1. The Cirrhosis Tsunami are we ready?
Mary Patricia Pauly MD FACP AGAF
Kaiser Permanente
Sacramento Medical Center

4. Diagnosis

6. 45 year old elementary school teacher with cirrhosis calls in to clinic
Trouble focusing
Slow
Slurred speech
Confused

7. Outline Cirrhosis Portal hypertension--Anatomy and physiology
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

8. 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

9. Survival in Cirrhosis Survival Probability Compensated 100
After first major complication 80 60
Patients (%) 40
HCV, hepatitis C virus. 20 12 24 36 48 60 72 84 96
108
120
Mos
Pts at Risk, n
384 65
342 21
288 11
236 7
165 4
126 4
79 3
52 3
39 2
25 1
Fattovich G, et al. Gastroenterology. 1997;112: 9 9

10. NAFLD Hepatitis B 350 million worldwide HBsAG positive
15 – 40% -> cirrhosis or HCC
15% progress to NASH
xx% -> cirrhosis
170 million infected worldwide
Up to 40% cirrhosis after 40 years

11. The Cirrhosis Tsunami

12. Spider angiomata
Pathogenesis incompletely understood
Possibilities: Alterations in sex hormone metabolism- increase in estradiol to free testosterone ratio in men.
Note the central pulsating arteriole surrounded by many smaller vessels or “legs.”
The pathogenesis of spider angiomata is incompletely understood, but they are believed to result from alterations in sex hormone metabolism. One study suggested that the presence of spider angiomata in men was associated with an increase in the estradiol to free testosterone ratio [14]. Acquired spider angiomata are not specific for cirrhosis since they may also be seen during pregnancy (picture 1) and in patients with severe malnutrition. They can also be seen in otherwise healthy people, who usually have fewer than three small lesions. As a general rule, the number and size of spider angiomata correlate with the severity of liver disease [15,16]. Patients with numerous, large spider angiomata may be at increased risk for variceal hemorrhage.
Head and neck findings — Head and neck findings in patients with cirrhosis may include parotid gland enlargement and fetor hepaticus.
Number and size correlate with severity of disease

13. Palmar erythema
Palmar erythema is an exaggeration of the normal speckled mottling of the palm and is believed to be caused by altered sex hormone metabolism [23]. It is most frequently found on the thenar and hypothenar eminences, while sparing the central portions of the palm. Palmar erythema is not specific for liver disease and can be seen in association with pregnancy, rheumatoid arthritis, hyperthyroidism, and hematological malignancies
Pathogenesis: It is thought to be caused by altered sex hormone metabolism

14. Gynecomastia
Gynecomastia is seen in up to two-thirds of patients with cirrhosis. It is possibly caused by increased production of androstenedione from the adrenals, enhanced aromatization of androstenedione to estrone, and increased conversion of estrone to estradiol [19]. Men may also develop other features reflecting feminization, such as loss of chest or axillary hair and inversion of the normal male pubic hair pattern. Gynecomastia can be seen in a variety of conditions other than cirrhosis.
Pathogenesis: increased conversion of androstenedione ( produced in adrenals) -> estrone -> estradiol.

15. Dupuytren’s contractures
Dupuytren's contracture results from the thickening and shortening of the palmar fascia, which causes flexion deformities of the fingers (picture 3). Pathologically, it is characterized by fibroblastic proliferation and disorderly collagen deposition with fascial thickening. The pathogenesis is unknown but may be related to free radical formation generated by the oxidative metabolism of hypoxanthine [31]. It is relatively common in patients with alcoholic cirrhosis, in whom it may be found in as many as a third of patients [32]. However, it can also be seen in several other conditions, including in workers exposed to repetitive handling tasks or vibration, and patients with diabetes mellitus, reflex sympathetic dystrophy, cigarette smoking and alcohol consumption, and Peyronie's disease. (See "Dupuytren's contracture".)
Neurologic findings — Asterixis (bilateral but asynchronous flapping motions of outstretched, dorsiflexed hands) is seen in patients with hepatic
Due to thickening and shortening of the palmar fascia
Fibroblastic proliferation and disorderly collage deposition --> fascial thickening and flexion deformities of the fingers.

16. 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.

17. 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

18. 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

19. APRI APRI = (AST elevation/platelet count) x 100 Example APRI =
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.

22. The Liver: Progression of Disease
TIME course > years .

23. Hepatic Fibrosis: Metavir score

25. Histopathologic Features of HBV Infection
The above show the progression of liver disease—from the healthy liver to hepatocellular carcinoma (HCC) secondary to chronic hepatitis B infection.
Reference
Slide courtesy of Z Goodman, MD, Armed Forces Institute of Pathology Washington, DC.

27. Portal Hypertension Vasodilation Increased CO
More than mechanical obstruction
Vasodilation
increased
Glucagon
Nitrous oxide
Decreased SVR
Decreased MAP
Increased collaterals
Increased CO
Increased portal blood flow
Hyperdynamic circulation
Glucagon??
Nitrous oxide??
May be stimulated by endotoxins or other bacterial products

28. Cirrhosis Varices Increased resistance to portal flow
Decreased splanchnic arteriolar resistance
Increased portal pressure
Increased portal blood flow
Varices

29. Clinical Cirrhosis Histology Clinical Symptoms none None Ascites <6
F 1-3
F4 cirrhosis-
--------F4
-> F4
Clinical
No cirrhosis
Compensated
No varices
Compensated with varices
Decompensated
Symptoms
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

30. 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

31. Esophageal varices Small 7% 2% Large 30% 14% Non bleeding 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
Esophageal variceal bleeding
associated with >20% mortality
60 -80% of rebleed within the next 2 y

32. Treatment of varices Actively bleeding Active variceal bleed
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
Somatostatin inhibits the release of vasodilator hormones such as glucagon [11], indirectly causing splanchnic vasoconstriction and decreased portal inflow. It has a short half-life and disappears within minutes of a bolus infusion. Octreotide is a long-acting analog of somatostatin. Somatostatin is not available in the United S

33. 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

34. Ascites Increased vasodilaton affects the kidneys
Increased CO and decreased MAP->
Stimulates endogenous vasoconstrictors ->
Salt and water retention
Ascites and edema
Dilutional hyponatremia

35. 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

36. Management of Ascites Dietary Sodium restriction Diuretics
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

37. 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

38. 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

39. Presence of VARICES and ASCITES determines prognosis patients with cirrhosis

41. 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
Hepatic encephalopathy describes a spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction and/or portosystemic shunting. Overt hepatic encephalopathy develops in 30 to 45 percent of patients with cirrhosis and in 10 to 50 percent of patients with transjugular intrahepatic portal-systemic shunts [1,2]. The International Society for Hepatic Encephalopathy and Nitrogen Metabolism consensus defines the onset of disorientation or asterixis as the onset of overt hepatic encephalopathy [3]. Some patients with hepatic encephalopathy have subtle findings that may only be detected using specialized tests, a condition known as minimal hepatic encephalopathy [4-6]. Minimal hepatic encephalopathy is seen in up to 80 percent of patients with cirrhosis [7-13].

43. 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

44. 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

45. Treatment of encephalopathy
Rifaximin
Nonabsorbable antibiotic
Comparable efficacy to lactulose
Wide bacterial activity against
aerobic and anaerobic gram-negative
and gram-positive
Superior safety profile
compared with neomycin

46. Treatment of encephalopathy

47. 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

48. 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.

49. Impact of Antiviral Treatment* on Risk of HCV-related Complications
HR=2.59
Bruno S, et al Hepatology 2007; 45:579.
*Pts with compensated cirrhosis treated with IFN monotherapy between 1992 and 1997.

50. Time to Disease Progression in CHB Cirrhotics
In a study conducted by Liaw et al, 651 CHB patients with histologically confirmed cirrhosis or advanced fibrosis were randomized (2:1, lamivudine 100 mg daily: placebo). The study was planned for a maximum of 5 years. The primary end point of the trial was time to disease progression, which was defined by the first occurrence of hepatic decompensation, HCC, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease. The study was terminated at a median duration of treatment of 32.4 months, owing to a significant difference between the active treatment arm and placebo in the number of end points reached.
This slide is a depiction of the Kaplan-Meier estimates of the proportion of patients with disease progression after three years. Overall, 72 patients reached clinical end points; 34 of 436 (7.8%) in the active treatment arm and 38 of 215 (17.7%) in the placebo arm (P = 0.001).
Reference
Adapted from Liaw YF, Sung JJY, Chow WC, et al. N Engl J Med. 2004;351:

51. 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
Hereditary hemochromatosis (HH) is an autosomal recessive disorder in which mutations in the HFE gene cause increased intestinal iron absorption. (See "Genetics of hereditary hemochromatosis", section on 'The HFE protein'.) The clinical manifestations of this disorder, and of other forms of iron overload, are related to excessive iron deposition in tissues, especially the liver, heart, pancreas, and pituitary.

52. 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

54. 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

55. 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 (18)

56. 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.