Module 2.3: Liver Flashcards

Question

Risk of Recurrence – After Resection in HCC

Answer 1

``` • 70% at 5 years • Incs. dissemination and de novo tumors • Usually multifocal • Predictors of recurrence: o Microvascular invasion o Additional tumor sites • HCC molecular profiling hoped to refine risk assessment – none validated • STORM Trial: Chemoembolisation prior to resection/adjuvant chemotherapy - no benefit ```

Answer 2

• Best option for patients  underlying cirrhosis in patients with HCC means there is a high risk of recurrence by simple resection, liver transplantation not only removes HCC but also cirrhosis • Milan Criteria: Mazzaferro et al. NEJM 1996 o Solitary HCC <5 cm OR up to three nodules < 3 cm o 5-year survival > 70% o Waiting time for transplant long - chance that HCC will grow beyond criteria o Most powerful predictor of recurrence = macro/microscopic vascular invasion o This correlates with tumour size & number o Most groups treat HCC upon listing

Answer 3

• Tumour cells destroyed by injection of chemicals (ethanol, acetic acid, boiling saline) or by temperature modification (radiofrequency, laser, cryotherapy) • No RCT comparing local ablation to resection • Efficacy assessed by imaging 1 month post Rx: o Absence of contrast uptake = tumour necrosis o Persistence of uptake = treatment failure • Recurrence rate after ablation similar to resection • Usually performed under US or CT guidance ``` • Necrosis rate o 90-100% in <2cm o 70-80% if 2-3cm o 50-60% if 3-5cm • Child-Pugh A 50% 5y survival ```

Answer 4

o Insertion of single/multiple cooled tip electrodes or single electrodes with J-hooked needles deliver heat around the tip induces a wide region of tumour necrosis o Microwave being used increasingly o Procedure-related mortality 0-0.3% o Best published results  necrotic effect more predictable and efficacy superior to injecting alcohol in large tumours

Answer 5

Non-Curative Treatment • Used for large (>4cm) lesions / multifocal HCC (with no vascular invasion or extrahepatic spread) o Transarterial chemoembolisation (TAE) - the only option o HCC exhibits intense neo-angiogenic activity during its progression. o Very early stage HCC not highly vascularised & its blood supply comes from portal vein o As HCC grows, blood supply progressively arterialized, so that even well differentiated HCC is mostly dependent on hepatic artery o Hepatic artery obstruction by TAE - angiographic procedure, usually Gelfoam • TAE and TACE induce tumour necrosis in > 50% of the pts

Answer 6

* If TAE is combined with prior injection into hepatic artery of chemotherapeutic agents, e.g. doxorubicin, cisplatin = transarterial chemoembolisation (TACE) * TAE and TACE induce tumour necrosis in > 50% of the pts * Chemotherapy drugs mixed with lipiodol: selectively retained within tumour * Main contraindication: ↓portal blood flow (portal vein thrombosis) * Side effects of TACE are same as for systemic chemotherapy

Answer 7

>50% of pts of TAE/TACE o Hepatic artery obstruction with acute ischemia o Fever, abdominal pain, ileus o NBM 24 hours, IV hydration (prophylactic antibiotics are not routine) o Fever reflects tumour necrosis, minority develop severe infectious complications e.g. hepatic abscess or cholecystitis o Usually self-limited < 48 hours

Answer 8

• Multikinase inhibitor: anti-angiogenic, pro-apoptotic SHARP trial; 2007 ASCO Meeting; Journal of Clinical Oncology o Median survival 10.7 vs 7.9m (placebo)  i.e. 2 month difference in survival • Serious adverse events similar for Sor vs P (52% vs 54%). * Diarrhoea (11% vs 2%), skin reaction (8% vs 1%), fatigue (10% vs 15%), and bleeding (6% vs 9%) * Sorafenib is 1st agent to demonstrate statistically significant improvement in survival for pts with advanced HCC

Answer 9

previously good or stable liver function acute deterioration over a short period induced by a precipitating event resulting in organ failure and high risk of death + potentially reversible

Answer 10

infection GI bleed Surgery trauma alcoholic hepatitis, PVT etc.

Answer 11

- The hepatic reserve is markedly reduced in patients with ACLF and much lower in those with decompensated cirrhosis. - After acute insult or injury, the condition of a patient with ACLF is likely to rapidly deteriorate and in the first 1–2 weeks after injury onset, the patient could also develop sepsis - This intervening period is a therapeutic ‘golden window’, in which there are opportunities to ameliorate the acute injury and modulate the patient’s immune response to prevent the development of sepsis, and supplement liver regeneration to reverse the decline towards multiorgan failure and death. - A progressive downhill course often occurs in a patient with decompensated cirrhosis compared with ACLF. - After mitigating the acute injury, spontaneous recovery is more likely in those with ACLF than decompensated cirrhosis because of a higher baseline hepatic reserve

Answer 12

No ACLF - no organ failure OR - single organ failure (non-kidney), no HE, creat <132 - single cerebral failure, creat <132 umol/L - 4,7% 28-day mortality, 14% 90d mortality ACFL Grade 1 - single kidney failure OR - single non-kidney failure + creat 132-168 umol/L - 22,1% 28-day mortality, 40,7% 90d mortality ACFL Grade 2 - 2 organ failures - 32% 28-day mortality, 52.3% 90d mortality ACFL Grade 3 - 3+ organ failures - 76.7% 28-day mortality, 79.1% 90d mortality

Answer 13

Acute Decompensation, Organ Failure &High 28d Mortality Early identification and management of SEPSIS is the most important thing you can do

Answer 14

* Systemic inflammation * Raised WCC and CRP * Pro-inflammatory molecules * IL-6, IL-1β, IL-A8 * Principles of inflammatory response

Answer 15

systemic inflammation is likely due to the presence in the systemic circulation of PAMP molecules released by Gram-positive/-negative bacteria or DAMP molecules from dead, dying, injured, or stressed nonapoptotic liver cells. These interact with specific receptors present in cells of the innate immune system, especially monocytes and neutrophils, resulting in the bulk release of inflammatory (IL-1β, IL-6, IL-8, and TNF-α) and hematopoietic (GM-CSF and G-CSF) cytokines, accompanied by the production of eicosanoids (small lipid mediators with inflammatory properties) and reactive oxygen (ROS) and NO species (NOS). The concerted action of these inflammatory mediators may cause organ failure through mechanisms related to organ hypoerfusion, tissue ischemia, tissue cell dysfunction /necrosis, and hypercoagulopathy.

Answer 16

• Migration of viable microorganisms from gut lumen to mesenteric lymph nodes & extra-intestinal sites • Pathogenic mechanism of “culture-negative” sepsis (30-50%)  SBP and other infections  Activation of innate immune & systemic inflammatory responses • Circulatory bacterial DNA is a biomarker for translocation of bacteria in cirrhosis

Answer 17

ductular billirubinostasis extensive necrosis eosinophilic degeneration advanced fibrosis with nodule formation.

Answer 18

ballooning degeneration of hepatocyte with cellular cholestasis acinar disarray with hepatocellular and canalicular bile thin septa and mild fibrosis.

Answer 19

- Increased intrahepatic resistance: incorporates both static and dynamic factors o The initial event leading to PH is – increased vascular resistance to portal blood flow at the hepatic microcirculation. o Increased hepatic vascular resistance is not only –mechanical consequence of hepatic architectural distortion casued by fibrosis, regenerative nodules, sinusoidal remodelling and vascular occlusion that is characteristic of a cirrhotic liver. o Increasingly recognised is a dynamic component: that is thought to account for a 1/3 of increased resistance to portal blood flow 1. Active contraction of portal/septal myofilbroblasts 2. Activated hepatic stellate cells/vascular smooth muscle cells 3. Hepatic endothelial cell dysfunction - These events are believed to reflect an imbalance between endogenous vasocontrictors and vasodilatory mediators - Second factor contributing to PH: increased blood inflow through portal venous system due to splanchnic arteriolar vasodilatation o Splanchnic vasodilatation - occurs due to increase in levels of vasodilators e.g. NO, glucagon etc. This results in the hyperkinetic/hyperdynamic circulatory syndrome that we will discuss shortly.

Answer 20

- Bacterial infections in cirrhosis: o leading cause morbidity/mortality in cirrhosis o 15-35% of hospitalised cirrhotic patients vs 5-7% general population (Verbake et al; Crit Care ‘11) o 50% mortality rate increase patients with sepsis*  increased susceptibility to secondary infections  increased frequency of extra-hepatic organ failure & requirement for organ support  Delisting from listing transplant

Answer 21

- When considering how patients develop this increased predisposition to infections- one needs to consider it in 3 main area- gut, liver and systemic components. - Firstly we know that impaired local immunity, SBBO and increased intestinal permeability lead to increased translocation of bacteria in regional lymphatics, portal circulation.

Answer 22

- Common in ACLF - 40-50% hospital admissions of cirrhotics - 20-40% develop nosocomial infections - SIRS criteria for sepsis unreliable in cirrhotic patients o (present in 57-70% infected patients) - Infection confers four-fold increase in MR (Arvaniti et al; Gastro ’10) Infection triggers development of organ failure & ACLF • 35% with proven infection required organ support (n=507) • Infection triggered organ failure (ACLF) increased mortality rate Secondary infections in ACLF confers poor outcome - 28% hospitalised patients - Associated wit high mortality (53% vs 20%) & independent of admission MELD - Commoner in patients with MODS/shock - SIRS confers poor outcome in cirrhotics irrespective of infection

Answer 23

* High incidence of infections in cirrhotics with variceal bleeding * (20% at admission; 50% during first few days) * Meta-analysis reduction in infection (45% vs 14%) and mortality (24% vs 15%) with antibiotic prophylaxis (Bernard et al, Hepatology ‘99) * Infection is associated with failure to control bleeding & variceal re-bleeding (Goulis et al Lancet 1999; Hou et al Hepatology ‘04) • Antibiotic prophylaxis associated lower incidence early variceal re-bleeding (Hou et al, Hepatology ‘04)

Answer 24

* Prevalence of circulating bacterial DNA with severity of liver disease: * Child’s A: 3.8% * Child’s B: 8% * Child’s C: 30% * Cirera et al; J Hep ’01 * Such et al; Hepatology ‘02 * Positive ascitic and peripheral bact DNA associated with worse outcome in culture negative decompensated liver disease * Zapater et al; Hepatology ‘08 • Child-Pugh score more predictive of presence of bact DNA vs portal hypertension * Associated with circulatory dysfunction/↑ intrahepatic resistance * Bact DNA+: low MAP, SVR, ↑ pro-inflammatory cytokines, PRA renal dysfunction * (Frances et al Hepatology ‘08; Bellot et al Hepatology)

Answer 25

 Splanchnic vasodilatation/ effective arterial blood volume/MAP  SNS/RAAS activation  renal vasoconstriction/shift in the renal autoregulatory curve*  Cardiorenal dysfunction: “relative cardiac insufficiency” to systemic vasodilatation*  Renal vasocontrictor/vasodilator imbalance: alters renal blood flow/GFR (e.g. NO, ET-1,leukotrienes, thromboxane A2) SEE IMAGE p107

Answer 26

* Most data extrapolated from advanced hospitalised cirrhotics; * AKI occurs in 25% patients with ACLF * AKI associated with increased 7-day MR: 38% vs 7%) (Jindal et al; Liver Int ‘15) * Causes: * Infection (46%) * Hypovoloaemia (32%) * HRS (13%) * Parenchymal nephropathy (9%) * Drug-induced (7.5%)

Answer 27

- Cardiac dysfunction: blunted contractile responsiveness to stress, and/or altered diastolic relaxation with electrophysiological abnormalities in the absence of other known cardiac disease ``` - Reported in 40-50% cirrhotic patients o Clinical relevance:  Increased MR  Renal failure/HRS (“cardiorenal failure”)  Cardiac failure following TIPS/OLT ``` Polonged QT in 50% patients with cirrhosis electromechanical coupling is compromised leading to impariedcardiac contractility (depolaristion of ventricles is coupled with ventricular contraction during systole. - Diastolic dysfunction o most common manifestation of cardiac dysfunction o present in 50% cirrhotics (decompensated >>compensated)

Answer 28

* Drugs * Viral Hepatitis (A and B) * Alcohol * Autoimmune

Answer 29

``` • Liver cell damage o Alcohol o Autoimmune o Viral Hepatitis (B and C) o Haemochromatosis o Wilson’s Disease o Alpha 1 antitrypsin deficiency ``` • Biliary o Primary Biliary Cirrhosis o Primary Sclerosing Cholangitis

Answer 30

* Ascites * SBP * Hepatic encephalopathy * Oesophageal varices * Hepatocellular carcinoma

Answer 31

• Definitve treatment: liver transplantation o 600-700 liver transplants a year in UK o Waiting time for low-risk patients 6 - 12 months. o 350 patients awaiting transplant at one time. o 8% die awaiting transplant  This is where stem cell therapy may come in use as a bridging therapy for definitive treatment (although not currently part of clinical practice as of yet)

Answer 32

* A stem cell is a cell that has the ability to divide (self replicate) for indefinite periods—often throughout the life of the organism * They are unspecialized cells that renew themselves for long periods through cell division. * Under certain physiologic or experimental conditions, they can be induced to become cells with special functions * Adult stem cell is an undifferentiated (unspecialized) cell that is found in a differentiated (specialized) tissue.

Answer 33

totipotent - can differentiate into embroynic and non-embryonic cells pluripotent - all three germ layers but can't form extra-embryonic tissue multipotent - cells of different lineages within a single germ layer oligopotent - only a few lineages unipotent - one cell type but can self-renew

Answer 34

* Progenitor/precursor cells cannot divide to produce a replicate of itself. Instead when it divides it can give rise to two different types of specialised cells. * Stem cells can divide to replicate itself (an unspecialised cell) or it can divide to become a specialised (differentiated) cell e.g. neurone.

Answer 35

• Plasticity is the ability of an adult stem cell from one tissue to generate the specialized cell type(s) of another tissue. o In this case, haematopoietic stem cells can be engineered to differentiate into hepatocyte cells

Answer 36

o Multipotent haematopoietic stem cells express markers of stem cells (CD34, CD133, Rex-1, Oct-4, Nanoq, Tie-2, TAL-1, CXCR4) but also express liver cell markers too including: AFP, A1AT, HGF and LDLr. o If these are then cultured in medium with hepatocyte growth factors (to create an artificial environment like the liver), these cells begin to express more specific hepatocyte markers  Stem cell markers are still expressed: CD34, CD133, Rex-1, Oct-4, GATA-4  Hepatocyte markers: Albumin, AFP, A1AT, C-MET, HGF, Transferrin, Vimentin • Proposed mechanisms of stem cell plasticity: Forbes et al. J Pathol 2002 o Transdifferentiation: hematopoietic stem cells injected are transported to the liver, differentiate into hepatocytes and take over the function/repairment of residing hepatocytes o Fusion: 2-step process where stem cells fuse forming hybrids that adopt the phenotype of resident cells

Answer 37

Gordon MY et al, Stem Cells, 2006 o To study the potential benefit of infusing adult stem cells into the hepatic artery or portal vein of patients with chronic liver failure and to find out whether this leads to clinical benefit. o To assess safety and treatment related toxicities o To determine clinical benefit or deterioration by monitoring changes in liver function. o No significant side effects in these patients (fever, nausea, vomiting) o Initial increase in albumin in these patients (mild % increase) o Some degree of decreased in bilirubin

Answer 38

Pai M, et al. Am J Gastroenterol. 2008 Overall: There is clinical and biochemical improvement in cirrhotic patients injected with bone-marrow derived stem cells.

Answer 39

• Various routes of administration seen o Injection into portal vein o Injection into peripheral vein – easier to do as does not require a expertise but thought to be less efficient than directly injecting into target organ o Injection into hepatic artery (angiography through femoral route) o Intra-splenic injection • Different routes make it difficult to compare studies All have shown improvement in liver function scores/markers (MELD/Child Pugh Score). * It is thought now that rather than the HSCs transdifferentiating into hepatocytes, it is the cell factors produced that improve native liver cells for a period (hence why function deteriorates over time). * Hence, with this in mind, it is the group that would benefit the most would be those with acute liver failure, to allow liver to recover to its normal state. * Given current studies, stem cell treatment will only ever become a bridging therapy for those with chronic liver disease awaiting liver transplantation. * For very sick CLD patients, one may have to use HSCs from donors.

Answer 40

• Aetiology unknown: Gallstones, porcelain gallbladder, chronic typhoid infection (all cause chronic irritation of the gallbladder) • Without treatment: median survival 5-8m, 5 year survival <5% • Systemic chemotherapy ineffective, no other effective Tx options • Optimal Tx is surgical excision with curative intent (i.e. more than one operation needed to remove all cancer, lymph nodes [cancer metastasises very quickly] and CBD if thought to be involved) o 5-year survival: stage II 64%, stage III 44%, stage IV 8% o <15% suitable for surgery

Answer 41

• Aetiology: 70-90% have underlying cirrhosis; aflatoxin • Without treatment: Median survival 4-6m, 5y survival <5% • Systemic chemotherapy ineffective (RR <20%) • Other effective Tx options o Liver transplant (best option in those with cirrhosis) o Transarterial chemoembolization (TACE) o RFA o Surgical excision with curative intent  Optimal Tx: 5y survival >30%  However only 5-15% suitable for surgery  Background of cirrhosis means that resection can have profound effect on liver function  decompensation

Answer 42

• Aetiology: PSC (1.5% of getting CCA per year from date of diagnosis) & UC, liver fluke (clonorchis sinesis), choledochal cyst • Without treatment: median survival <6m (depends on site), 5 year survival <5% • Systemic chemotherapy ineffective: o GEMCIS median overall survival 11.7 months (Valle et al, NEJM 2010), no other effective Tx options (LTx) • Optimal treatment surgical resection with curative intent o 5-year survival 20-40% (difficult to provide an accurate figure as it is variable depending on where cancer is found) o 20-30% suitable for surgery [as peripheral cancers are more easily resectable] o Hilar ChCA difficult and tend to have poorer prognosis

Answer 43

• 15-20% synchronous, 25% metachronous • Without treatment: median survival <1 year, 5-year survival 0% • Systemic chemotherapy improving, and RFA and SIRT are also effective treatment options • Optimal Tx: Surgical excision with curative intent • 5y survival rates 25-50% • 25% suitable for surgery o Surgery now incurs greater benefit as surgery is safer o Repeated resections limited by how much functional liver remains o Most operable synchronous liver mets have chemotherapy first o Chemotherapy is also used to downstage inoperable mets

Answer 44

• Functional anatomical terms means the right and left lobe of the liver are defined/divided by middle hepatic vein (comes off IVC) o Falciform ligament only divides the left lateral segment from median and right segments • Right lobe is predominantly posterior so is less accessible  right hepatic vein divides this lobe into a further three segments • Left lobe is divided by left hepatic vein into a further three segments too • Functional anatomy allows for types of resections to form  if you know your anatomy you can do more niche procedures (see below)

Answer 45

* Clear resection margins * Leave adequate liver functional reserve * Reasonable resection time * Minimise post-operative complications (e.g. bile leak  difficult to visualise) * Minimal blood loss

Answer 46

• Risk of liver failure post resection if FLR too small o Normal liver: FLR needs to be 25% o Cirrhotic liver: FLR needs to be 40% • Selective Portal vein embolization induces hypertrophy of contralateral liver. o Increases size of functional liver remnant  Heptocellular injury  Hepotocytes de-differentiate and clonally expand (increase in hepatic cell mass and number) = hypertrophy o Only use if planning to resect

Answer 47

BLOOD LOSS • Excessive blood loss is associated with: o Increased operative morbidity and mortality o Immunosuppression o Shorter disease free interval o Serious Hazards of Transfusion (SHOT)  I.e. of 27 million blood components issued in 1996-2004 (SHOT Report 2004), there were 2626 incidents, with >3500 near misses. Of these, the major reason for incidents was due to incorrect blood transfusion being given.  Reports show figures increasing (2007 and 2008) • Is bloodless liver resection possible? o Technically yes, but probably not – liver resections are unpredictable o Many factors can help to control blood loss:  Prothrombotic tissue glues and collage fleece  Low CVP  Inflow (pringle)/total vascular exclusion (TVE)  Haemodilution  Autologous transfusion  Cell salvage o Requires good anatomical understanding and liver parenchymal transection techniques

Answer 48

* Resect wherever there is tumour, dependent on adequate FLR * Conclusion: take away as little as possible

Answer 49

* Resect segments IV/V * Remove all LN * If involves cystic duct must remove common hepatic duct * Anastomose small bowel

Answer 50

• Intrahepatic – straightforward • Distal – Whipple’s • Hilar - difficult. Often requires Radical resection which encompasses: o Excision of the bile duct confluence en bloc with extended liver resection  Excision of the caudate lobe (segment 1)  Excision of portal vein bifurcation  Complete lymphadenectomy of hepatoduodenal ligament  (PVE before is necessary)

Answer 51

• One way is to do minimal surgery, non-anatomical resection • Increasingly use 2 stage liver resection, because normal liver resection would not leave adequate functional liver o Remove tumours in one lobe (local resection) e.g. of left lobe o PVE to atrophy other side (e.g. right lobe and hypertrophy left lobe) o Remove area with masses at second stage Because PVE does not eliminate blood supply from other side, increasingly use ALPPS (Associating liver partition and portal vein ligation for staged hepatectomy), to allow hypertrophy but also block off blood supply from other side. This is possible but often complicating for patients as they would have to suffer through constant operations given primary CRC as well.

Answer 52

* Correct clotting: Vit K, FFP, platelets * CT angiogram * Consider angiography * Re-operate

Answer 53

• Very little can be done to correct this as liver has a number of functions: o Bile acid/BR/protein/carbohydrate/fat metabolism, detoxification of drugs and toxins, immunological function, manufacture of plasma proteins, synthesis, reduction & conjugation of hormones, synthesis of all coagulation proteins except VWF and factor VIIIC Encephalopathy --> Reduce protein intake, phosphate enemas/lactulose, no sedation Hypoglycaemia --> Infusion 10-50% dextrose Hypocalcaemia --> 10ml 10% calcium gluconate Renal failure --> Haemofiltration Respiratory failure (hyperventilation, intrapulmonary shunts, ARDs, pulmonary aspiration) --> Ventilation Hypotension --> Albumin, vasoconstrictors Infection --> Frequent cultures A/Bs Bleeding --> Vit K, FFP, platelets

Answer 54

• Fibrosis (scarring) is the end result of many types of liver disease • Progessive fibrosis leads to cirrhosis • Transition is gradual and often asymptomatic • Result = Disruption of liver architecture with fibrosis bands and nodule formation = CIRRHOSIS • Note: fibrosis is reversible o i.e. motivate patients to remove insult e.g. alcohol Cirrhosis  fibrosis from nodules (seen on a microscope), and small shrunken liver (initially diagnosed via imaging of this kind of liver) ``` • Compensated cirrhosis o Preserved synthetic function o Often asymptomatic • Progresses to decompensated cirrhosis • Both compensated and decompensated cirrhosis confer a risk of developing HCC (hepatocellular carcinoma) ```

Answer 55

o Impaired synthetic function  PT ↑, ALB ↓, BIL ↑ o Portal Hypertension  Ascites  Varices  Hepatic encephalopathy

Answer 56

* Death rate when one decompensates increases exponentially | * Compensated cirrhosis 5 yr survival = 90% VS. Decompensated cirrhosis (median survival of 12-48 months)

Answer 57

• Minority of patients: Chronic Hepatic Decompensation o Have chronic decompensation i.e. no trigger, they simply gradually deteriorate as underlying disease progresses  at some point develop organ dysfunction where only option for treatment is liver transplantation and chances of reversibility is only option for treatment • Majority of patients: Acute on Chronic Liver Failure o Patient begins with good liver reserve o Presence of a precipitating factor causes patient to have a steep decline over the following weeks. Hence:  High risk of death due to multiple organ failure  Potential to recover to original sate the patient was in prior to acute event

Answer 58

``` o Direct liver injury  Alcohol hepatitis  Drug induced liver injury  Viral hepatitis (e.g, A and E)  Ischaemic injury  PVT (portal vein thrombosis) ``` ``` o Extra-hepatic insult  Infection – common precipitant (SBP or Lung)  Variceal bleed  Surgery  Trauma ```

Answer 59

o Prompt identification of precipitating factor o Prompt treatment (if applicable) of any precipitating factor:  Rapid control of bleeding secondary to varices (PHT talk)  Treatment of infection  Treatment of Alcohol Hepatitis  Cessation of drug in drug induced liver injury

Answer 60

PHT = pathological increase in the heptic venous pressure gradient (pressure difference between the portal vein and the hepatic vein) * Portal vein goes through liver and is formed by splenic vein and SMV * Most blood supply of liver comes from portal vein (75% vs 25% from hepatic artery) * All blood supply leaves via hepatic vein * If you have obstruction of portal circulation  collaterals develop (in cirrhosis this means the liver) as vessels look for a path of least resistance * Portal Hypertension: important because the majority of mortality in liver disease is due to this/majority of complications are derived from this * Normal HVPG= 1-5 mmHg * 5-9 mmHg = pre-clinical portal hypertension * Clinical significant PHT: HVPG> 10 mmHg * Threshold for variceal bleed HVPG > 12 mmHg

Answer 61

• Cirrhosis is the most common cause (90%) • Non-cirrhotic causes (10%) o Pre-hepatic  PVT o Intrahepatic  Cirrhosis, NRH (nodular regenerative hyperplasia) o Post-Hepatic  Budd-Chiari, VOD (veno-occlusive disease)

Answer 62

• Ohm’s law: Portal Pressure Flow x Pressure o Both increased blood flow to the liver and increased resistance to flow through the liver cause increase in pressure of portal system  portal hypertension

Answer 63

* Primary factor in development of PHT * Classically attributed to distortion of liver architecture inherent to cirrhosis (static/mechanical) * Over last 20 yrs – apparent a dynamic component at a liver microcirculatory level * Both a static and dynamic component • Static Component: o Primarily due to architectural disturbances / disruption o Driven by fibrosis → architectural distortion with nodule formation o Additional vascular obliteration, occlusion and capillarization o Majority component of IR (2/3) • Dynamic Component: o Results in increased hepatic vascular tone o Active contraction of portal/septal myofibroblasts o Activated hepatic stellate cells/vascular smooth muscle cells o Hepatic sinusoidal endothelial cell (SEC) dysfunction – vasoconstrictor phenotype o Increased vasoconstrictors in the liver o Reduced bioavailability of intrahepatic vasodilators Intrahepatic resistance only makes up 2/3 of the story.

Answer 64

• Key effect is splanchnic vasodilatation • Mediators include systemic NO, PG12, CO, endocabinoids • Splanchic angiogenesis contributes • Note: role of splanchnic vasoconstrictors in treatment. • Clinical manifestations: other organs - Splanchnic vasodilatation - ↓ MAP resulting in: o Kidney – Na retention/renal vasoconstriction o Lung – AV shunts (hepato-pulmonary)  Increased pulmonary vasculature resistance (port-pulmonary) o These effects further contribute to increased splanchnic blood flow o Heart: ↑ baseline CO, impaired contractility to stimuli o Brain: changes in cerebral blood flow, vasc reactivity- contributes to encephalopathy o Blood:  Low plats/Hb, WCC (pancytopaenia)  Splenomegaly/”hyperplenism”  Reduced thrombopoietin production (plats) o Skin: bounding pulses, palmar erythema, spider naevi

Answer 65

``` • Portal Hypertension related bleeding o Varices (oesophageal / gastric) o Portal HT gastropathy • Ascites / hydrothorax / HRS • Shunting – HE / HPHT • Blood: o Low plats/Hb, WCC (pancytopaenia) o Splenomegaly/”hyperplenism” o Reduced thrombopoietin production (plats) ``` Understanding the pathophysiology allows for planning of potential interventions of: treatment of complications and prophylaxis.

Answer 66

``` • Portal hypertension leads to formation of collaterals • Portal blood flows through these channels in an attempt to circumvent the resistance of the liver • Examples of these collaterals are o Oesophageal varices o Gastric varices o Caput medusae o Spleno -renal shunts o Many others ```

Answer 67

o Volume Resuscitation - BUT “Permissive hypotension” aim SBP 100 / HR <100  De Franchis et al 2005 o Coagulation/ blood support: Hb 8 g/dl : Cautious transfusion improves outcome  Avoid rebound PHT  Colomo et al 2008 o INR < 1.5. No role for FVIIa. platelets > 50, fib >1.0 o Airway protection (prior to endoscopy) o Role of prokinetics  Frossard et al 2002 o Broad-spectrum antimicrobial cover (iv Ceftriaxone)  Fernindez et al 2006 o Haemostatic measures (rationale)  Drugs which lower portal pressure may arrest haemorrhage hence re-bleeding and subsequent mortality may be reduced  Endoscopic expertise may not be available  Drugs may make endoscopic therapy easier/ more effective (Avgerinos 1997)  Drug of choice: Terlipressin (contraindicated in heart conditions as can cause myocardial ischaemia) o Endoscopic Band Ligation  EBL is superior to sclerotherapy in the control of active variceal haemorrhage (Villanueva et al 2008)  Bleeding control in 90% but re-bleed rates in 30%  Delay in endoscopy ? Increase in mortality: Scope within 12 hours

Answer 68

• Definition: pathological accumulation of fluid within peritoneal cavity [not only due to liver disease] • Portal Hypertension can lead to ascites and if big enough it can leak, leading to: o Rupture hernia  leaking ascites o Hydrothorax (ascites moves into lung) o (SBP) • Ascitic fluid accumulation – excess of total-body sodium and water • Mechanism: o Portal hypertension  reduces MAP  overall reduction in effective blood volume  activation of RAAS, SNS, ADH  Na/H20 retention by kidneys to increase plasma volume  persistent activation of mechanisms  ascites • Treatment o Na+ restriction: Increase net Na+ loss by reducing intake (40-60mmol/day , 1-1.5g salt/day) o Diuretic therapy: ↑ urinary Na+ excretion (reducing renal tubular Na+ reabsorption)  Aldosterone antagonist – Spironolactone (mineralocorticoid rec in collecting tubular epithelial cells)  Loop diuretics - Frusemide (inhibition of Na+-K+-2Cl- co transporter at loop of Henle) o Must maintain patients on ascites free on lowest dose of diuretics (tail down dose if controlled). Stop if: progressive renal failure, Na<125, worsening encephalopathy, incapacitating muscle cramps, SBP (SBP increases risk of renal failure, so two insults would increase problems) Both Na+ restriction and diuretic therapy is needed!

Answer 69

brain dysfunction caused by liver insufficiency and/or porto-systemic shunting; • A wide spectrum of neurological or psychiatric abnormalities ranging from subclinical (minimal) to coma (grade 4)  see right • Management o Rule out other causes of reduced consciousness o Identify and tx any precipitant acutely:  Consider Intubation if Grade 3-4.  IV Fluids  Correct any electrolyte disturbances  Enemas and Lactulose  IV Antibiotics  Stop any potential ppt medications eg sedatives o Rifaximin in prevention of HE

Answer 70

``` • CLD (chronic liver diease): Decompensated cirrhosis o HCV o Alcohol related liver disease o Non alcoholic fatty liver disease o HBV o Cholestatic Liver disease (PBS, PSC) o Auto Immune Hepatitis o Hereditary Haemachromatosis o Alpha-1-antitrypsin o Wilson’s disease o Glycogen storage disorders ``` • Hepatocellular Carcinoma ``` • Acute liver failure o Paracetamol Overdose o Acute viral hepatitis o Drug injury o Wilson’s disease ``` • Other Metabolic liver diseases (extrahepatic manifestations) o Amyloid o Urea and branched chain amino acid disorders

Answer 71

• Patient assessed with chronic or acute liver failure • Confirm any other potential treatment options have been attempted • Refer to transplant centre for assessment o Full liver work up. o Imaging (CT Triple phase) o Cardiovascular and Pulmonary assessment (ECHO, PFTs) (DSE/Carotid dopplers if Diabetic) o Renal assessment (UPCR) o Psychological assessment including risk of addictive behaviour and non-compliance. • Listed for transplantation (MDT decision – Hepatologists, Surgeon, Anaesth/ Addiction specialist/Dietician) • Regular follow-up while on waiting list o Repeat imaging (US or CT every 3/12// 6/12 ECHO) o Prioritisation if deterioration (FU 1/12)

Answer 72

• Complex operation • Most performed using a whole liver from a deceased donor • Matched for blood group and size of patient • Donor liver placed in orthotopic (normal) position • Ability however to use: o Split livers – left lobe / right lobe to two adults or a child and adult o Use living donors – proportion given from donor to recipient o Use domino livers - Amyloid patient transplanted and their liver given to another patients o DCD livers / Older livers / Steatotic livers  quality of livers are worse than brain dead body organs • Involves vascular reconstruction of HA, PV, HV into IVC • Biliary anastomosis  usually end to end (R to D); if diseased ducts may require Roux-en-Y loop

Answer 73

``` • Post transplantation – ITU stay • Start Immunosuppression: o Steriods o CNIs: Tacrolimus o Other agents: MMF / Azathioprine • Life-long follow-up and Immunosuppression: o Compliance o Abstinence from addictive behaviours ```

Answer 74

Absolute 1. Uncontrolled extra-hepatic infection 2. Active extra-hepatic malignancy 3. Severe irreversible damage to vital organs, e.g severe pulmonary HT (PA > 45mmHg despite therapy) or severe COPD.

Answer 75

• No definite age limit • All up to 65 yrs. • Over 65 years screening for co-morbidities more vigorous due to o Biological effects of age. o Assessing for > 50% likelihood of survival at 5 years post OLT. o Severity of liver disease little impact on outcome in older patients (unless severe end of spectrum). o More related to presence of renal failure / need for ventilatory support/ cardiac vascular risk

Answer 76

• Renal dysfunction: o Need to differentiate between HRS and intrinsic renal disease • Only 30 done in the UK every year  much harder to get a transplant for two organs rather than 1 (very robust system) • The worse your kidney disease the worse the survival but possible

Answer 77

• No definite age limit • All up to 65 yrs. • Over 65 years screening for co-morbidities more vigorous due to o Biological effects of age. o Assessing for > 50% likelihood of survival at 5 years post OLT. o Severity of liver disease little impact on outcome in older patients (unless severe end of spectrum). o More related to presence of renal failure / need for ventilatory support/ cardiac vascular risk

Answer 78

• Addictive behaviour: o Alcohol dependency – must show at least 6 months abstinence in UK o Recreational drugs dependency • Mental Health issues: o Any psych condition needs to be formally assessed o Compliance and attendance issues o Support network

Answer 79

• Very restricted access. • Vast majority of ALD patients are screened out in primary/secondary care. • 6-month rule in the UK: Why? o To test ability to maintain period of prolonged abstinence o Degree of recoverability: Benefits of a prolonged period of abstinence on liver function (resolving ACLF) Cases of ALD, previous drug use, current methadone use are professional assessed for risk of re-occurence of addictive behaviour.

Answer 80

• Risk of reoccurrence with immunosupression • KCH experience - Myeloproliferative disease: 2/6 patients had re-occurrence of solid tumors (colon, renal, Bladder, breast) o < 3 yrs: 2/12 patients reoccurrence • Guidelines o Tumour free periods of at least 2-5 years recommended for breast, colon, melanoma. o Oncology opinion if required

Answer 81

• No excess BMI cut off for listing • Evidence of post-operative morbidity • But no impact on post-transplant survival o However, this is most likely secondary to selection bias – highly selective to ensure good outcome. • Role of pre- or peri-operative bariatric strategies in the future

Answer 82

• Other comorbidities to be considered – Murray et al 2011, AASLD guidelines o Cardiac: Increased mortality if coronary artery disease (Stress ECHO) o Cigarette smoking: increased risk of hepatic artery thrombosis post op o Osteoporosis: needs to be treated before OLT. o HIV: needs a joint approach to follow-up o Portal Vein Thrombosis: extent of thrombosis. If extension beyond PV with no viable splanchic blood flow – surgical contraindication. o Previous extensive abdominal surgery (big problem: due to adhesions  surgeon cannot dissect down to liver)

Answer 83

 Childs-Turcotte-Pugh (CTP)  MELD score  UKELD score • Need to compare survival rates post-transplant vs. survival rates of natural disease: o Compensated: 1% 1 year mortality  no benefit from transplant o No Ascites, varices: 3.4% 1 year mortality o Ascites +/- varices: 20% 1-year mortality o Ascites +/- bleeding: 57% 1 year mortality ``` Therefore the development of decompensation: (Would indicate need for assessment for transplantation) o Ascites o Variceal Bleeding o Spontenous Bacterial Peritonitis (SBP) o Hepatic encephalopathy o Hepato-renal syndrome ```

Answer 84

• Designed to stratify risk of surgery in patients with cirrhosis (Pugh et al 1973) • Never formally validated as a prognostic tool • Useful rapid method of assessing risk of mortality in cirrhotics • Widely adopted for risk stratifying before OLT. o Three objective measures o Two subjective measures o Minimum score is 5 o Maximum is 15 • Simply: o Grade A = compensated cirrhosis o Grade B and C = equivalent to decompensated cirrhosis

Answer 85

• Originally designed to assess short term prognosis in for TIPS • Complex score based on serum bilirubin, INR, serum creatinine o (9.57 x log Creat + 3.78x log Bil + 11.2 x log INR + 6.43) • Score range 6-40 high MELD = low 3m survival MELD > CTP in estimating 3 month survival Higher the MELD, higher the benefit from transplant MELD > 11 = benefit from transplant

Answer 86

* Modified version of the MELD score: addition of Na to algorithm * Scoring system used by UK transplant centres * Developed retrospectively in 1103 patients and validated prospectively in 452 patients * In UK. OLT survival = 90% at 1 yr * UKELD > 49. Indicates >10% mortality if patient not transplanted. * Therefore UKELD score of 49 used as cut off (since chance of surviving < the risks of having a OLT)

Answer 87

• Clinically decompensated o Child-Pugh score of >7 (i.e. Grade B or C) o MELD score > 10 o UKELD score > 49.

Answer 88

HCC • Hepatocellular carcinoma, most often occurs in the background of cirrhosis, but not always • Mazzaferro et al 1996 (NEJM) described criteria for liver transplantation known as the ‘Milan’ criteria o 1 tumour up to 5cm OR o 3 tumours up to 3cm each. o No evidence of vascular invasion o No extrahepatic spread. o No exception points in the UK for HCC • Extended criteria: Duvoux et al 2012, Gastro o USCF criteria (USA/ India etc)  One lesion <6.5cm Multiple lesions – largest 4.5cm/ cumulatively • Yao et al 2001, Hepatology o Duvoux Criteria  AFP > 1000 predictive of high risk of reoccurrence  AFP model: score based on size of largest lesion/ number of lesions/ AFP level  Score <2: infers low risk of reoccurrence  High risk patients can become low risk patients after loco-regional therapy (ablation/TACE/TAE) CCA • Controversial – high risk of reoccurrence • No UK centre • Limited number of centres worldwide: limited to perihilar and hilar CCA. • Very narrow selection criteria: 65% disease free reported. Acute Liver Failure – Very rare! • ALF is a syndrome of rapidly progressing liver failure with coagulopathy (INR >5) and encephalopathy. With a duration < 26 weeks, with no evidence of pre-existing chronic liver disease.  AASLD guidelines. Lee et al 2010 • All patients with ALF should be discussed with a transplant centre, with a view to early transfer if they are encephalopathic. • Common causes are: o Paracetamol overdose (POD) o Acute viral hepatitis e.g HBV o Drug reactions (including herbal remedies) o Post transplant – HA thrombosis / early graft dysfunction o Other causes – Wilsons disease / Budd Chiari

Answer 89

* Early stage A * Primary Rx of small, localised tumours * Bridge to transplantation * Mechanism of action: destroy tumour cells directly or fluctuations in temperature (electrocution of cancer itself) * Patients have to be well enough to have a sedative to then have ablation. Very few contraindications which include: Child-Pugh D, unable to take a sedative, location of tumour (near diaphragm or gallbladder) ``` • Thermal (done mostly in UK) o Cryo-ablation  freeze cancer o High intensity focused ultrasound o Microwave ablation o Radiofrequency ablation ``` • Non-thermal o Alcohol ablation (done in third-world countries where ablation techniques are not common) o Irreversible electroporation Evidence – Ng, 2007 • N= 207. Median follow-up 26months • Mortality & morbidity: 1% & 16% o Complete ablation: 93% o Local recurrence: 15% o Distant mets: 10% • Overall 1, 3 & 5yr survival : 87, 67 & 42%

Answer 90

* Normal liver receives 75% blood supply from portal vein * Hepatic malignancies receive 75% from hepatic artery * Embolisation of hepatic artery selectively induces tumour necrosis * Response rates of most malignancies proportional to area under drug concentration-time curve (AUC) * Arterial delivery increases drug concentration in liver tumours 10-100X * Embolisation prolongs the dwell time from hours to weeks – increase AUC by order of magnitude * Hypervascular liver lesions accumulate lipiodol * Lesion does not contain Kupffer cells * Lipiodol/cytotoxic agent emulsion persists in lesion, lipiodol blocks arterioles at 30um level * Arterial occlusion increases ischaemic insult * Cellular pump that removes doxorubicin from the cell is reduced in an ischaemic environment

Answer 91

* In 10% patients, it shows leaking into circulation resulting in the complications. * Toxic hepatitis/Liver failure * Abscess or infarction (5%)  biliary/enteric anastomosis, sphincterotomy * Biloma, biliary stricture * Cholecystitis or gallbladder infarction (<1%) * Cardiac toxicity – doxorubicin (due to anatomical differences as some patients will have a connection between portal vein and hepatic artery so chemotherapy can spread) * Renal failure * Potential extrahepatic chemoembolisation * 30d mortality 1-3% with some deaths being disease related

Answer 92

• Infusion of radiolabelled glass or resin beads into tumour-feeding blood vessels  i.e. targeting microvessels instead of blocking the whole hepatic artery and using theranostic approach • 2 studies: SARAH (n=476) & SIRveNIB (n=360) o beads vs sorafenib for advanced stage disease SARAH Study • No significant improvement in overall survival (primary endpoint not met) • Significantly better-tolerated treatment • Significantly reduced frequency and severity of side effects • Significantly better Quality of Life • Significantly improved PFS and TTP in the SIRveNIB study (overall and in the liver; treated population) A combination of TARE + Sorafenib also showed no significant improvement in survival of advanced stage disease. No-one has compared TARE vs TACE – important to address.

Answer 93

Signalling Transduction Pathways • 2 pathologic processes predominant in HCC o Cirrhosis o Mutations in oncogenes or tumor suppressor genes • Trigger signaling cascades • 5 independent pathways that act as molecular drivers of carcinogenesis in HCC, including: o VEGF  angiogenesis o EGFR o Wnt signaling o Pi3k o Ras/RAF pathway • Difficult to design a drug as these are all independent  blocking off one will not fix the other Angiogenesis • Liver is a highly vascular organ • Balance between pro- & anti-angiogenic factors • Balance disturbed in HCC Function of Sorafenib • Inhibits VEGF/PDGF RTKs as well as Raf Kinase • Inhibits migration/metastasis + angiogenesis ``` SHARP study – Llovet 2008 (n-602) • RCT, double blind • Improved life by 3 months (7.9 to 10.7 months) • Approved 1st line • Child Pugh A (only A in UK) or good B • Adverse events: well-tolerated o Grade 3 side-effects only 3/297 o Hand-foot skin reaction (skin of hands and feet peel off), diarrhoea and hypertension are the major side-effects ```

Answer 94

• Inhibitor of multiple receptor tyrosine kinases, VEGFR 1-3, FGFR 1-4, PDGFRα, RET, KIT • RCT (n=950), REFLECT study o Sorafenib vs Lenvatinib o Non-inferior OS (13.6 vs 12.3 months for sorafenib (HR, 0.92; 95% CI, 0.79-1.06)  as good as Sorafenib, side effects are similar

Answer 95

• Analogue of sorafenib • RCT, childs pugh A only o 3month improvement in survival compared with best supportive care • ‘the most ridiculous drug in the world’

Answer 96

• It is known that persistent infection leads to chronic inflammation which then leads to cancer • Examples of this theory include: o HBV  HCC o HPV  cervical cancer o H. Pylori  gastric cancer o UC  colorectal cancer • There are direct and indirect mechanisms for each of Hepatitis B, C and D

Answer 97

• HBV DNA integrates within chromosome of infected hepatocytes • Typically HBV DNA integration is in random / non critical regions but sometimes viral genetic material in critical location in cellular genome eg HBV DNA within genes crucial for cell growth: o retinoic acid receptor α gene o human cyclin A gene o P53, Wnt/b-catenin o TGF b, Ras signaling • Length and component of DNA varies • Animal models have shown that HBx gene may be important for replication and regulation of cellular transcription and proliferation o HBX gene is a implicated as a transcriptional activator of cellular genes associated with cell growth o HBx gene expression is associated with activation of Ras-Raf-mitogen activated protein kinase (MAPK) pathway  implicated in hepatocarcinogenesis o HBx interacts with p53  impairs its function as a TS gene • Of note: the integrated HBV genome cannot support HBV replication (as it disrupts circular nature of viral genome) but it can activate/disrupt gene expression/activity of host cellular proteins [e.g. in woodchucks integrated woodchuck hepatitis virus genome often located near N-MYC2 gene is involved in cellular transformation]

Answer 98

• Indirect viral effect: o Inflammation  regeneration  fibrosis • Combination of virus and cirrhosis is important Evidence for Indirect mechanism • 70% HBV associated HCC occurs with cirrhosis • Cirrhosis of any cause associated with HCC • Patients with undetectable HBV DNA still get HCC

Answer 99

• Tend to be older patients • Less aggressive HCC compared to other causes o Can remain as a single nodule for many years • More common if associated with alcohol excess • Risk of HCC persists in cirrhotic patients even after viral eradication • HCC = commonest cause of death in HCV cirrhosis • HCV more important as a cause of HCC in Western countries than HBV • Risk is proportionate with severity of fibrosis/time of acquisition • HCV RNA o No reverse transcription activity so cannot integrate into host genome o Hence carcinogenesis is indirect: cell death, inflammation, proliferation, cirrhosis

Answer 100

Indirect Mechanism • Unable to integrate into host genome o Need reverse transcriptase to make DNA from an RNA template (not found in host cells) • HCV requires continuous replication for viability • HCV progression to HCC is a multi-step process o Establishment of chronic HCV infection  persistent chronic hepatic inflammation  progressive fibrosis  initiation of neoplastic clones with irreversible genetic changes  progression of malignant clones in carcinogenic tissue microenvironment o This process takes 20-40 years and is dependent on genetic susceptibility

Answer 101

• HCV in non-cirrhotic HCV is rare • Some developing experimental evidence that HCV contributes directly to malignant transformation of hepatocytes o 3 different HCV core transgenic mice develop steatosis and HCC suggesting the HCV core protein is oncogenic  Mechanism for this is unclear  oxidative stress?  HCV core protein can bind to several tumour suppressor proteins including p53, p73 pRb, ie transcriptional regulatory function  When comparing mice transgenic for the non-structural NS5a protein do not get HCC • HCV cannot integrate into host genome but can still interact with host proteins and induce host responses that may contribute to malignant transformation of cells

Answer 102

• Heterogeneity of genetic events in HCV HCCs: o Complex mechanisms o Viral proteins implicated in several cellular signal transduction pathways o ® cell survival, transformation, proliferation, migration • NS3 protein and NS5A protein both may interact with various signal pathways including cell cycle/apoptosis • Hepatocarcinogenesis is a multistep slow process (20 yr+) • Progressive accumulation of different genetic alterations ® malignant transformation o Liver cell turnover, induced by chronic liver injury and regeneration  inflammation and oxidative DNA damage etc • Mechanism of fibrosis and hepatocarcinogenesis o Liver injury  activation of hepatic stellate cells (HSC)  lay down ECM  cirrhosis o Activated HSC  up-regulated response to cytokines in MAPK (regulate proliferation/mitosis/apoptosis) • Cirrhosis = a pro-carcinogenic environment (fosters initiation and promotion of neoplastic clones): o Telomere shortening i.e. chromosomal instability o Reduced tumour surveillance function due to loss of NK cell function o Severity of fibrosis is tightly correlated with risk of HCC in HCV (main mechanism) • HCV proteins stimulate profibrogenic mediators (e.g. TGF-beta) and proinflammatory chemokines e.g. IL-8 o Hepatocyte death = major stimulator to hepatic stellate cells

Answer 103

• Delta coinfection o HCC mean age 48 v 62 yo (Verme et al 1991) • HIV coinfection o HCC in HCV/HIV earlier compared to if only one infection • S.mansoni o ↑ HCC in HCV/S.mansoni coinfection • Alcohol o ~ 2fold ↑ in HCC in HBV and HCV in heavy drinkers (>60g/d) • Diabetes, especially with alcohol o Odds ratio 9.9 (Hassan et al 2002 Hepatol) • HBV • Obesity 2-4 fold - steatosis associated with HCV o HCV core proteins involved in lipid metabolism

Answer 104

• Vaccination o Remember not all are vaccinated if baby is not born in a hospital • Antiviral treatment – HBV and HCV o RCT lamivudine v placebo  Advanced chronic HBV, high titre HBV DNA  ↑ decompensation events and HCC in placebo group 7.4% v 3.9% p=0.047 o Now much more successful treatments (>95% success)  Pegylated interferon and Ribavirin (now historic)  Protease/polymerase/NS5 inhibitors  Risk of HCC eradicated if treated before cirrhosis develops  HCC ↓ in those who achieve SVR after interferon in HCV. But risk of HCC continues in HCV cirrhosis even after SVR. Long term peg IFN (in those without SVR) does not prevent HCC - HALT Study 2009  RCT – maintenance lamivudine decreases HCC occurrence in patients with advanced fibrosis - Liaw 2005, NEJM  Development of resistance with virological breakthrough associated with loss of beneficial effects of treatment on HCC development - now overcome with more potent antiviral – new generation antiviral;s: tenofovir - Di Marco Hepatol 2004 • Surveillance o All cirrhotics should be screened o High risk HBV carriers without cirrhosis  Asian men>40, Asian women >50  FH HCC  Africans >20  Age >40 and persisting active disease ie ↑ALT / HBV DNA >10,000c/ml o Screening = 6 monthly Ultrasound and αFP  Very expensive • Antifibrotics

Answer 105

• HBV vaccination in children in Taiwan – first example of cancer prevention by vaccination • Universal vaccination programme – 3-4 doses , 1st week of live • Results: o HBsAg reduced from 10-17% to 0.7-1.7% o HCC incidence in children 6-14 reduced from 0.52 to 0.13 per 10000 • Vaccination can fail – causes: o In-utero infection before vaccination can be established o Vaccine escape mutants can emerge in vaccinated subjects (surface antigen mutations) o Genetic hyporesponsiveness – vaccine failure in 5-20% o Poor compliance/infrastructure o Very high maternal virus levels * ~90% countries now vaccinate new borns against HBV * ~70% achieving 3 vaccination doses

Answer 106

* Progressive acute renal failure in patients with advanced liver disease, with no identifiable intrinsic renal disease * Intimately linked to portal HTN

Answer 107

• ‘Functional disorder’ – i.e. anatomy is normal, it is the environment that the kidneys are in that cause the disorder o Evidence:  Renal function returns to normal after liver transplant  Kidneys from HRS patents work well in renal transplant recipients • Pathophysiology o PARADOXICAL renal vasoconstriction in face of systemic vasodilation (i.e. (perceive that there is not enough volume in your circulation and they shut down to maintain volume) o This occurs as a result of competing pressor and vasodilator influences in cirrhosis o In HRS  Splanchnic vasodilation  shear stress (frictional force generated by blood flow)  Nitric oxide release locally (signalling cascade by endothelial cells)  released systemically  further splanchnic vasodilation increase portal inflow  worsening of portal HTN (NB: although the architectural changes in the liver are associated with deficient NO in liver and increased vascular tone (therefore increased hepatic resistance and portal pressure), opposite effect in splanchnic arterial circulation where NO production increased splanchnic VD etc).  Activation of RAAS: Splanchnic VD  reduced effective circulatory volume  activation of RAAS  Angiotensin release in response to vasodilation but has reduced systemic effect in face of vasodilators  However – angiotensin effect maintained in renal circulation  renal vasoconstriction blood flow to kidneys restricted (‘peripheral vasodilation hypothesis’)  HRS Increased synthesis vasoactive mediators e.g. endothelium-1, thromboxane A2  decrease renal blood flow/function Additionally, renal sodium avidity  ascites. o Hyperbilirubinaemia  increased renal vasoconstrictor response to pressors o Furthermore, impaired cardiac function (cirrhotic cardiomyopathy)  relative impairment of the compensatory CO increase in response to VD

Answer 108

* Peripheral vasodilation * Decreased systemic response to vasoconstrictors * Increased cardiac output * Increased HR * Bounding pulse * Warm peripheries

Answer 109

``` • Urine output decreased • Creatinine increased • Urine sodium low/non-existent • Urine concentrated: o High urine: plasma creatinine ratio o High urine: plasma osmolality • Clinical: o Ascites, hypotension, oliguria, jaundice ```

Answer 110

* GFR measures kidney function =sum of the filtration rates of all your functioning nephrons * Estimate normal GFR: eGFR : GFR = 140 – [your age]. E.g. fit, healthy 30 year old – GFR should be ~110mls/min i.e. kidney filters 110ml/min. OR use eGFR calculator/MDRD equation

Answer 111

GFR Clinical result (ml/min/1.73m2) Stage 1 >90 Kidney damage, normal function Stage 2 60-90 Kidney damage, mildly impaired function Stage 3 30-60 Kidney damage, moderately impaired function Stage 4 15-30 Severe reduction in function Stage 5 <15 Kidney failure (need dialysis or kidney transplant)

Answer 112

``` 1. Hypovolaemia/Acute tubular necrosis o Commonest cause of renal failure in cirrhosis  GI bleeding  Post-paracentesis  Over-vigorous diuretic treatment ``` ``` 2. Drugs (nephrotoxic) o Aminoglycoside Abx o NSAIDs o Diuretics o ACE I/ATII inhibitors, alpha-1 blockers ``` 3. Intrinsic renal disease o Associated with liver disease:  Glomerulonephritis – viral hepatitis, alcohol  Autoimmune disease  Α1 antitrypsin deficiency  Fanconi’s syndrome (seen in Wilson’s disease)  Polyarteritis nodosa (seen in HBV) Risk of HRS after onset of ascites • 20% - 1 year • 40% - 5 year Hence if patient does not have ascites then it is rare for HRS to develop – HRS is a late stage in the manifestation of liver disease.

Answer 113

Type 1 • Acute clinical course (<2 weeks) (rapidly progressive) • Precipitating event e.g. bleed, peritonitis (with close temporal relationship) o Precipitating factors for T1 HRS: Over diuresis, bleeding varices, large-volume paracentesis, infection, liver failure (Wong et al, 2012, Nat Rev Gastroenterol Hepatol). These are the same even for those whose HRS persisted after liver transplantation (however if done early enough, HRS should reverse with liver transplant). Yellow = HRS- after liver transplantation, blue = HRS+ after liver transplantation. • Creatinine ≥2.5mg/dl &twice baseline in <2 weeks – definitions in clinical studies, not necessarily used in clinical practice Type 2 • Chronic course (slower and more modest renal impairment) • Refractory ascites (sodium retention) • Steady deterioration in renal function over several weeks/months • Can develop type 1 after trigger

Answer 114

Major criteria • Acute or chronic liver disease with synthetic liver failure ± portal HT • No hypovolemia, sepsis, nephrotoxic drugs • GFR<40ml/min • Not improved by fluid challenge (1.5l NS) • Proteinurea<0.5g/d (protein in urine indicates an intrinsic problem) • Normal renal tract on USd ``` Minor criteria • Urine Na <10mmol/d • Urine vol <500ml/d • Urine osm>plasma osm • Serum Na <130 mmol/l • Urine rbc <50 cell/HPF (red blood cells in urine imply intrinsic problem with kidneys) ```

Answer 115

• Supportive / treat other complications of cirrhosis o Monitor UO/fluid balance/BP – CVP o Screen for sepsis o Prophylactic Antibiotics if indicated • Avoid fluid overload / exacerbation of hyponatremia • Paracentesis with albumin if tense ascites • Stop diuretics/avoid potassium sparing diuretics • Vasoconstrictor – Terlipressin: vasopressin analogue (used in oesophageal varices) o Reduce systemic vasodilation  increase BP  increase renal perfusion pressure o Vasoconstricts splanchnic vascular bedsystemic BP,  portal pressure (but reducing portal inflow) o Large no. placebo controlled RCT shows  Improves renal function in type 1 HRS ± survival  Effective in 40-50% o Lack of dose finding studies  Usually 1mg 4-6 hourly  2mg 4-6hrly  Continue until creatinine is normalised  Also  BP, urine vol, serum Na  Median time 14d  SE: ischaemia - Cardiac , digital, mesenteric o Give with albumin 1g/kg day 1 then 40g/d (100ML 20%HAS = 20G albumin) o Monitor CVP o Other vasoconstrictors: Noradrenaline and midorine o Albumin and terlipressin better than terlipressin alone (Arroyo J Hepatol 2007)  Increase in mean arterial pressure of >5mm Hg on day 3 predictive of positive response.  Less data for type 2 HRS but still useful (1 RCT shows that norfloxacin 400mg/d reduced incidence og HRS in cirrhosis, prophylactic albumin during treatment for SBP reduced incidence of HRS)

Answer 116

• Treatment of choice for HRS (type 1 and 2) • Expect transient worsening: Continue to require renal support transiently • Improvement: Increase in urine Na • However o complication rate cf OLT for non HRS o Slight  survival 60% 3year o Reduced survival in type 1 – 65%  renal failure predictor of poor outcome post OLT, high mortality on waiting list and combined liver and kidney transplant is not needed • Main limitation is organ availability in HRS type 1: HRS prioritised due to UKELD scoring (INR,bili, creat , Na) • HRS does not recur in majority - Recurrence in 20% • Survival dependent on reversal of HRS

Answer 117

• Transjugular intrahepatic portacaval shunt • As portal HT is driver to hemodynamic changes of HRS TIPSS = logical treatmentportal sinusoidal pressure  Returns splanchnic blood volume to central circulation • Reverses HRS in ~50% • Contraindications: o Marked Jaundice o Encephalopathy • Hepatic encephalopathy common post TIPS ~50% • Not commonly used since HRS patients have very advanced liver disease • ?greater role in type 2 HRS where vasoconstrictors /albumin less useful due to high rate of recurrence ie LIMITED IN TYPE 1 BECAUSE ALREADY SEVERE LIVER DYSFUNCTION)

Answer 118

• 3 limited studies addressing prevention: o IV albumin in patients with diagnosis of SBP beneficial  HRS develops in ~30% with SBP, so use if high risk for HRS ie BR>68, PT, baseline renal impairment o Primary prophylaxis with norfloxacin in cirrhotic patients with ascites o Prophylactic antibiotics after GI bleed o Pentoxyfilline in patients with acute alcoholic hepatitis reduced HRS (8% v 35%)  no benefit in survival so not widely taken up

Answer 119

• Average median survival type 1 HRS – 3months o Untreated median survival 1 month • survival with MELD score (bili , creat , INR , age) • Reversibility dependent on: o resolution of sepsis o age o bilirubin o nosocomial infection – more resistant to treatment so harder to reduce HRS o rate of reduction in creatinine ie improvement at day 3 of antibiotic • No reversibility associated with more severe circulatory disturbance (Gines et al hepatol 2013)

Answer 120

* Intermediary metabolism * Protein synthesis * Xenobiotic metabolism (external e.g. drug metabolism) * Hormone metabolism * Bile synthesis * Reticulo-endothelial  in foetus RBCs are made in the liver, if BM is compromised e.g. in myelodysplastic syndrome, the liver can take over haematopoiesis

Answer 121

* Metabolism is zonal  Lobular structure * Blood flows in from portal tracts (portal vein and hepatic artery) and leaves lobule through the central vein to IVC through hepatic veins * Hepatic artery carries oxygen hence area 3 = less oxygenated as that is where central vein lies * Sinusoids are found between three zones * In Zone 1 = more gluconeogenesis, and zone 3 more glycogenesis * Protein is made in all zones * But CytP450 is more active in the central zone as this is where drugs can cause most damage

Answer 122

• Glycogen storage (and release  can go wrong in glycogen storage diseases) • Glucose synthesis (gluconeogenesis) o Hence why hypoglycaemia can occur in ALF • Fatty acid synthesis • Lipoprotein metabolism

Answer 123

• Lots of proteins made by the liver o Most important = albumin • 2 sorts of proteins can be misleading if measured: o Acute phase reactant à these go up in inflammation giving misleading high levels (CRP is used in clinical practice) o Vitamin K dependent à particularly in patients that are yellow

Answer 124

``` • Conjugation o Glucoronate o Sulphate • Chemical modification o P450 enzyme system o Acetylation/de-acetylation o Oxidation/Reduction • Excretion ```

Answer 125

``` • Vitamin D o Hydroxylation o Absorption • Steroid hormone o Conjugation o Excretion • Peptide hormone o Catabolism ```

Answer 126

``` • Bile acids • Bilirubin o Metabolism: Red cells are broken down à release unconjugated bilirubin  BR then conjugated in the liver and exported to biliary system  various bacterial enzymes break down this conjugated bilirubin into urobilinogen that is excreted by the kidneys (see right) • Phospholipids • Cholesterol • Proteins • Drugs and metabolites ```

Answer 127

* Excretion * Micelle formation * Digestion

Answer 128

``` • Erythropoiesis • Kupffer cells (found in sinusoids, similar to macrophages) o LPS clearance o IgA receptors o Clearance of portal infection ```

Answer 129

N.B. Typical liver function enzyme tests do not tell you anything about the function of the liver (AST/ALT/ALP/GGT). Urine dipstick tests • Bilirubin o Not normally detected in urine o Large amounts detected with the naked eye • Urobilinogen o Normally detected in small amounts in urine o Cannot be detected in extra-hepatic biliary obstruction Alkaline Phosphatase • Derives either from liver or bone (isoenzyme analysis or gGT test will discriminate, i.e. if GGT normal then it is likely to be related to bone metabolism) • Hepatocyte damage leads to increased synthesis and release into serum through leaky bile canaliculae Aminotransferases • Cytosolic enzymes found in a number of tissues • ALT more liver specific than other enzymes • Increases reflect hepatocyte necrosis but are very non-specific  reflects inflammation occurring in liver gGT • Raised in both hepatocellular damage and in cholestasis • May be raised by alcohol abuse or certain drugs (e.g. anticonvulsants)

Answer 130

``` Coagulation Serum albumin Aminopyrine Breath test Galactose elimination Indocyanine Green - Haegele S, PLOs One, 2016 ``` ``` Other Tests used in Diagnosis Used to uncover aetiology of liver disease. • Viral serology • Auto-antibodies • Iron studies • Copper studies • Radiological imaging – US and CT • Histopathology • ERCP ```

Answer 131

• All coagulation proteins (except von-Willebrand factor VIIIC) are synthesised in the liver • Synthesis of 2, 7, 9, 10 are vitamin K dependent • Vitamin K is fat soluble and cholestasis may impair its absorption • Coagulation factors are measured by the prothrombin time o N.B. after vitamin K administration if cholestasis expected

Answer 132

``` • Serum albumin reduces with worsening liver function, but this affected by other things e.g. patients nutrition hence: • First exclude o Protein losing enteropathy o Nephrotic syndrome o Sepsis o Diet ```

Answer 133

• Measures microsomal function o 13C-methyl aminopyrine is taken by mouth or IV o Demethylated in the liver by the microsomal P450 enzyme system o 13CO2 measured in breath • Pros o Correlates with survival in cirrhotics o Correlates with survival in fulminant liver disease • Cons o Susceptible to p450 enzyme induction or inhibition o No better than clinical parameters in prediction of survival in cirrhotics hence not used in clinical practice

Answer 134

• Measures cytosolic function o Intravenous admin o Serial blood sampling o OR Oral/IV administration of 13C-labelled galactose with serial breath tests • Pros o Reproducible o Correlated with survival in cirrhotics o Correlated with survival in fulminant liver disease • Cons o Repeated sampling required o Diabetes and variation in oral absorption affect breath test results (NAFLD is important)

Answer 135

- Haegele S, PLOs One, 2016 * This is used to check for enough residual function prior to liver resection * Correlates with post-surgical morbidity and mortality

Answer 136

``` Encephalopathy • Early symptoms and signs o Personality change o Anti-social behaviour o Nightmares o Headaches, dizziness o Delirium and mania o Fits o Asterixis o Hepatic foetor ``` • Late symptoms and signs o Decerebrate rigidity  spasticity, extension and hyperpronation of the arms  extension of the legs with initially plantar and ultimately extensor plantar responses o Dysconjugate eye movements o Respiratory and circulatory failure (secondary to brain stem failure)

Answer 137

1- confused or altered mood 2- inappropriate behaviour or drowsiness 3- stuperous but arousible, markedly confused 4- coma, unresponsive to stimuli

Answer 138

• Prognosis in cirrhosis o Selection for transplantation • Prognosis in ALF • Feasibility of resection in HCC

Answer 139

* Originally developed in pts with variceal hemorrhage to predict outcomes * Scores can be turned into grade (A, B, C) * Ascites and encephalopathy = clinical assessments so a disadvantage to scoring system Score 1 2 3 Ascites None Mild Severe Albumen >35 28 – 35 <28 Bilirubin <34 34-51 >51 Encep. None I / II III/IV INR <1.7 1.8 – 2.3 >2.3 Grade Score 1 year survival 2 year survival A - 3-6 100 85 B - 7-9 80 60 C - >9 45 35 ``` A = Compensated cirrhosis B = Intermediate C = decompensated cirrhosis ```

Answer 140

``` • Definirion of decompensation is dependent on development of: o Ascites o Encephalopathy o Variceal haemorrhage o Cancer ``` When decompensation occurs = QOL decreases, increased mortality and so patients are in need of liver transplantation.

Answer 141

Score = 9.57 x Ln(creatinine) + 3.78 x Ln (bil) + 11.2 Ln (inr) + 6.43 – Kamath Hepatology 2001 * N.B: Creatinine = kidneys start to fail with increasing liver failure * MELD score correlates with 3 month mortality

Answer 142

``` • King’s College Criteria Paracetamol o Either Arterial pH < 7.3 o Or three of  PT > 100  Creatinine > 300  Encephalopathy > 2 ``` ``` • King’s College Criteria Non-Paracetemol o PT > 100 o Or three of  Age< 11, > 40  Bilirubin > 300  Jaundice – Coma time > 7 days  INR > 3.5 ``` Kanofsky Performance Status A method of assessing how well people are functionally – irrespective of disease form.