The Cirrhosis Tsunamiare we ready?

Mary Patricia Pauly MD FACP AGAF

Kaiser Permanente

Sacramento Medical Center

Diagnosis Diagnosis

• 45 year old elementary school teacher with cirrhosis calls in to clinic – Trouble focusing – Slow – Slurred speech – Confused

Outline• Cirrhosis

– Definition , • Survival w and wo Decompensation• causes

– Physical signs and lab signs • Portal hypertension--Anatomy and physiology• Manifestation of decompensated cirrhosis – how it fits with portal

hypertension – Ascites, variceal bleed , encephalopathy

• Only a certain percentage,

– TREATMENT OF complications of cirrhosis and portal hypertension- cancer surveillance

– Making the diagnosis– Prognosis –

• Childs class, MELD – Treatment may decrease incidence of cirrhosis

Cirrhosis

• Late stage of progressive hepatic fibrosis – Distortion of hepatic architecture – Regenerative nodules – Irreversible in advanced stages

• Patients with cirrhosis – Decreased life expectancy – Susceptible to complications

• Decompensation – Ascites, Variceal bleeding and encephalopathy

• Cancer– HCC and – Cholangiocarcinoma

Survival in Cirrhosis

Fattovich G, et al. Gastroenterology. 1997;112:463-472.

Compensated

After first major complication

Survival Probability

100

Pat

ien

ts (

%)

80

60

40

20

01200 12 24 36 48 60 72 84 96 108

Mos

384 65

Pts at Risk, n 376 39

34221

28811

2367

1654

1264

793

523

392

251

170 million infected worldwide

Up to 40% cirrhosis after 40 years

Hepatitis B

350 million worldwide HBsAG positive

15 – 40% -> cirrhosis or HCC

NAFLD

15% progress to NASH

xx% -> cirrhosis

The Cirrhosis Tsunami

Spider angiomata

Note the central pulsating arteriole surrounded by many smaller vessels or “legs.”

Pathogenesis incompletely understood

Possibilities: Alterations in sex hormone metabolism- increase in estradiol to free testosterone ratio in men.

Number and size correlate with severity of disease

Palmar erythema

Pathogenesis: It is thought to be caused by altered sex hormone metabolism

Gynecomastia

Pathogenesis: increased conversion of androstenedione ( produced in adrenals) -> estrone -> estradiol.

Dupuytren’s contractures

Due to thickening and shortening of the palmar fascia

Fibroblastic proliferation and disorderly collage deposition --> fascial thickening and flexion deformities of the fingers.

Caput medusae

In portal hypertension the umbilical vein ( normally obliterated at birth) can dilate Blood is shunted from periumbilical veins-> to the umbilical vien -> abdominal wall.

Physicial findings in cirrhosis•Physical findings

–Stigmata of portal hypertension:• Spider angiomata

• Caput medusae

• Palmar erythema

• Dupuytren’s contracture

• Gynecomastia

• Ascites

• Signs of encephalopathy– Jaundice --- does not necessarily indicate cirrhosis

» acute hepatitis

» CBD obstruction

Laboratory Finding consistent with cirrhosis

• Laboratory findings–Low platelet count

< 100 K

Low WBC and Anemia. – Splenic sequestration

–Low albumin–Elevated prothrombin

time –Elevated Bilirubin

– Liver biopsy – Non invasive markers

of Fibrosis • Fibrosure/fibrospect

F3-4• Fibroscan and similar

technologies measures elasticity

– >12.5 Kpa

• APRI > 2

APRI

• APRI = • (AST elevation/platelet

count) x 100• Example

– AST = 90 IU/L • ULN = 45 IU/L

– Platelet count =120,000/mm3

• APRI =• 90/45=2• (2/120) x 100 = 1.67• APRI > 2 correlates

with cirrhosis • <0.5 correlates with

no cirrhosis.

The Liver: Progression of Disease

TIME course 10 --> 40 years .

Hepatic Fibrosis: Metavir score

Portal Hypertension

• More than mechanical obstruction • Vasodilation

– increased

» Glucagon

» Nitrous oxide

– Decreased SVR

– Decreased MAP

– Increased collaterals

• Increased CO– Increased portal blood

flow

– Hyperdynamic circulation

Cirrhosis

Increased resistance to portal flow

Increased portal pressure

Varices

Decreased splanchnic arteriolar resistance

Increased portal blood flow

Clinical Cirrhosis

Histology F 1-3 F4 cirrhosis- --------F4 ->--------F4

Clinical No cirrhosis Compensated

No varices

Compensated with varices

Decompensated

Symptoms none None none Ascites

Hemodynamics

HVPG mm Hg<6 <6 - 10 >10 >12

Biologic Fibrogenesis and angiogenesis

Scar and

x-linking

Thick acellular scar and nodules

Insoluble scar

Gastro esophageal varices

• 50% of patients with cirrhosis

• 5-15% Risk of bleeding per year – Directly related to

portal pressure– SIZE if most important

predictor of bleeding *• Large varices 30%• Small varices 7%

• Recommended EGD• Surveillance for varices

in cirrhosis

– If no varices –• Recheck 2-3 y

– If small varices • Recheck 1-2 y

– If large varices • Primary prophylaxis

*over 2 years

Esophageal varices

Varices 2 y risk of bleeding without BB

2 y risk of bleeding with BB

Small 7% 2%

Large 30% 14%

• Non bleeding varices• Primary prophylaxis

– Non cardioselective beta- blockers

• Propranolol• Nadolol

• Titrate to 25% decrease in HR from baseline

– EVBL• if intolerant of BB

Treatment of varices

• Actively bleeding– Band ligation– Octreotide

• ->Splanchnic vasoconstriction and Decreased portal blood flow

– Inhibits release of vasodilator hormones (glucagon)

– IV Antibiotics

• Active variceal bleed – 20% mortality – 60 – 80% rebleeding

within 2 years

• Secondary prophylaxis – Band ligation – Non cardioselective

beta blockers

Prophylactic antibiotics improve outcomes in

cirrhotic patients with GI Hemorrhage

Control antibiotic Absolute rate difference

(95% CI)

Infection 45% 14% - 32%-42-23%

SBP/

Bacteremia

27% 8% -18%-26-11%

Death 24% 15% -9%-15-3%

Barnard et al J Hepatology 1998; 29: 1685

Ascites

• Increased vasodilaton affects the kidneys – Increased CO and

decreased MAP->– Stimulates

endogenous vasoconstrictors ->

• Salt and water retention– Ascites and edema

» Dilutional hyponatremia

–

Ascites

• Most common complication of cirrhosis– Pathologic

accumulation of fluid in peritoneal cavity

– Risk of developing ascites

• 50% - 70% within 10 years of diagnosis of cirrhosis

• Requirements for Ascites in cirrhosis

– Portal hypertension

• Actually sinusoidal Hypertension

Management of Ascites

• Dietary Sodium restriction – 88 meq sodium daily – 2000 mg sodium daily

• Diuretics• Combination of lasix

and spironolactone

• Spironolactone (aldactone)– Aldosterone antagonist

– Weak diuretic

– More effective than lasix alone in cirrhosis

• Furosemide (Lasix) – Loop diuretic

• Must enter the lumen of the tubule to work

– Proximal tubular secretion is impaired in cirrhosis

Refractory ascites

• Diuretic resistant• No weight loss

– Despite adequate doses of diuretics

– And salt restriction

•

• Diuretic intractable– Something precludes the use

of effective doses of diuretics• Hyponatremia • Elevated creatinine

Hepatorenal syndrome

Treatment of Refractory Ascites

• Large Volume Paracentesis– Beware of post

paracentesis circulatory dysfunction

– Can cause renal failure and

• Decreased survival

– Many advocate IV Albumin

• to prevent PPCD.

• Terlipressin *– Vasoconstrictor

• Splanchnic and systemic

– Increases effective blood volume

• Decreases renin and angiotensin secretion

• Increases renal vasodilation and perfusion

– Improves creatinine

* Not yet approved in US

Presence of VARICES and ASCITES determines prognosis

patients with cirrhosis

Hepatic Encephalopathy

• Definition– A spectrum of potentially reversible

neuropsychiatric abnormalities seen in patient with liver dysfunction and / or porto systemic shunting.

• Overt Hepatic Encephalopathy – 30-45% of patients with cirrhosis

• Minimal Hepatic Encephalopathy– Up to 80% with cirrhosis

Encephalopathy work up and diagnosis

• High index of suspicion – Physical exam – Clinical setting

• Rule out other causes of mental status changes – Intracranial process

• Check for precipitating factor– Infection

• SBP

– GI Bleed– Drugs – Renal Insufficiency – Worsening liver

function

Lactulose

• Increases stool volume

• Increased acetate and lactate change acid base balance

• pH = 5– NH3 -> NH4– Increases excretion of

fecal nitrogen

• Problems• Side effects ->

– Increased number of BMs

– Loose stools – Gas

Non compliance

Treatment of encephalopathy

Rifaximin Nonabsorbable antibiotic

Comparable efficacy to lactuloseWide bacterial activity against

aerobic and anaerobic gram-negativeand gram-positive

Superior safety profile compared with neomycin

Treatment of encephalopathy

Hepatocellular carcinoma

• Surveillance recommended in all with cirrhosis– Incidence HCC varies with

cause of cirrhosis• Up to 5% per year

• Surveillance decreases mortality– detects small HCC– HCC 1-2 cm can be cured

in >50% of cases

• Patients listed for transplant with HCC– Get Priority on list – Exception points for certain

cases are available

• Must be small – One lesion < 5 cm – or < 3 lesions

• None greater than 3 cm

• No vascular invasion

• No extrahepatic lesions

Causes of Cirrhosis

• Most common • Chronic viral hepatitis

– HBV– HCV

• Alcoholic liver disease

• Hemochromatosis

• NASH– Non alcoholic

steatohepatitis

• Less common causes– Autoimmune hepatitis– Primary and secondary

biliary cirrhosis– Primary sclerosing

cholangitis– Medications– Wilson disease– Alpha-1 antitrypsin

deficiency– Granulomatous liver

disease– Polycystic liver disease– Right-sided heart failure– Veno-occlusive disease.

Impact of Antiviral Treatment* on Risk of HCV-related Complications

Bruno S, et al Hepatology 2007; 45:579.*Pts with compensated cirrhosis treated with IFN monotherapy between 1992 and 1997.

P<0.01

P<0.01HR=2.59

Hereditary Hemochromatosis

• Genetic disorder – Autosomal recessive– increased intestinal

iron absorption – Increased iron

deposition in • Liver • Heart • Pancreas • pituitary

• Diagnosis can be made early – Good family history – High index of

suspicion • Serum iron /TIBC• Ferritin • +/- liver biopsy

Survival in HHC

• Survival in those pre cirrhosis– if you start treatment before a person

develops cirrhosis• Is the same as control population without HHC

– 65% 20 year survival

– After cirrhosis survival is decreased• Due to complications of cirrhosis• And HCC

– From Niedarau et al. NEJM 1985

HCV: Effect of Weight Loss on Grade of Inflammation

• 19 pts HCV + steatosis• 3 month weight loss

– 5.9 kg – 16/19 ALT decrease– Decrease fasting insulin 16 –

11 mmoles/l. (p=<0.002)• 10 had paired liver biopsies ( 3-6

mos post)– Decreased Knodel fibrosis

score 3 to 1. (p=0.04)– Decreased activated stellate

cells (p=< 0.004)

Hickman IJ et al. Gut 2002;51: 89-94

Drug therapy for treatment of NASH

• Vitamin E**– Decreased hepatic

steatosis– Decreased

inflammation • No effect on fibrosis• Dose was 800 U daily

– Use with caution in pts with CAD and DM

• Obeticholic acid– Currently

investigational – Clinical trial halted

after 50% of the patients enrolled met endpoint.

• Statistically significant efficacy.*

•*Intercept press release

•**Sanyal AL et al NEJM. 2010. 362 (18) 1675

Summary

• Cirrhosis is end result of years of ongoing liver damage– We will be called on to manage complications of

cirrhosis in our daily practice• Ascites, varices, encephalopathy and HCC.

– Treatment of the most common causes of cirrhosis are emerging

• In the future we should seen decrease in cirrhosis• If we can manage the

– upcoming tsunami of NASH.