Liver DiseaseThe Silent Killer

Dr Allister Grant

Consultant Hepatologist

Leicester Liver Unit

Spire Conference Sat 11th Oct 2014

Death rates for liver disease

Facts

� Liver disease is the 4th largest cause of premature death in the U.K (<75yrs)

� Nationally, there has been a 20% overall increase in premature deaths from liver disease since 2000

� The average age of death from liver disease is 59 years, compared to 82-84 years for heart & lung disease

� UK is one of few developed nations with an upward trend in mortality.

CirrhosisCirrhosis

Expanded Portal Tracts(Blue)

Prognosis- Child Pugh Score

Score 1 2 3

Encephalopathy 0 I/II III/IV

Ascites Absent Mild-moderate Severe

Bilirubin (µmol/l) <34 34–51 >51

Albumin (g/l) >35 28–35 <28

INR <1.3 1.3–1.5 >1.5

Child-Pugh class A ≤ 6

B = 7–9

C ≥10

Prognosis

1 Year Survival

– Child Pugh A 80 - 100%

– Child Pugh B 60 - 80%

– Child Pugh C 35 - 45%

Complications of End Stage Liver Disease

� Decompensated Cirrhosis

� Variceal bleeding

� Ascites/ SBP

� (Encephalopathy)

� Other

� Sepsis

� Hepatorenal syndrome

� Hepatocellular carcinoma

Oesophageal varices

Management of Bleeding Varices

� Prevention - Propranolol/Carvedilol

� Resuscitation

� Endoscopy - Band LigationSclerotherapy

� Pharmacotherapy- Terlipressin

� Balloon Tamponade

� TIPS/Transplantation

Oesophageal varices

Bleeding Gastric Varices

Variceal Bander

Variceal Band Ligation

Variceal Band Ligation

Ascites

Hepatic Ascites and Oedema

General Management

� Salt restriction

� Diureticsspironolactonefrusemide

� Water restriction if sodium < 125 mmol

� Paracentesisdiagnostic (SBP, tumour)therapeutic (Total vs partial + colloids)

� Daily weight

Spontaneous Bacterial Peritonitis

Definition-

“SBP is a bacterial infection of ascitic fluid which arises in the absence of any other source of sepsis within the peritoneum or adjacent tissues”

PMN>250 cells/mm3

Mortality rate similar to that of a variceal bleed (20-40%)

Secondary prevention of SBP

� Patients who survive SBP have a 1y recurrence rate of 40-70%

� Norfloxacin 400mg/day reduces recurrence from 68% to 20%

� Locally we use Septrin 960mg od Mon-Fri

� Median survival of these patients is 9mo

� These patients should be considered for liver transplantation/ GSF

Sepsis in Cirrhosis

� Incidence-

1% of all admissions to hospital are due to sepsis

30-50% of cirrhotic patients admitted to hospital due to sepsis

Once admitted 15-35% of cirrhotics develop infection (c.f. 5-7% general hospital population)

Encephalopathy

General Management

Minimize effects of liver disease

Treat precipitants• sepsis• GI bleed• medications (over-diuresis)

(Avoid) sedatives, hypnotics, opiates

Lactulose (NG/PR/PO)

Metronidazole/ Rifaximin/ neomycin -deafness

Hepatorenal Syndrome

� Hepatorenal Syndrome is a severe complication of end stage liver disease associated with an 80%-95% mortality at 2 weeks.

� The only interventions that have been shown to improve survival are liver transplantation, the vasopressin analogues and TIPS

� Type 1 (Acute)

� Type 2 (Chronic)

HRS Survival

Gines et al Lancet 2003

Hepatocellular Carcinoma

� All UK cirrhotic patients undergo 6 monthly HCC surveillance with USS and AFP

� AFP >400 is diagnostic of HCC

� Focal lesion – MRI/triple phase CT

� Arterialised nodule, washout in venous phase

Surveillance in Cirrhosis

� Surveillance for Hepatoma

6 monthly AFP and USS

Case - Mr Z

59y Architect

Type 2 DM 15 yrs on diet alone

BMI 35

HypertensionAmlodipine , Ramipril

Minimal Alcohol

Mr Z

� Generally unwell for 2 years

� Cytopaenia� Low Hb/platelets

� Normal haematological Ix (peripheral consumption)

� May 07� LGH admission with ataxia/drowsiness

� Extensive Ix

Mr Z

� CT abdo� cirrhotic liver, portal hypertension, splenomegaly

� OPD referral� Alb 28, Pl 65 LFT’s normal, INR 1.5

� Imaging compatible with cirrhosis

� Reversal of sleep pattern, lack of concentration

� Daytime somnelence, intermittant confusion

� OGD- varices

NAFLD Natural historyNAFLD Natural history

� Simple steatosis: relatively benign “liver” prognosis with a risk of developing clinical evidence of cirrhosis over 15–20 years in the order of 1%–2%.

� NASH and fibrosis: risk of progress to cirrhosis upto 12% over 8 years.

� Cirrhotic: high risk of developing hepatic decompensation and of dying from a liver-related cause including HCC.

SteatosisSteatosis

SteatohepatitisSteatohepatitis

CirrhosisCirrhosis

Hepatocellular carcinoma

Hepatocellular carcinoma

Non Alcoholic Fatty Liver Disease (NAFLD)Spectrum of Hepatic Pathology

Non Alcoholic Fatty Liver Disease (NAFLD)Spectrum of Hepatic Pathology

Diseases Associated with Steatohepatitis

1.Alcoholism2.Insulin resistance

a.Metabolic Syndromei.Obesityii.Diabetesiii.Hypertriglyceridemiaiv.Hypertension

b.Lipoatrophyc.Mauriac Syndromed.PCOS

3.Disorders of lipid metabolisma.Abetalipoproteinemiab.Hypobetalipoproteinemiac.Andersen’s diseased.Weber-Christian syndrome

4.Total parenteral nutrition5. HCV (certain genotypes)

6. Untreated coeliac disease

7.Severe weight lossa.Jejuno-ileal bypassb.Gastric bypassc.Severe starvation

8.Iatrogenica.Amiodaroneb.Diltiazemc.Tamoxifend.Steroidse.HAARTf. tetracyclineg.glucosamine

9.Refeeding syndrome10.Exposure to toxic agents

a.Environmentb.Workplace – Sb,Th,Ba

NASH

Affects 3.5-5% of the population

The rates of progression to cirrhosis have been estimated at between 5% and 20% over 10 years.

There aren't any non-invasive means of predicting which patients are at risk of progression, and there are no agreed guidelines on how to monitor progression.

Initial Investigation

� Look for risk factors� BMI, DM, HBP, Lipids, FHx, Drugs, Alcohol

� Liver screen (to exclude other diseases)� Including Glc/GTT/HbA1c/Lipids/AST

� Pl, Alb, INR

� USS� Spleen size, fatty liver, collaterals

F1

F2

F4

F0-F4

What about aLiver Biopsy?

Fibroscan®

� Electronic platform� Ultrasonic signals acquisition

� Numerical signal processing

� Integrated computer� Stiffness measurement

� Examinations database

� Dedicated probes with unique technology

Vibrator (50 Hz)

US Transducer (3,5 MHz)

Fibroscan® (Echosens, Paris, France)

Position of probe & explored volume

Cylinder of 1 cm wide & 4 cm long

From 25 mm to 65 mm below skin surface

This volume is at least 100 times bigger than a biopsy sample

Results

Stiffness (kPa)

Median value of 10 shots

3.9 Kilo Pascals

� At least 10 shots

� Success Rate: ≥ 60%

� IQR * (kPa)

Interval around median

Contains 50% of valid shots

≤ 25% of median value

NASH Management

1) All patients should be encouraged to exercise, as there is good evidence that even in the absence of weight loss exercise improves NASH.

Obese PatientsWeight reducing diet (aim for 10%, 1-2lb per week)In patients with BMI>28 with risk factors, or >30 without risk factors, consider treatment with Orlistat etc.

2) Diabetic PatientsGood diabetic control (HbA1c <6.5%) Metformin ThiazolidinedionesDietician for re-education.Diabetologist if glucose control is difficult.

NASH Management

3) Patients with Hyperlipidaemia and abnormal LFT’s

Dyslipidaemia should be aggressively addressed

Dietician Review

Hypercholesterolaemia -Statins

Hypertriglycerideaemia -Fibrate.

Lipid Clinic

Avoid Drugs

amiodarone, glucocorticoids, methotrexate, nifedipine, synthetic estrogens, tamoxifen

Antioxidants?

Alcohol Related Deaths

E&W 1979-2010

http://www.statistics.gov.uk/cci/nugget.asp?id=1091

Mo

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UHL Alcohol Admissions 2004-8

Spectrum of Alcoholic Liver Disease

� The most common manifestations of alcoholic

liver disease are:

� Alcoholic steato-hepatitis

� Acute alcoholic hepatitis

� Cirrhosis due to alcohol

Alcoholic Hepatitis

� Most florid manifestation of ALD

� Cholestatic liver disease associated with the long term heavy use of alcohol

� Often a precursor to the development of cirrhosis

� More severe forms are associated with a high mortality

� 1yr mortality after initial hospitalisation is 40%

� Best treatment

� Stop drinking

� Resolution occurs within weeks-months +/- cirrhosis

Symptoms

� Fever

� Hepatomegaly

� Jaundice

� Coagulopathy

� Features of hepatic decompensation

� However, milder forms of alcoholic hepatitis

often do not cause any symptoms

Glasgow Alcoholic Hepatitis Score

Age <50 ≥ 50

WCC(109/l) <15 ≥15

Urea (mmol/l) <5 ≥5

PT ratio <1.5 1.5-2.0 >2.0

Bili (µmol/l) <125 125-250 >250

Score 1 2 3

Patients score from 5-12 points.

Score >8 was used to define the high risk population and maximised sensitivity and specificity.

Corticosteroids

� If the patient has severe alcoholic hepatitis

mDF>32, MELD >11, GAHS>8

� Therapeutic trial of prednisolone 40mg PO

� 7 days

� If no improvement in bilirubin then discontinueMathurin P Hepatol 2003;38;1363-9

Louvet A Hepatol 2008;45:1348-54

Pentoxifylline

� PTX is a phosphodiesterase inhibitor which modulates the transcription of the TNFα-gene, lowers blood viscosity and reduces portal hypertension.

� RCT

� 101 patients with severe alcoholic hepatitis (mDF>32).

� Given 400mg tds for 28 days vs placebo

� Mortality 24% vs 46% at 28 days

� Significant reduction in hepatorenal syndrome

Acriviadis E, Gastro 2000 119;1637-48

Future

� Nationally, there has been a 20% overall increase in premature deaths from liver disease since 2000

� Mortality from Alcoholic liver disease doubled in 10 years

� Incidence of liver cancer has doubled in 10 years

� 4% of the population have abnormal liver function

� 50% people with colorectal cancer develop liver metastases, 20% resectable

The End“All right, let's not panic.

I'll make the money by selling one of my livers.I can get by with one “

Doh!