Ebook Sherlock’s diseases of the liver and biliary system (13/E): Part 1

Part 1 book “Sherlock’s diseases of the liver and biliary system” has contents: Anatomy and function, liver function in health and disease, biopsy of the liver, coagulation in cirrhosis, acute liver failure, hepatic fibrogenesis, hepatic cirrhosis, hepatic encephalopathy in patients with cirrhosis,… and other contents.

Table of Contents

Cover

Preface to the Thirteenth Edition

Preface to the First Edition

Chapter 1: Anatomy and Function

Development of the liver and bile ducts

Anatomy of the liver

Functional liver anatomy: sectors and segments

Anatomical abnormalities of the liver

Anatomy of the biliary tract (Fig 1.6)

Surface marking (Fig 1.7, Fig 1.8)

Methods of examination

Microanatomy of the liver

Hepatic ultrastructure (electron microscopy) and organellefunctions

Functional heterogeneity of the liver (Fig 1.20)

Dynamics of the hepatic microenvironment in physiologyand disease (Fig 1.21)

Hepatocyte death and regeneration (Fig 1.22)

References

Chapter 2: Liver Function in Health and Disease

Bilirubin metabolism (see Chapter 13)

Bile acids

Lipid and lipoprotein metabolism

Amino acid metabolism

Plasma proteins

Carbohydrate metabolism

Markers of hepatocellular injury: the serum transaminasesMarkers of cholestasis: alkaline phosphatase (ALP) andgamma glutamyl transferase (GGT)

Haematology in liver disease

Effects of ageing on the liver

References

Chapter 3: Biopsy of the Liver

Selection and preparation of the patient

Techniques

Risks and complications

Sampling variability

Naked eye appearances

Preparation of the specimen

Interpretation: a stepwise diagnostic approach

Bleeding and thrombosis in cirrhosis

Clinical laboratory tests of the coagulation system in cirrhosisConclusion

Chapter 6: Hepatic Fibrogenesis

Introduction

Natural history of hepatic fibrosis

Cellular and molecular features of hepatic fibrosis (Fig 6.2)Clinical aspects of hepatic fibrosis

Emerging antifibrotic targets and strategies

References

Chapter 7: Non invasive Assessment of Fibrosis and CirrhosisIntroduction

The use of invasive and non invasive tests

Non invasive tests: specifics

Clinical cirrhosis: compensated versus decompensated

Prognosis (Child–Pugh score, MELD, UKELD)

Clinical and pathological associations

Spontaneous bacterial peritonitis (Table 9.3)

Treatment of cirrhotic ascites

Hyponatraemia

Refractory ascites

Pathophysiology and rational basis of therapy

Evaluation and diagnosis

Natural history and prognosis

Hepatic artery occlusion

Aneurysms of the hepatic artery

Hepatic arterioportal fistula

Hepatic vascular malformations in hereditary haemorrhagictelangiectasia

Congenital portosystemic shunts – Abernethy malformationBudd–Chiari syndrome – hepatic venous outflow tract

obstruction

Extrahepatic portal vein obstruction – portal vein thrombosisand portal cavernoma in the absence of cirrhosis

Portal vein thrombosis in patients with cirrhosis

Idiopathic non cirrhotic intrahepatic portal hypertensionHypoxic hepatitis

Congestive cardiac hepatopathy

Non obstructive sinusoidal dilation (NOSD) and peliosisReferences

Chapter 13: Jaundice and Cholestasis

Introduction

Mechanics of bile formation

Syndrome of cholestasis

Causes of isolated hyperbilirubinaemia

Causes of cholestatic and hepatocellular jaundice

Bile duct and hepatocellular diseases

Consequences of cholestasis and their management

Investigation of the jaundiced patient

Decisions to be made in the jaundiced patient

Management of cholestatic disorders

Asymptomatic gallbladder stones

Non surgical treatment of gallstones in the gallbladder

Common bile duct stones

Acute gallstone pancreatitis

Large common duct stones

Relationships to malignant change

Benign biliary strictures

Anastomotic strictures following biliary surgery

IgG4 related sclerosing cholangitis

Chronic pancreatitis

References

Chapter 15: Malignant Biliary Diseases

Carcinoma of the gallbladder

Carcinoma of the bile duct (cholangiocarcinoma)

Other biliary malignancies

Metastases at the hilum

Ampullary and periampullary carcinomas

Autosomal recessive polycystic kidney disease

Congenital hepatic fibrosis

Caroli disease [58]

Microhamartomas (von Meyenberg complexes)

Choledochal cysts

Solitary non parasitic liver cyst

Congenital anomalies of the biliary tract

Primary sclerosing cholangitis

Secondary sclerosing cholangitis

Sclerosing cholangitis in systemic inflammatory diseasesReferences

Chapter 19: Autoimmune Hepatitis and Overlap SyndromesIntroduction

Pretreatment and on treatment considerations

Treatment challenges and alternative agents

Pregnancy and autoimmune hepatitis

The elderly and autoimmune hepatitis

Childhood onset autoimmune hepatitis

Autoimmune hepatitis and liver transplantation

Overlap syndromes

Conclusion

References

Chapter 20: Enterically Transmitted Viral Hepatitis

General features of enterically transmitted viral hepatitisHepatitis A virus

Pathology and pathogenesis

Diagnostic tests for hepatitis C

Drug metabolism and pharmacokinetics

Hepatic drug metabolism

Molecular mechanisms in drug induced liver injury

Non genetic risk factors for DILI

Diagnosis of DILI

Medical management

Pharmacogenetic risk factors

Potential immunological mechanisms in idiosyncratic DILILiver injury from specific drugs

Chapter 26: Iron Overload States

Normal iron physiology

Iron overload and liver damage

Genetic haemochromatosis

Other iron storage diseases

References

Chapter 27: Wilson Disease

Molecular genetics: pathogenesis

Further definitions, terminology, and diagnosis

Liver biopsy, classification of NAFLD, and non invasivemarkers of NASH and fibrosis

Natural history of NAFLD (Fig 28.9)

NAFLD and hepatocellular carcinoma (HCC)

Therapy for non alcoholic fatty liver disease

Other forms of NAFLD

Diagnosis and assessment

Treatment and management

References

Chapter 30: Pregnancy and the Liver

Introduction

Normal physiology in pregnancy

Pregnancy related liver diseases

Pre existing liver diseases and pregnancy

Liver transplantation and pregnancy

Liver disease coincidentally arising with pregnancy

Inherited disease in the neonate

Genetic cholestatic syndromes

Structural abnormalities: biliary atresia and choledochal cyst

Acute liver failure in infancy

Liver disease in older children

Metabolic disease in older children

Cirrhosis and portal hypertension

Liver transplantation

Tumours of the liver (see also Chapters 35 and 36)

References

Chapter 32: The Liver in Systemic Diseases

Collagen vascular and autoimmune disorders

The liver in haemolytic anaemias

The liver in myelo and lymphoproliferative disease [102]Bone marrow transplantation

Kala azar (visceral leishmaniasis)

Echinococcosis (hydatid disease)

Chapter 35: Benign Liver Tumours

Diagnosis of focal liver lesions

Chapter 37: Hepatic Transplantation

Selection of patients (Table 37.1)

Candidates (Table 37.2)

Absolute and relative contraindications (Table 37.4)

General preparation of the patient

Donor selection and operation

The recipient operation (Fig 37.3)

Hepatitis B and liver transplantation

Hepatitis C and liver transplantation

HIV and liver transplantation

Table 2.2 Blood tests in hepatobiliary disease

Table 2.3 Properties of lipoproteins

Table 2.4 Serum (plasma) proteins synthesized by the liverChapter 03

Table 3.1 History of liver biopsies

Table 3.2 Indications for transjugular liver biopsy

Table 3.3 Fatalities from needle liver biopsy

Table 3.4 Indications for liver biopsy

Chapter 04

Table 4.1 Important terms and concepts in coagulation ofcirrhosis

Table 4.2 Components of coagulation

Table 4.3 Alterations of coagulation system in cirrhosis

Chapter 05

Table 5.1 Causes of acute liver failure

Table 5.2 Some drugs that may cause idiosyncratic acute liverfailure

Table 5.3 Investigations of acute liver failure

Table 5.4 Intensive care of acute liver failure

Table 5.5 King’s College Hospital criteria for liver

transplantation in acute liver failure [72]

Table 8.1 Aetiology and definitive treatment of cirrhosis

Table 8.2 General investigations in the patient with cirrhosis(see also Table 9.1)

Table 8.3 Child–Pugh staging system Child A class is 5 and 6points; B is 7–9 points; and C is 10–15 points

Table 8.4 Pulmonary changes complicating chronic

hepatocellular disease

Table 8.5 Hepatopulmonary syndrome

Table 8.6 Diagnostic criteria for acute on chronic liverfailure using the CLIF Organ Failure score

Table 8.7 Table illustrating the dynamic nature of ACLF

Chapter 09

Table 9.1 Circulatory changes in patients with cirrhosis

Table 9.2 Differential diagnosis among the three most

common causes of ascites

Table 9.3 Spontaneous bacterial peritonitis

Table 9.4 General management of ascites

Table 9.5 Advice for ‘no added salt diet’ (70–90 mmol/day or1.5–2.0 g/day)

Table 9.6 Therapeutic paracentesis as initial treatment ofascites

Table 9.7 Hyponatraemia

Table 9.8 Treatment of refractory ascites

Table 9.9 Criteria for diagnosis of hepatorenal syndromeTable 9.10 Iatrogenic causes of acute kidney injury in

Table 10.2 Factors which may precipitate hepatic

encephalopathy in patients with cirrhosis

Table 10.3 The Glasgow Coma Score [32]

Table 10.4 Guidelines for the diagnosis of hepatic

encephalopathy in patients with cirrhosis

Table 10.5 Patterns of cognitive dysfunction observed in

patients with hepatic encephalopathy and in several otherpotentially confounding disorders

Table 10.6 Management of recurrent or episodic hepatic

encephalopathy

Table 10.7 Management of persistent hepatic encephalopathyTable 10.8 Management of minimal hepatic encephalopathyTable 10.9 Nutritional management of patients with hepaticencephalopathy

Chapter 11

Table 11.1 Classification and aetiology of portal hypertension:haemodynamic characteristics, imaging, and elastographicfindings

Table 11.2 New targets for the pharmacological treatment ofportal hypertension

Table 11.3 Available non invasive methods to assess thepresence of clinically significant portal hypertension (CSPH)

in cirrhosis in clinical practice

Table 11.4 Baveno VI recommendations regarding screeningand surveillance of gastro oesophageal varices in cirrhosis(the grade of evidence is given at the end of each statement)Table 11.5 Drugs used in clinical practice for treating portalhypertension in cirrhosis

Table 11.6 Management of portal hypertension according tothe stage of cirrhosis

obstructive sinusoidal dilation

Table 13.3 Stepwise medical treatment of pruritus

Chapter 14

Table 14.1 Benign biliary diseases

Table 14.2 Classification of gallstones

Table 14.3 Factors in cholesterol stone formation

Table 14.4 Non surgical treatments for gallbladder stonesTable 14.5 Non surgical treatment options for large

common duct stones

Table 14.6 Causes of benign biliary stricture

Table 14.7 Classification of benign biliary strictures

Chapter 16

Table 16.1 Inherited fibrocystic diseases of the liver: clinicalpresentation and associated renal disorders

Table 16.2 Malformation syndromes reported with liver

histological changes resembling those of congenital hepaticfibrosis [56]

Table 16.3 A classification of congenital anomalies of thebiliary tract

association studies and other related approaches at

genome wide level of significance (p < 5 × 10−8) Data aregiven for the UK PBC patient cohort and related meta

Table 18.4 Diagnostic criteria for recurrent primary

sclerosing cholangitis (PSC) following liver transplantation[76] (confirmed diagnosis of PSC prior to liver

transplantation is a prerequisite)

Chapter 19

Table 19.1 Differential diagnosis for elevated transaminaseactivity

Table 19.2 Clinical differences between serological

classifications of autoimmune hepatitis

Table 19.3 Autoantibodies commonly associated with chronicliver disease

Table 19.4 Drugs implicated in precipitating an

autoimmune like hepatitis

Table 19.5 Revised diagnostic criteria for autoimmune

Table 19.9 Common practice pre and on treatment withcorticosteroids ± azathioprine

Table 19.10 General measures in patients with autoimmuneliver disease

Table 19.11 Pregnancy and autoimmune hepatitis

Table 19.12 Summary features of autoimmune liver diseasedemonstrating traditional descriptions

Chapter 20

Table 20.1 Viral hepatitis A, B, C, D, and E contrasted

Table 20.2 Groups for which the hepatitis A vaccine is

recommended by CDC (2006 and 2017)

Chapter 21

Table 21.1 Patterns of HBV infection

Table 21.2 Indications for hepatitis B vaccination

Table 21.3 Hepatitis B vaccines and dosage recommendationsTable 21.4 Causes of non response to HBV vaccine

Table 21.5 Interpretation of HBV serological markers

Table 21.6 Diagnosis of HBV infection

Table 21.7 Recommendations on who should be screened forHBV

Table 21.8 Factors associated with increased risk of cirrhosis

Table 22.2 Hepatitis D: significance of serological and

virological markers

Table 22.3 Diagnosis of acute and chronic hepatitis D

Chapter 23

Table 23.1 Groups at risk of HCV infection

Table 23.2 Approved direct acting antivirals in current useTable 23.3 Drug–drug interactions with commonly usingimmunosuppressants

Table 23.4 IFN free combination treatment regimens

available as options for each HCV genotype

Table 23.5 Current treatment options for genotype 1 IFNtreatment nạve or experienced patients with or without

Table 23.11 AASLD guidelines on recommendations for

patients with renal impairment

Table 23.12 Control of hepatitis C

Chapter 24

Table 24.1 Prospective registry studies of DILI patients

Table 24.2 Recent FDA regulatory actions regarding

hepatotoxicity of prescription drugs and selective herbal anddietary supplement (HDS) products

Table 24.3 Diagnostic approach to patients with suspecteddrug induced liver injury

Table 24.4 Expressions of drug induced liver injury

Table 24.5 The Drug Induced Liver Injury Network

(DILIN) grading system for causality assessment

Table 24.6 The Drug Induced Liver Injury Network

(DILIN) grading system for liver disease severity

Table 24.7 Genome wide association studies of DILI

susceptibility

Table 24.8 Clinical features of recent reports of patients withhepatotoxicity from herbal and dietary supplement (HDS)products

Table 24.9 Single herbal products and herbal mixtures

reported to cause liver injury

Chapter 25

Table 25.1 Possible hepatotoxic effects of acetaldehyde

Table 25.2 Alcoholic hepatitis histology score (AHHS) (poorprognosis if score >5)

Table 25.3 Alcohol use disorders identification test (AUDIT)questionnaire

Table 25.4 Liver biopsy in alcohol related liver diseaseTable 25.5 Treatments for alcohol dependence

Table 25.6 Treatments for alcohol related hepatitis

Chapter 26

Table 26.1 Causes of inherited hepatic iron overload

Table 26.2 Causes of hepatic iron overload from

haematological, hepatic, and other sources

Table 26.3 Lessons from the Haemochromatosis and IronOverload Screening (HEIRS) study [60]

Chapter 27

Table 27.1 Treatment of Wilson disease

Chapter 28

Table 28.1 The spectrum of NAFLD

Table 28.2 National Cholesterol Education Program: AdultTreatment Program III (NCEP ATP III) Guidelines –

metabolic syndrome components

Table 28.3 Fibrosis staging in non alcoholic steatohepatitisTable 28.4 Emerging therapies for the treatment of NASHChapter 29

Table 29.1 Consequences of malnutrition, sarcopenia, andovernutrition in advanced liver disease

Table 29.2 Nutritional assessment in patients with cirrhosisTable 29.3 Parameters included in Subjective Global

nutritional Assessment (SGA) and in Royal Free HospitalSubjective Global nutritional Assessment (RFH SGA)

Table 29.4 Standard nutritional approach in a patient withcirrhosis

Chapter 30

Table 30.1 Classification of liver disease and pregnancy

Table 30.2 Characteristic features and laboratory indices inthe pregnancy specific liver disorders

Table 30.3 Swansea diagnostic criteria for the diagnosis ofacute fatty liver of pregnancy

Table 30.4 Adverse outcomes in pregnant women with

cirrhosis

Chapter 31

Table 31.1 Approximate mean liver span of infants and

children based on four studies on 470 subjects [4]

Table 31.2 Investigations of the jaundiced newborn

Table 31.3 Unconjugated hyperbilirubinaemia in neonatesrelated to time of onset

Table 31.4 Conjugated hyperbilirubinaemia in neonates

Table 31.5 Genetic cholestatic syndromes

Table 31.6 The hepatic glycogen storage diseases

Table 32.4 Important causes of granulomatous drug

reactions

Table 32.5 Classification of amyloidosis of particular hepaticrelevance

Table 32.6 Types of porphyria

Table 32.7 Hepatobiliary disease and bone marrow

Table 33.3 Classification of ultrasound appearances in

hydatid disease by WHO – Informal Working Group on

Echinococcosis (WHO IWGE) [128]

Table 33.4 Treatment of hydatid liver cysts – the PAIR

technique

Chapter 35

Table 35.1 Benign liver tumours and pseudotumours

Table 35.2 Hepatocellular adenoma – classification and

features

Table 37.4 Absolute and relative contraindications to livertransplantation

Table 37.5 Liver transplantation evaluation

Table 37.6 Deceased donor screening

Table 37.7 Strategies to overcome shortage of heart beating,brain stem dead liver donors

Table 37.8 Interaction between ciclosporin (and tacrolimus)and other drugs

Table 37.9 Complications of liver transplantation

Table 37.10 Grading of acute liver allograft rejection [140]Table 37.11 Recommended vaccinations in adults prior toliver transplantation

Chapter 38

Table 38.1 Antiviral therapy in HBV infected patients onthe waiting list

Table 38.2 Prevention strategies for HBV in liver transplantrecipients

Table 38.3 Factors associated with higher risk of recurrentcirrhosis in absence of treatment among HCV positive livertransplant recipients

Table 38.4 Treatment options for HCV infected liver

transplant recipients

Table 38.5 Factors to consider in decisions regarding thetiming of HCV treatment among wait listed patients

Table 38.6 Drug–drug interactions between currently

approved hepatitis C virus direct acting antivirals and

immunosuppressants

List of Illustrations

Chapter 01

Fig 1.1 Anterior view of the liver

Fig 1.2 Posterior view of the liver

Fig 1.3 Inferior view of the liver

Fig 1.4 The sectors of the human liver

Fig 1.5 Schematic representation of the functional anatomy

of the liver Three main hepatic veins (dark blue) divide theliver into four sectors, each of them receiving a portal

pedicle; hepatic veins and portal veins are intertwined as thefingers of two hands [6]

Fig 1.6 Gallbladder and biliary tract

Fig 1.7 The surface marking of the liver

Fig 1.8 Surface markings of the gallbladder Method I: thegallbladder is found where the outer border of the right

rectus abdominis muscle intersects the 9th costal cartilage.Method II: a line drawn from the left anterior superior iliacspine through the umbilicus intersects the costal margin atthe site of the gallbladder

Fig 1.9 The structure of the normal human liver

Fig 1.10 Normal hepatic histology H, terminal hepatic vein;

P, portal tract (H & E, ×60.)

Fig 1.11 Normal portal tract A, hepatic artery; B, bile duct; P,portal vein (H & E.)

Fig 1.12 The complex acinus according to Rappaport Zone 1

is adjacent to the entry (portal venous) system Zone 3 is

adjacent to the exit (hepatic venous) system

Fig 1.13 Blood supply of the simple liver acinus, zonal

arrangements of cells and the microcirculatory periphery.The acinus occupies adjacent sectors of the neighbouringhexagonal fields Zones 1, 2, and 3, respectively, representareas supplied with blood of first, second, and third qualitywith regard to oxygen and nutrient content These zones

centre on the terminal afferent vascular branches, bile

ductules, lymph vessels, and nerves (PS) and extend into thetriangular portal field from which these branches crop out.Zone 3 is the microcirculatory periphery of the acinus sinceits cells are as remote from their own afferent vessels as from

those of adjacent acini The perivenular area is formed by the

most peripheral portions of zone 3 of several adjacent acini

In injury progressing along this zone, the damaged area

assumes the shape of a starfish (darker tint around a

terminal hepatic venule [THV] in the centre) 1–3,

microcirculatory zones; 1′–3′, zones of neighbouring acinus[22]

Fig 1.14 The organelles of the liver cell

Fig 1.15 Colourized scanning electron micrograph of livershowing hepatocytes in green, sinusoids (S) in light pink,erythrocytes (E), Kupffer cells (K), and bile canaliculi (BC).Fig 1.16 Electron microscopic appearances of part of a

normal human liver cell N, nucleus; M, mitochondrion; P,peroxisome; L, lysosome; ER, rough endoplasmic reticulum.Fig 1.17 Transmission electron micrograph showing an

hepatocyte (right) with its microvillus membrane surfacefacing onto the space of Disse (spD) and the overlying

endothelium (End) The endothelium has fenestrations (F)and there are a few collagen bundles (C) in the space of

Disse Erythrocytes (E) are present within the sinusoidallumen M, mitochondrion; P, peroxisome; G, glycogen

granules

Fig 1.18 Scanning electron micrograph of sinusoid showingfenestrae (F) grouped into sieve plates (S) D, space of Disse;

E, endothelial cell; M, microvilli; P, parenchymal cell

Fig 1.19 Transmission electron micrograph of an hepaticstellate cell Note the characteristic fat droplets (F) C, bilecanaliculus; D, space of Disse; M, mitochondria; N, nucleus;

P, parenchymal cell; S, lumen of sinusoid (×12 000)

Fig 1.20 The functional heterogeneity of hepatocytes in

perivenular (acinar zones 3) versus periportal (acinar zones1) regions affects many synthetic and metabolic processes.Below, a portion of a lobule immunostained with antibody toglutamine synthetase shows localization of the enzyme toseveral layers of hepatocytes surrounding the central vein(CV) Negative staining is present elsewhere PT, portal tract.Fig 1.21 Hepatocellular uptake and transport processes

include: (1) surface Toll like receptors (TLRs) for bindingmicrobes and their constituent products; (2) endocytosis intoclathrin coated pits of ligands bound to cell surface

receptors results in clathrin uncoating, ligand release fromthe endosome, and further intracellular trafficking of theligand; (3) certain receptor ligand moieties (e.g HCV entryinto cells) require further interaction with claudins and

occluden in tight junctions; and (4) bile transport proteins onthe bile canalicular membrane (see text for further detail).CLDN, claudin; OCC, occluden; BC, bile canaliculus; L,

ligand; R, cell surface receptor; TJ, tight junction; OATP,organic anion transport protein; BSEP, bile salt export

pump; MDR3, multidrug resistance protein 3; FIC1, familialintrahepatic cholestasis 1; (5) intercellular communicationsbetween hepatocytes and other cells occur by release of threemain types of extracellular vesicles (EVs): exosomes,

microsomes, and apoptotic bodies and, in the case of

hepatocellular carcinoma cells, the larger caliber oncosomes.Fig 1.22 Liver cell death and regeneration Hepatocytes arelost either through apoptosis or necrosis The liver normally

regenerates through cellular replication Priming is necessaryfor hepatocytes to respond to growth factors If hepatocyteloss is massive or the toxic attack persists, cellular replicationmay not be possible Liver cells may then be derived fromprogenitor/stem cells either from within the liver or from thebone marrow.

microsomes After further modifications, including 12α

hydroxylation for precursors of cholic acid, the mitochondrialenzyme sterol 27 hydroxylase cleaves the side chain, withthe formation of chenodeoxycholate or cholate The asterisks(*) indicate the site of conjugation with glycine and taurine.Alternate pathway: cholesterol is transported to

mitochondria CYP27 catalyses 27 hydroxylation This

reaction can occur in many tissues 7α Hydroxylation

follows, by an oxysterol 7α hydroxylase distinct from

CYP7A in the classic pathway The alternate pathway leads tothe predominant formation of chenodeoxycholic acid

Fig 2.3 The enterohepatic circulation of bile acids in normalsubjects and in cholestasis

Fig 2.4 Hepatic cholesterol balance Free cholesterol is

derived from intracellular synthesis and uptake of

chylomicron remnants and lipoproteins from the circulation

It is stored as cholesterol ester, which is the result of

esterification of free cholesterol with a fatty acid by ACAT(acyl CoA cholesterol ester transferase) CEH (cholesterylester hydrolase) hydrolyses this ester linkage Bile acids aresynthesized from free cholesterol Both are secreted into bile

3 Hydroxy 3 methylglutaryl coenzyme A (HMG CoA)reductase is the rate limiting step in cholesterol synthesis.HDL, high density lipoprotein; LDL, low density

Fig 2.5 The role of the liver in lipoprotein metabolism CH,cholesterol; FFA, free fatty acid; LDLR, LDL receptor; LL,lipoprotein lipase; TG, triglyceride (For lipoproteins seeTable 2.3.)

Fig 2.6 The plasma amino acid pattern in cryptogenic

cirrhosis (mean of 11 patients) compared with normal

individuals The aromatic amino acids and methionine areincreased while the branched chain amino acids are

decreased ILE, isoleucine; MET, methionine; PHE,

phenylalanine; TYR, tyrosine; VAL, valine [45]

Fig 2.7 The turnover of plasma albumin in a 70 kg adult inthe context of the daily protein economy of the

gastrointestinal tract and overall nitrogen balance The totalexchangeable albumin pool of about 300 g is distributedbetween intravascular and extravascular compartments in aratio of approximately 2 : 3 In this simplified schema thebalance sheet is expressed in terms of grams of protein (6.25

× grams of nitrogen) Losses do not include relatively minorroutes, for example 2 g/day from the skin [61]

Fig 2.8 The absolute synthesis of serum albumin (14C

carbonate method) in cirrhosis is reduced [62]

Fig 2.9 Algorithm for managing a patient with an isolatedincrease in serum aminotransferase on routine screening.Fig 2.10 Algorithm for managing a patient with an isolatedincrease in serum alkaline phosphatase or serum γ

glutamyl transpeptidase (γ GT) CT, computed

tomography; MRCP, magnetic resonance

cholangiopancreatography; PBC, primary biliary cholangitis.Fig 2.11 Scanning electron micrograph of abnormal red cellsfrom a patient with alcoholic hepatitis, showing echinocytes(E) at various stages of development, and an acanthocyte (A).Chapter 03

Fig 3.1 Three biopsy devices – a standard Trucut needle, anautomated Trucut device, and a Menghini needle

Fig 3.2 (a,b,c) The cutting bevel of the Trucut needle, whichmust be advanced forward, over the tissue in the recession inthe needle.

Fig 3.3 Longitudinal section of the Menghini liver biopsyneedle Note the nail in the shaft of the needle

Fig 3.4 Transvenous liver biopsy The catheter is in the

hepatic vein and the Quick Core needle is taking the liverbiopsy

Fig 3.5 A CT scan showing a bleed following a biopsy Asharp, white area of contrast is present within the

parenchyma of the pseudoaneurysm

Fig 3.6 Haemobilia following needle liver biopsy ERCPshows linear filling defects in the common bile duct

Fig 3.7 Hepatic arteriography taken post liver biopsy shows

an arteriovenous fistula (arrow)

Fig 3.8 Same patient as in Fig 3.7 The arteriovenous fistulahas been successfully embolized (arrow)

Fig 3.9 Stage components of the Ishak system *Proportion(%) of area of illustrated section showing Sirius red stainingfor collagen (collagen proportionate area) Histopathologicalchronic liver disease stage ‘scores’ are descriptive categoricalassignments which are different from liver fibrosis

measurements

Chapter 04

Fig 4.1 Cell based model of coagulation cascade Greenarrows represent activation pathways and red arrows

represent inhibitory pathways vWF, von Willebrand factor;

AT, antithrombin; PC, protein C; PS, protein S; TFPI, tissuefactor pathway inhibitor; TM, thrombomodulin

Fig 4.2 The Fibrinolytic System Green arrows indicate

activation pathways Red arrows indicate inhibitory

pathways tPA, tissue plasminogen activator; UK, urokinase;PAI, plasminogen activator inhibitor; TAFI, thrombin

activator factor inhibitor; TM, thrombomodulin

Fig 4.3 Example of a thrombogram in a normal healthy

patient The lag time measures the moment at which

thrombin generation begins and is measured in minutes Thetime to peak measured in minutes indicating the time untilpeak thrombin generation is produced The start of the tailrepresents the termination of thrombin generation and ismeasured in minutes The peak height is the peak level ofthrombin generated in nanomoles The velocity index is

measured by dividing peak height by the difference betweenthe lag time and time to peak (i.e nanomolar/minute; theslope of thrombin formation curve) The endogenous

thrombin potential is the measured area under the curve andthe units are measured in nanomolar/minute

Chapter 05

Fig 5.1 Differences of aetiologies of acute liver failure

worldwide (unpublished data, WM Lee) APAP,

acetaminophen; HBV, hepatitis B virus; HEV, hepatitis Evirus; DILI, drug induced liver injury; IND, indeterminate.Fig 5.2 Causes of non paracetamol drug induced acuteliver failure [2]

Fig 5.3 Aetiologies and outcomes for forms of acute liverfailure Bars indicate number with outcomes as either

spontaneous survival, transplanted, or died prior to

transplantation The Xs indicate percent spontaneous

survival (legend on right hand side)

Fig 5.4 Histological features of acute liver failure (a)

Autopsy specimen from a patient who died of cerebral

oedema following paracetamol ingestion Haematoxylin andeosin slide demonstrates centrilobular necrosis with

surviving periportal hepatocytes (b) Explanted liver in a case

of paracetamol toxicity Necrotic hepatocytes with

eosinophilic cytoplasm around the central vein (CV) withviable hepatocytes surrounding the portal tracts (PT) (c)Explanted liver of a patient with fulminant acute hepatitis B.Multilobular hepatic necrosis centred around the central vein(CV) with inflammatory infiltration of the portal tracts (PT).(d) Explanted liver of a patient with acute liver failure

following black cohosh ingestion Massive hepatic necrosiswith minimal centrilobular (C) parenchyma remaining

Portal tracts (PT) expanded by inflammatory cells and bileduct reaction (DR) (e) Higher magnification demonstratingfeatures of autoimmune hepatitis with interface hepatitis andmultiple plasma cells (PL) (f) Explanted liver of a 20

year old patient with Wilson disease Trichrome stain

shows cirrhosis with bands of fibrosis surrounding

regenerative nodules Haematoxylin and eosin slide (right)shows severe hepatocyte injury with ballooning

degeneration, microsteatosis, and cholestasis Victoria bluestain highlights copper pigment within the hepatocytes (H)and Kupffer cells (K) Histology courtesy of Jay Lefkowitch,

MD, Columbia University College of Physicians and

Surgeons, New York, NY

Fig 5.5 Cerebral oedema on CT scanning in a patient withacute liver failure (a) Head CT at presentation showing cleardemarcation between white and grey matter (b) Head CT 48

h later demonstrating loss of demarcation between white andgrey matter and effacement of sulci

Fig 5.6 Suggested algorithm for triage, diagnosis, and

treatment of the patient with acute liver failure ALT, alanineaminotransferase; INR, international normalized ratio; ICP,intracranial pressure; FFP, fresh frozen plasma

Fig 5.7 Prognosis in acute liver failure is largely determined

by aetiology and encephalopathy grade on admission

Fig 5.8 Adjusted survival after liver transplant for acute liverfailure versus cirrhosis Data adjusted for recipient age,

gender, race, body mass index, medical condition, dialysis,diabetes, life support, previous abdominal surgery, HCV

positivity, portal vein thrombosis, as well as donor factorsincluding age, race, cause of death, donation after cardiacdeath, cold ischaemia time, partial or split liver, and livingdonor [2]

Chapter 06

Fig 6.1 Analysis of fibrosis progression in patients with

chronic hepatitis C Longitudinal studies allowed separationinto rapid, intermediate, and slow fibrosers based on

METAVIR scoring of fibrosis in liver biopsies HCV, hepatitis

Plated on plastic they are initially vitamin A rich cells,

exhibiting autofluorescence Subsequently, they lose theirvitamin A droplets, becoming more proliferative and spindleshaped Culture induced activation is a model system used

to study in vivo activation.

Fig 6.4 Pathways of hepatic stellate cell (HSC) activation.HSC activation can be divided into two phases: initiation andactivation Initiation is provoked by soluble stimuli that

include oxidant stress signals (reactive oxygen

intermediates), apoptotic bodies, lipopolysaccharide (LPS),and paracrine stimuli from neighbouring cell types includinghepatic macrophages (Kupffer cells), sinusoidal endothelium,and hepatocytes Perpetuation follows, characterized by anumber of specific phenotypic changes including

proliferation, contractility, fibrogenesis, altered matrix

degradation, chemotaxis, and inflammatory signalling

PDGF, platelet derived growth factor; VEGF, vascular

endothelial growth factor; FGF, fibroblast growth factor;

ET 1, endothelin 1; NO, nitric oxide; TGFβ1, transforminggrowth factor β1; CTGF, connective tissue growth factor;MMP, matrix metalloproteinase; MT MMP, membranetype matrix metalloproteinase; TRAIL, TNF related

apoptosis inducing ligand; TIMP, tissue inhibitor of

metalloproteinase; TLR, toll like receptor

Fig 6.5 Pathway of extracellular matrix production and

degradation Individual extracellular matrix components arecleaved and released into the blood (e.g tissue inhibitor ofmetalloproteinase [TIMPs], matrix metalloproteinases

[MMPs], transforming growth factor β1 [TGF β1],

connective tissue growth factor [CTGF]) These have beenincluded in various serum biomarker panels

Chapter 07

Fig 7.1 Schema representing the use of non invasive andinvasive tests at corresponding clinical stages The clinicalprogression of patients with liver disease is represented bythe horizontal green arrow The term ‘advanced chronic liverdisease’ applies to patients with advanced fibrosis and

cirrhosis who are at risk of clinical decompensation,

hepatocellular carcinoma, and death This risk increases withdisease progression (red graph) and HVPG Validated testsare located at the bottom of the figure with those requiringfurther study listed higher HVPG, hepatic venous pressuregradient; CPA, collagen proportionate area

Fig 7.2 Areas under the receiver operating characteristiccurve (AUROCs) The ROC curve is plotted using

experimental data such that a progression of points are

placed on the graph that give the false positive rate and truepositive rate at different test thresholds The curve is

generally used to find the maximal sensitivity and/or

specificity cut off values for a test, whilst the total area

under the curve (AUROC) represents the diagnostic accuracy

of the test An ideal test (red curve), a well performing test

(blue curve, e.g APRI or AST to Platelet Ratio Index) and an

inadequate test (green curve) for detecting ≥ F2 fibrosis are

represented here Point x represents a chosen test cut offvalue (e.g APRI of 1.6) with a sensitivity of 40% and

specificity of 95% Point y corresponds with a cut off value(e.g APRI of 0.48) with a sensitivity of 90% and specificity of55% The number of patients correctly classified by the testare not represented by the AUROC (0.8 in this case), but aredependent on the cut off values chosen and their respectivesensitivities and specificities

Fig 7.3 Ultrasound based elastography techniques (a)

Mechanical pulses are generated by the probe (yellow arrow),which result in elastic shear wave propagation (green wave).The speed at which the shear wave propagates through theliver parenchyma is measured by one dimensional

ultrasound (blue lines) in a fixed region of interest (red box).The data obtained are displayed graphically as an

elastogram, rather than an anatomical representation (b)Acoustic radiation force impulse imaging/point shear wave

elastography Acoustic radiation pulses (purple arrows) aregenerated by an ultrasound probe Elastic shear waves (greenwaves) are propagated perpendicularly to the acoustic pulse.These are measured in a moveable region of interest (redbox) under B mode ultrasound (c) 2D Shear wave

elastography Focused acoustic excitation (purple arrow andpurple shaded areas) from an ultrasound probe result in

shear wave propagation (green arrows) The velocities arecaptured by high frame rate ultrasonography (blue lines) in

a moveable region of interest under B mode ultrasound(red circle) A colour map (boxed area within ultrasound

image) provides real time shear wave data to assist in

selecting a homogenous region of interest

Fig 7.4 Transient elastography cut offs by disease

aetiology

Chapter 08

Fig 8.1 Cirrhosis is defined as widespread fibrosis and

nodule formation Congenital hepatic fibrosis consists offibrosis without nodules Partial nodular transformation (ornodular regenerative hyperplasia) consists of nodules

without fibrosis

Fig 8.2 Many liver diseases have a major initiating factorand a number of cofactors contributing to the development ofcirrhosis

Fig 8.3 The small finely nodular liver of micronodular

Fig 8.6 CT scan, after intravenous contrast, in cirrhosis

shows ascites (a), liver with irregular surface (L), patent

portal vein (p), and splenomegaly (S)

Fig 8.7 Prognostic indicators of survival in patients with

compensated and decompensated cirrhosis

Fig 8.8 Many of the complications of cirrhosis are due toarterial dilation and the hyperdynamic circulation.

Fig 8.9 The cardiac output is raised in many patients withhepatic cirrhosis but within normal limits in biliary cirrhosis.Mean normal cardiac index is 3.68 ± 0.60 L/min per m2.Mean in hepatic cirrhosis is 5.36 ± 1.98 L/min per m2

Fig 8.10 Mechanisms of arterial hypoxemia in the

hepatopulmonary syndrome in a two compartment model

of gas exchange in the lung In a homogeneous lung withuniform alveolar ventilation and pulmonary blood flow in ahealthy person (a), the diameter of the capillary ranges

between 8 and 15 µm, oxygen diffuses properly into the

vessel, and ventilation–perfusion is well balanced In

patients with the hepatopulmonary syndrome (b), manycapillaries are dilated, and blood flow is not uniform

Ventilation–perfusion mismatch emerges as the

predominant mechanism, irrespective of the degree of

clinical severity, either with or without intrapulmonary

shunt, and coexists with restricted oxygen diffusion into thecentre of the dilated capillaries in the most advanced stages(bold arrows)

Fig 8.11 IgA nephropathy: renal biopsy showing IgA

deposition in glomerulus of cirrhotic patient (alcohol

related) with creatinine clearance of 20 mL/min and

proteinuria (immunostaining with FITC rabbit antihumanIgA)

Fig 8.12 A vascular spider Note the elevated centre andradiating branches

Fig 8.13 Palmar erythema (‘liver palms’) in a patient withhepatic cirrhosis

Fig 8.14 Gynaecomastia in a patient with cirrhosis

Fig 8.15 The conceptual difference between decompensatedcirrhosis and acute on chronic liver failure

Fig 8.16 Mortality of patients with increasing severity ofacute on chronic liver failure

Chapter 09

Fig 9.1 Causes of ascites.

Fig 9.2 Natural history of cirrhotic ascites

Fig 9.3 The peripheral arterial vasodilatation hypothesis forascites formation in cirrhosis [8]

Fig 9.4 Mechanisms of increased sodium and water

reabsorption in cirrhosis *Increased ADH stimulated waterreabsorption in collecting ducts

Fig 9.5 Time course of circulatory, neurohormonal and renalfunction abnormalities in cirrhosis (in sequence of peripheralarterial vasodilation theory) ADH, antidiuretic hormone;HRS, hepatorenal syndrome; RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system

Fig 9.6 A right sided pleural effusion may accompany

ascites and is related to defects in the diaphragm

Fig 9.7 CT scan showing an irregular cirrhotic small liver,splenomegaly and ascites (arrow)

Fig 9.8 The pathogenesis of spontaneous bacterial

peritonitis (SBP) in patients with cirrhosis GI,

gastrointestinal; RE, reticuloendothelial

Fig 9.9 Site of action of diuretics 1 = loop diuretics:

frusemide (furosemide), bumetanide 2 = distal

tubule/collecting duct: spironolactone, amiloride,

Chapter 10

Fig 10.1 Deficits commonly encountered in patient with

cirrhosis with minimal evidence of cognitive dysfunction and

in the absence of gross tremor or visual disturbance Thesemay be useful for detecting and monitoring impairment

Above: Constructional apraxia: the inability to draw or

construct simple configurations; the patient is attempting tocopy the five pointed star drawn by the examiner on the left

side of the page Below: Writing difficulties: the patient is

attempting to write: ‘Hello dear How are you? Better I hope.That goes for me too’

Fig 10.2 ‘Flapping’ tremor elicited by attempted dorsiflexion

of the wrist with the forearm fixed

Fig 10.3 The Psychometric Hepatic Encephalopathy Score(PHES) comprises five paper and pencil tests that betweenthem assesses attention, visual perception, and

visuoconstructive abilities [36] Number connection tests A and B: the time taken to join the numbers, or numbers and letters, in sequence, is recorded Digit symbol test: the

number of correct symbols inserted into the blank squares

below the numbers in 90 seconds is recorded Serial dotting:

the time taken to place a dot in the centre of each circle on

the page is recorded Line tracing: the time taken to trace a

line between the two guidelines, without moving the paper,and the number of errors made are recorded

Fig 10.4 T1 and T2 weighted MR images of the brain of a

53 year old man with cirrhosis and overt hepatic

encephalopathy (a) The T1 weighted MR image shows

bilateral, symmetrical hyperintensity of the globus pallidus(arrowed) (b) No corresponding changes are observed in the

characterized by a relative increase in the Glx resonance andrelative reductions in the Ins and Cho resonances

Fig 10.6 1H MR spectroscopy water suppressed spectra,