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home - Liver - Liver Failure - Cirrhosis Written by Dr Sebastian Zeki
Knowledge


Assesses the severity of liver dysfunction and its prognostic
significance following haemorrhage

Knows importance of correcting hypovolaemia preventing
complications of GI bleeding and deterioration of liver function and
stopping bleeding

Knows the potential use of blood & clotting factors the role of
antibiotics the use of vasoconstrictors therapeutic endoscopy the
indication for transjugular intra-hepatic portosystemic shunt (TIPS) or
surgical shunt surgery

Aware of the specific complications of bleeding in cirrhotic patients –
including hepatic encephalopathy need for airway protection
nutrition identification of alcohol withdrawal

Skills
Shows proficiency in endoscopy – including emergency endoscopic
techniques of variceal band ligation endoscopic sclerotherapy
injection of cyanoacrylate glues for gastric varices

Can place safely and manage a Sengstaken tube in refractory
variceal bleeding

Can prevent and treat complications including hepatorenal failure
ascites spontaneous bacterial peritonitis and hepatic encephalopathy

Behaviours
Appreciates criteria for referral to specialist centre when appropriate –
such as with bleeding gastric or ectopic varices or consideration of
TIPS

Appreciates need to treat patients using a multi–disciplinary approach
Shows understanding of an empathic approach which may involve


Also....

Knowledge
Knows risks and prognosis of recurrent variceal bleeding in cirrhotic
patients

Aware of role of secondary prophylaxis with either non–selective ?-
blockers endoscopic ligation or both

Skills
Can select suitable endoscopic therapy and perform the appropriate
procedure competently

Behaviours
Appreciates the potential role of other specialists e g interventional
radiologists and nurse specialists

Also...

Knowledge


Understands the mechanisms of biliary metabolism the various
abnormalities that lead to hyperbilirubinaemia and knows and
recognises the causes of the various forms of jaundice

Skills
Selects and interprets appropriate investigations and formulate
management plans

Behaviours
Approaches patients presenting with jaundice in a logical and
methodical manner

Also...
Knowledge


Can define the different types (I and II) of hepatorenal
syndrome(HRS)

Knows the differential diagnosis of different types of renal
failure/impairment in liver disease

Understands the major and minor criteria in diagnosis of HRS and be
able to differentiate between HRS and acute kidney injury

Appreciates the prognostic significance of renal impairment in
patients with chronic liver disease

Knows the options for management and treatment of HRS the role of
colloids and vasoconstrictors as well as renal supportive treatment by
dialysis

Skills
Uses and interprets result of sometimes complex investigations
appropriately

Behaviours
Can judge when to involve other specialists especially nephrologists
radiologists and intensivists

Also...

Knowledge


Understands the pathogenesis of hepatic encephalopathy (HE)
Knows the differential diagnosis of HE including the existence of risk
factors for its causation including metabolic disorders and intracranial
structural disorders (such as subdural haematomas)

Knows factors that may precipitate HE including bleeding electrolyte
disturbance drugs or other organ failure

Knows the various treatment options appropriate for grade of severity

Skills
Can grade the mental state (Glasgow coma score and West Haven
Criteria)

Shows ability to differentiate between acute and acute on chronic liver
injury

Can identify the patient at risk of raised intracranial pressure and
cerebral oedema

Selects and use investigations appropriately and determine timing of
airway protection

Behaviours
Appreciates the role of other specialists and interacts in a
professional manner with intensivists neurologists
neurophysiologists radiologists and other specialists

Makes referral where appropriate to specialist centre for liver
transplantation

Also...

Knowledge


Understands the causes of acute hepatitis including viral druginduced alcohol-induced and auto-immune liver disease

Knows the appropriate plan of investigation and management of
specific diseases including the role of serological investigations and
liver biopsy

Skills
Takes an accurate history from patients with acute liver disease and
performs detailed clinical examination

Utilises investigation in a structured manner
Behaviours
Considers all therapeutic modalities and preparedness to refer to
specialist centre where diagnosis remains in doubt or appropriate
management cannot be performed

Also...

Knowledge
Assessment
Methods GMP
Recognises and knows how to diagnose acute and chronic drug
induced liver injury and dysfunction
SCE 1,2
Aware of methods of diagnosis, role of liver biopsy and therapy
including role of steroids in treatment in selected cases
SCE, CbD 1
Skills
Understands the role of both prescription and recreational drugs and
the aetiology of a wide variety of liver disease and dysfunction often
requiring prompt intervention or involvement of specialist services
SCE, CbD 1,2,3
Has awareness of the range of iatrogenic liver dysfunction SCE, CbD 1,2,3
Behaviours
Able to interact with specialist pharmacy services. Can use yellow
card reporting system of potential adverse effects of drugs.

Also....

Knowledge


Understands the causes and pathophysiology of acute liver failure
Can plan appropriate investigation evaluate prognosis and construct
a detailed management plan

Identifies those potentially suitable for emergency liver transplantation
Skills
Develops ability to make accurate evaluation of patients with liver
failure at the stage of initial presentation

Can deliver management plan appropriately evaluate changes in
patient’s condition and react accordingly

Utilises the range of medical interventions necessary to support
critically ill patients

Behaviours
Demonstrates ability to identify patients at risk of developing acute
liver failure and understand the criteria for referral to specialist centres

Works collaboratively with nurses and all ITU staff as well as
colleagues in other clinical disciplines to deliver the highest standard
of clinical care

Communicates effectively and relates with empathy to family and
close friends of patients

Cirrhosis

Cirrhosis -Alterations in both cellular responses and extracellular matrix composition.- Stellate cell activation leads to accumulation of scar (fibril-forming) matrix.-Leads to hepatocyte microvilli loss and sinusoidal endothelial fenestrae, therefore worse hepatic function.-Kupffer cell (macrophage) activation accompanies liver injury and contributes to paracrine activation of stellate cells Following liver injury, hepatic stellate cells undergo "activation," into prolifera-tive, fibrogenic and contractile myofibroblasts. Corticosteroids Colchicine Malotilate — Reduces fibrogenesis due to CCl4 or dimethylnitrosamine .Ursodeoxycholic acid — Used in PBC and autoimmune hepatitisReceptor antagonists — Strategy in developmentImmune modulation — For schistosomiasis-induced fibrosis give IL-12 + worm egg antigen to modulate host immune response.Results in replacement of Th2-dominated pattern of cytokine expres- NK cell stimulation/immunomodulationNK cells can kill activated stellate cells with two antifibrotic cytokines, interferon-alpha and interferon-gamma (suppressed by EtOH)Hepatoprotectants Hepatocyte growth factor- Suppresses TGF-beta (therefore fibrosis), induces collagenase expression, growth inhibition and apoptosis of HSCs; blocks biliary epithelial cells from undergoing epithelial-to-mesenchymal transition.HGF also inhibit TGF-beta from activating its downstream targets, thereby suppressing TGF-beta mediated transcription of collagen type I in activated HSCs.Mediated by increased interaction between galectin-7 and phosphorylated Smad3, so sequestering the p-Smad3 to cytoplasm and preventing collagen promoter activation.Caspase inhibitorsBlock hepatocyte apoptosis (which itself causes profibrogenic inflammation). Interferons — Inhibits hepatic stellate cell activation/ reduces type I and IV collagen expression and fibronectin in activated hepatic stellate cells grown in tissue culture, inhibits stellate cell proliferation, and reduces smooth muscle actin expression.Cytokine-directed therapyTGF-beta antagonists — TGF-beta is a major fibrogenic cytokineTGF-beta antagonists under investigation :Soluble TGF-beta type II receptor Antisense oligonucleotides Angiotensin II converting enzyme inhibitors Serine protease inhibitors (such as camostat mesilate) to inhibit proteolytic activation of latent TGF-betaEndothelin receptor antagonists Bosentan, is antifibrotic and reduces stellate cell activation in experimental fibrosis- its relative tezosentan may be less hepatotoxicSignaling inhibitors —Gamma-linoleic acid, lipoxygenase inhibitors simvastatin (inhibits HMG CoA reductase), and pentoxifylline (inhibits PDGF receptor signaling).Dilinoleylphosphatidylcholine (DLPC), the active component of polyunsaturated lecithin, experimentally protects against fibrosis and cirrhosis.HOE 077 and safironil Halofuginone — Halofuginone, a low molecular weight derivative of the anti-coccidial quinoazolinone, has been studied as a potent inhibitor of type I collagen synthesis. Retinoids — In view of the export of retinoids during stellate cell activation, one might assume that restoration of cellular retinoid might reverse or downregulate activation. Herbal compounds — Sho-saiko-to (Xiao-Chaihu-Tang), one of the most prominent herbal medicines, inhibits stellate cell activation and reduces fibrosis in vitro and in vivo- may be antioxidant.Also: salvia miltiorrhiza (Dan-shen); inhibits fibrosis + downregulates TGF-beta-1, pro-collagen I and III Fumagillin TNP-470 — A semisynthetic analogue of fumagillin (TNP-470) inhibits angiogenesis and hepatic stellate cell proliferation.Y-27632 — Inhibits Rho-kinase, a protein that is involved in hepatic stellate cell activation.It inhibited collagen deposition and reduced hepatic hydroxyproline content and serum hyaluronic acid levels in a rat model of liver fibrosis .Rapamycin — Immunosuppressive used in liver transplantation. Inhibits stellate cell proliferationPentoxifylline Pentoxifylline (a methylxanthine derivative that decreases TNFalpha) inhibits hepatic stellate cell proliferation and collagen synthesis in vitro Cannabinoid receptor antagonists —Antagonists to the endogenous hepatic CB1 receptor decreased the wound-healing response to acute liver injury and inhibited progression of fibrosis in three models of chronic injury.Promote stellate cell apoptosis — Not yet feasible in practice. Activate Antioxidants Oxidative stress stimulates stellate cell activationVitamin E- may suppress fibrogenesis.Silymarin — Silymarin (milk thistle constituent)May inhibit Kupffer cellsAmiloride — Inhibits oxidative stress induced NA+/H+ exchange activation and cell proliferation in hepatic stellate cells.Angiotensin converting enzyme inhibitors — Activated stellate cells have upregulated angiotensin II receptors, which generate reactive oxygen species, the secretion of inflamm-tory and fibrogenic cytokines, cell growth, migration and fibrogenesisACE Inhibitors therefore may be antifibrotic Knodell Score —(=histologic activity index (HAI))Composed of sum of 4 scores representing:Periportal and/or bridging necrosisIntralobular degeneration and focal necrosisPortal inflammationFibrosis Ishak score is a modification of this with 6 stages.Metavir ScoreAssessed on a five point scale (0 = no fibrosis, 1 = portal fibrosis without septa, 2 = few septa, 3 = numerous septa without cirrhosis, 4 = cirrhosis).The activity score was graded according to the intensity of necroinflammatory lesions (A0 = no activity, A1 = mild activity, A2 = moderate activity, A3 = severe activity). Farnesoid X receptor ligandsActivated by binding bile acids and implicated in regulating genes controlling bile flow and secretion.Also downregulates stellate cell activationFXR ligands upregulate small heterodimer partner (SHP) in HSCs, and markedly reduce collagen I levels.Also,the FXR-SHP cascade effectively inhibits TIMP-1 expression in stellate cells, mediated by interaction of SHP with JunD, resulting in the inability of JunD to bind the TIMP-1 promoter.MMP-2 activity levels are also increased by 100 %.The inhibition of TIMP-1 is pivotal for two reasons: first, metalloprotease activity will no longer be inhibited, and second, stellate cells lose the crucial survival signals they receive from TIMP-1. Interestingly, FXR ligands can reverse the downregulation of PPAR-gamma in stellate cells in models of rodent liver fibrosis (porcine serum, CCl(4) and bile duct ligation), and submaximal effective doses of PPAR-gamma agonists and FXR ligands synergistically reduce levels of collagen type I.Combination targeting of these two pathways could reduce the likelihood of side effects resulting from higher doses of a PPAR-gamma agonist.Promote matrix degradation — Prevents upregulation of TIMP-1 + 2 during stellate cell activation may increase matrix degradation in vivo.TGF-beta antagonists can stimulate matrix degradation by downregulating TIMPs and increasing the net activity of interstitial collagenase. Histologic scoring systems. Immune Modulation Pathogenesis Suppress Hepatic Inflammation Downregulate stellate cell activation: Hepatocytes Quiescent stellate cell Endothelial cell Kupffer cell Normal liver Loss of hepatocyte microvilli Deposition of scar matrix Activated stellate cells Kupffer cell activation Loss of fenestrae Cirrhosis Normal state InitiationTranscriptional eventsParacrine stimulationEarly ECM changes PerpetuationIncreased cytokine secretionReceptor tyrosine kinase upregulationAccelerated ECM remodeling Injury Oxidative stress, cFn Proliferation Contractility Fibrogenesis Matrix degradation HSC chemotaxis Retinoid loss WBC chemoattraction Resolution Apoptosis? Reversion? PDGF ET-1 TGF-B1 MMP-2 PDGF MCP-1 PDGF serum MCP-1

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