage - **Anaphylactoid reaction**: NAC may cause an **anaphylactoid reaction** due to non-IgE mediated mast cell degranulation (10-50% of patients). It often occurs with lower paracetamol ingestions after the first bag of NAC and is usually managed by pausing the infusion and restarting at a reduced rate

Answer 399

Hepatic regeneration can take place, whereby function is normalised rapidly. However, patients with staggered overdose or delayed presentation have a higher risk of liver failure and mortality.

Hepatobiliary Flashcards

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