Module 2.3: Liver Flashcards
Epidemiology of HCC
- Commonest primary cancer of the liver worldwide
- 5th commonest cancer
- 3rd leading cause of cancer-related death (after Lung & GI)
- Incidence 500,000-1,000,000/year
- 750,000 deaths/year
Liver is also a common site for secondary metastasis.
• Most cases HCC occur in Asia
• Very high incidence in East Asia
o 99/105 people in Mongolia
o 49/105 Korea
o 29/105 Japan
o 35/105 China
• Sub-Saharan Africa, West Africa (Gambia, Guinea, and Mali)
• Moderately high risk (11–20 cases/100,000): Italy, Spain and Latin American
• Intermediate risk (5–10 cases/100,000): France, UK, Germany
• Relatively low incidence (less than 5 cases/100,000) US, Canada,
• Large areas of the world where the incidence is still unknown
o Due to resource poor countries poor data collection
• Men: HCC 2 - 5x more common than in women
- HCC incidence increases with age
- Highest prevalence in >65y
- HCC rare before 50y in North America & Western Europe
- But a shift in incidence towards younger persons noted in last two decades
Risk Factors in HCC
• Chronic hepatitis and cirrhosis of any cause: 2-4% annual incidence
o 80-90% of all HCCs occur on a background of chronic liver disease
• Hepatitis B virus and level of HBV-DNA
• Toxins:
o Aflatoxin: mycotoxin that commonly contaminates corn, soybeans, and peanuts
o Betel nut chewing
- Hepatitis C: 1/3 HCC cases
- Iron Overload/Haemachromatosis
- Tobacco and Alcohol abuse
- Nonalcoholic Fatty Liver Disease and Diabetes
Coffee in HCC
o Observational studies suggest coffee is a protective factor for HCC.
o 2 or more cups/day associated with 43% reduction of HCC
Role of Hepatitis B in HCC
55-65% of HCC cases related to HBV
• 100X more infectious than HIV
• 10X more infectious than HCV
• Worldwide, accounts for >50% of all HCC cases and virtually all childhood cases
• WHO rates Hep B as the 2nd most important human carcinogen (1st = tobacco)
Pathogenesis of HCC
risk factors cause chronic injury to the hepatocytes
This causes necrosis and subsequent regeneration and proliferation
Over time, there is proliferative arrest and increased stellate cell activation, causing liver cirrhosis
scarred and cirrhotic tissues, hyperplastic nodules form (regenerative)
They undergo genomic instability and become dysplastic
Marked genomic instability and loss of p53 causes carcinogenesis
Another important step between the formation of HCC and a dysplastic nodule is angiogenesis (formation of new blood vessels) this is used as basis to form a diagnosis and provide a target for treatment
Molecular Pathogenesis of HCC
150 mutation driver genes known in Human Cancer
0-40 mutations per tumour – not all cancer drivers (Volgenstein 2013)
Examples of signalling pathways in HCC which have been reported to be activated in differing studies (10-50% of HCCs)
o Beta-catenin o pERK o pAKT o p56 o mTOR o NOTCH o IGF-2 o kRas, Hras o Others: e.g. UHRF1, pRAF, MER
Hepatitis C Molecular Pathways in HCC
- Hep C = RNA Virus
* Wnt, Raf, ERK activation
Hepatitis B Molecular Pathways in HCC
- Integration of viral DNA randomly into host genome
- P53 mutation
- Ras activation
- Microdeletions e.g. PDGF, TERT
- HBx protein induces HCC in transgenic mice
Why is HCC more common in Men?
• Risk factors are more common in men e.g. men are thought to be more promiscuous hence higher chance of having Hep B/C/HIV, men drink and smoke more
• More recent epidemiological studies reveal risk factors are not the only cause (not just related to lifestyle)
• Molecular Mechanism thought to relate to IL-6
o Mediator produced by Kupffer cells that promotes HCC
o Oestrogens inhibit Il-6 women protected?
Explain the difference between screening and surveillance
• Screening - application of diagnostic tests in patients at risk for HCC, but in whom there is no a priori reason to suspect that HCC is present
• Surveillance - repeated application of screening tests in high risk groups
o >80% HCC cases develop in setting of cirrhosis/chronic liver disease
Describe the supporting evidence for surveillance of HCC
• Zhang et al. J Cancer Res Clin Oncol. 2004 (China):
o RCT: surveillance vs no surveillance;
o Showed survival benefit of 6-monthly surveillance with
serum AFP + liver USS
o 18,816 pts with hepatitis B infection
o Adherence to surveillance poor (60%)
o But in surveillance pts, HCC related mortality was reduced by 37% (5y f/up)
AFP in HCC surveillance
Alpha Feto Protein
• AFP only found in pregnant women as they produce it due to foetal production, otherwise levels should be low unless one has a tumour: HCC or teratoma
• AFP about 20 ng/mL provides optimal balance: sensitivity vs specificity
o Even then sensitivity only 60%
- Higher cut-off means a smaller proportion of HCCs will be detected
- Reducing cut-off means more HCCs identified, but an increase in false +ve rate
- AFP > 200ng/mL has a very high positive predictive value for HCC
- Persistently elevated AFP shown to be a risk factor for HCC
Ultrasonography (USS) in HCC surveillance
- Bolondi et al, Gut 2001
- HCC classically hypoechoic
- Sensitivity 65-80%; Specificity >90% as screening test
• But
o USS performance not well defined in nodular cirrhotic livers (<1cm)
o Operator dependent
o Difficult in obese patients
• Ideal surveillance interval 6 months proposed based on tumour doubling times
- 80-90% HCC cases develop in setting of cirrhosis
- Surveillance is cost-effective in cirrhosis
• Hepatitis B carriers (RR 100, ↑with age)
o Asian males >40 yrs
o Asian females >50 yrs
o All cirrhotics
o Family history HCC
o Africans over age 20
o Patients with high HBV [DNA] and with ongoing hepatic inflammatory activity remain at risk for HCC
Not screened:
• Non-hepatitis B cirrhosis
o Hepatitis C
o Alcoholic cirrhosis - up to 35% of all HCCs (Hassan et al. Hepatology 2002; Schoniger-Hekele et al. EJGH 2000)
o Genetic haemochromatosis – HCC RR x 20; incidence 3%/year
o Primary biliary cirrhosis – incidence same as for Hep C cirrhosis
Screening Hepatitis C Cirrhosis for HCC risk
• Hepatitis C - HCC risk 2-8%/year (RR x 20)
• Non-invasive markers to predict the stage of fibrosis?
o Platelet count, alpha 2-macroglobulin, apolipoprotein A1, haptoglobin, bilirubin and gamma-glutamyl-transpeptidase, AST/ALT ratio
o Fibroscan, MRI etc
o None validated, cannot be recommended
Co-infection with HIV in risk of HCC
- More rapidly progressive liver disease
- When cirrhotic, have ↑ risk of HCC
- MORTAVIC study - HCC caused 25% of all liver deaths in post-HAART era (Rosenthal AIDS. 2003; Puoti AIDS 2004)
• Treated Viral Hepatitis
o Regressed fibrosis is not a reason to withhold surveillance
• Patients on Liver Transplant Waiting List
o Continue surveillance
Importance of early diagnosis in HCC
- Nakashima et al. Hepatol Res. 2003: The smaller the lesion, the less likely there is to be microscopic vascular invasion
- Sala et al. Hepatology 2004: The smaller the lesion the more likely it is that local ablation will be complete
Diagnostic methods in HCC
• Radiology (inc cross-sectional): HCC vascular tumour, Biopsy, AFP
• Lesions <1cmØ
o Low likelihood of HCC
o US at 3 month intervals
o If no growth in two years, revert to routine surveillance (level III)
• Lesions >2cmØ (Torzilli et al. Hepatology 1999; Barcelona-2000 EASL conference)
o Detection of a >2cm mass within cirrhotic liver is highly suspicious of HCC
o If:
AFP > 200 ng/mL and
Radiology suggestive of HCC (e.g. characteristic arterial vascularization; “washout” in venous phase), seen on two imaging modalities, eg, triphasic CT scan and MRI (gadolimiun) if 1-2cm
• HCC is v likely and biopsy is not essential
o If imaging atypical/AFP low, differential Dx is broader, consider biopsy
o Positive Predictive Value >95% (radiology)
Changes in intranodular blood supply with the progression of hepatocarcinogenesis
- The more dysplastic and cancerous the hepatocyte, the less portal blood supply it receives and the more arterial supply
- Regenerative nodules mainly receive blood from portal blood, but the cancerous cells undergo angiogenesis and have their own arterial supply, with no portal supply
- Can make diagnosis without a biopsy
Staging Systems
• No worldwide consensus • Relates to prognosis • Various o TNM o Okuda o Child-Pugh o MELD o Barcelona, France, Italy, Austria, China, Japan • Ideally need to take into account the pathology and liver function
- None have been adequately cross-validated
- Barcelona-Clinic-Liver-Cancer (BCLC) staging system used in the UK
Barcelona-Clinic-Liver-Cancer (BCLC) staging system
- Includes tumour stage, liver function, physical status, cancer symptoms, Child-Pugh Score (estimates liver function most patients die from liver failure as opposed to actual cancer)
- Links with treatments + estimation of life expectancy based
• Early stage disease o Preserved liver function (CP A-B) o Solitary HCC or up to 2 nodules <3cm in size o Possibility of long term cure o 5y survival 50-75%
• Intermediate stage o Child-Pugh A-B o Large/multifocal HCC o No cancer related symptoms or macrovascular invasion or extrahepatic spread o 3y survival up to 50%
• Advanced stage
o Cancer symptoms and/or with vascular invasion or extrahepatic spread
o 1y survival 50%
o Therapeutic trials with new agents
• End stage
o Extensive tumour involvement
o Severe deterioration of physical capacity (WHO performance status >2)
o And/Or major impairment of liver function (Child-Pugh C)
o Median survival <3m
Treatment of HCC
see p34 for diagram
• Early stage treatments:
o Ablation
o Resection
o Transplant (must be within Milan criteria)
• Advance treatments:
o TACE: trans-arterial chemoembolization
o Sorafenib
o BSC: best supportive care
Performance status in HCC scoring
PS = performance status
- 0 = can function on your own
- 1 = can do most things but get tired easily
- 2 = need help with daily tasks such as getting dressed
- 3 = bed bound
- 4 = about to die
If you have a PS of 4, you are already very frail so you should NOT be given chemo as the chemo will kill you.
Surgical Resection in HCC Tx
• Treatment of choice for HCC in non-cirrhotics
o Only who account for 5% of HCCs in West (but 40% in Asia)
• Resection in cirrhosis
• Careful selection - risk postoperative liver failure
• Right hepatectomy higher risk of inducing decompensation than left
• 5-year survival rates >50%
• Llovet et al. Hepatology 1999: Selection of optimal pts for resection:
o Normal BR
o No clinically significant portal hypertension or as measured by hepatic vein catheter (hepatic vein pressure gradient <10 mmHg)
• These are best predictors of excellent outcomes after surgery
• Such patients do not decompensate after resection
• 5-year survival >70%
i.e. can only resect if patient has no evidence of liver decompensation.
Portal vein embolisation (PVE) of hepatic lobe hosting tumor
- Aim is to induce compensatory liver growth of future liver remnant (FLR) and functional capacity in non-affected lobe, prior to resection
- i.e. shrink the part of liver with cancer and enlarge normal part which will be left behind after resection
- Procedure: involves embolising blood supply to tumour causing ischaemia and necrosis to that part of the liver in compensation the liver regenerates and hypertrophies as a result
- If predicted FLR <25% in non-cirrhotics; <40% in cirrhotics
Benefits
• Post-resection morbidity reduced
• Decreased length of stay in ICU and inpatient hospitalisation
• Patients initially unresectable because of insufficient remaining normal hepatic parenchyma can undergo potential curative resection
Risk of Recurrence – After Resection in HCC
• 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
Liver Transplantation in HCC Tx
• 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
Percutaneous Ablation in HCC Tx
• 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
Radiofrequency ablation in HCC Tx
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
TAE in HCC Tx
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
TACE in HCC Tx
- 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
Post-embolisation syndrome
> 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
Sorafenib in HCC Tx
• 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
Characteristics of ACLF
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
Precipitating events in ACLF
infection
GI bleed
Surgery
trauma
alcoholic hepatitis, PVT etc.
Compare ACLF with decompensated cirrhosis
- 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
Describe the grading of ACLF
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
parameters required to diagnosed ACLF
Acute Decompensation, Organ Failure &High 28d Mortality
Early identification and management of SEPSIS is the most important thing you can do
Hallmarks of ACLF
- Systemic inflammation
- Raised WCC and CRP
- Pro-inflammatory molecules
- IL-6, IL-1β, IL-A8
- Principles of inflammatory response
role of systemic inflammation in the progression of organ failure in patients with acutely decompensated cirrhosis.
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.
Bacterial translocation in sepsis
• 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
Pathological indicators of poor prognosis in ACLF
ductular billirubinostasis
extensive necrosis
eosinophilic degeneration
advanced fibrosis with nodule formation.
Pathological indicators of good prognosis in ACLF
ballooning degeneration of hepatocyte with cellular cholestasis
acinar disarray with hepatocellular and canalicular bile
thin septa and mild fibrosis.
the pathogenesis of organ failure during an acute decpmesation of liver disease
- 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.
Sepsis in cirrhosis
- 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
Impaired immunity in liver disease
- 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.
ACLF precipitating factors: Infection
- 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
Infection & variceal bleeding
- 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)
Bacterial translocation in cirrhosis
- 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)
Pathophysiology of HRS (hepatorenal syndrome)
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
Acute kidney injury (AKI) in ACLF
- 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%)
Cirrhotic cardiomyopathy
- 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»_space;compensated)
Acute liver disease Causes
- Drugs
- Viral Hepatitis (A and B)
- Alcohol
- Autoimmune
chronic liver disease Causes
• 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
complications of cirrhosis
- Ascites
- SBP
- Hepatic encephalopathy
- Oesophageal varices
- Hepatocellular carcinoma
Basics of cirrhosis Tx
• 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)
What is a stem cell
- 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.
Potency of stem cells
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
Difference between Progenitor cells and Stem Cells
- 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.
Stem Cell Plasticity
• 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
How does stem cell plasticity occur?
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
Phase I Clinical Trial with HSC
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
Phase II Clinical Trial
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.
Clinical Trials of Bone Marrow Stem Cells in Liver Disease
• 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.
Gallbladder Cancer
• 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
Primary Hepatocellular Carcinoma (HCC)
• 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
Cholangiocarcinoma
• 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
