Cirrhosis and its complications

Mahajna Mohammad

• Definition

• Pathophysiology

• Etiology

• Clinical manifestation

• Complications

• Lab tests and diagnosis

• Treatment and management

Chronic liver disease

Definition of cirrhosis:

represents a late stage of progressive hepatic fibrosis

characterized by distortion of the hepatic architecture and the formation

of regenerative nodules. [ micro< 3mm vs macro > 3mm]

lack normal lobular organization surrounded by fibrous tissue

This results in a decrease in hepatocellular mass, and thus function,

and an alteration of blood flow

The process involves the whole liver and is essentially irreversible

histologically an “all or nothing” diagnosis

Clinically classified by its status as compensated or decompensated

Pathophysiology

The key pathogenic is activation of hepatic stellate cells which are known as Ito cells or perisinusoidal cells, are located in the space of Disse

Normally they serve as the main storage site for retinoids (vitamin A).

In response to injury, they become activated, as a result:

1. Increased fibrosis by myofibroblasts

2. Increased Connective tissue proliferation due to secreted TGF-β1

3. Decreased Collagen breakdown due to TIMP 1 and 2, naturally occurring inhibitors of matrix metalloproteinases

4. Increased Secretion of extracellular matrix (collagen types I and III, sulfated proteoglycans, and glycoproteins)

Etiology

History taking

• Drug use

• [ amoxicillin/clavulanate, amiodarone, methotrexate, nitrofurantoin, isoniazide, and

valproic acid] to name a few

• alcohol abuse

• Sexual activity Personal habits

• Drug injection

• Metabolic status [ BMI , HTN , diabetes …]

• Diet

• Recent travel

• Remote blood transfusion

• Birth control pills

• extrahepatic autoimmune diseases

• Family history of liver disease mainly

• Malignancy history

• amenorrhea or irregular menstrual bleeding

anorexia

weight loss, weakness, fatigue

Nausea , Vomitting, Bloating

Muscle cramps

Diarrhea- steatorrhea- foul smelling stool

• Fever

• Pruritus

• increasing abdominal girth

• confusion

• sleep disturbances (possibly indicating encephalopathy).

• Lower extremity edema

• Melena, hematemesis, hematochizia

Labs and tests

•A liver biopsy is "gold standard" for diagnosing , but the procedure is invasive and will not

detect every case.

Complete blood count (CBC) – e.g. anemia , thrombocytopenia , leukopenia

Albumin and total serum protein. decreased levels in the blood.

PTT or PT

Bilirubin

(AST), (ALT), (LDH).

Alkaline phosphatase (ALP) and Gamma-glutamyl transpeptidase (GGT).

Antinuclear antibodies (ANA) , anti-smooth-muscle antibody (ASMA) autoimmune

chronic hepatitis.

Antimitochondrial antibody test (AMA), primary biliary cirrhosis.

Ferritin and iron , transferrin saturation ≥45% hemochromatosis.

Serology for hepatitis B and hepatitis C

Serum ceruloplasmin , 24-hour urinary copper excretion > 100 mcg Wilson's disease.

Alpha1-antitrypsin level alpha1-antitrypsin deficiency

Alpha-fetoprotein (AFP) to screen HCC

Non-Laboratory Tests•Ultrasound nonalcoholic fatty liver disease (NAFLD)

•ERCP primary sclerosing cholangitis (PSC)

•Endoscopy Esophageal varices due to portal HTN

•MRI \Tri phasic CT hepatocellular carcinoma

Clinical manifestationphysical findingssymptoms and

complications

defined as the elevation of the

hepatic venous pressure

gradient (HVPG) to >5 mmHg

Cirrhosis is the most common

cause of portal hypertension in

the United States, and clinically

significant portal hypertension

is HVPG>10-12mmHG

present in >60% of patients with

cirrhosis

Portal hypertension

Signs of a hyper dynamic circulatory state include the following:

Bounding pulses

Warm, well-perfused extremities

Arterial hypotension

Flow murmur over the pericardium

Signs of Porto systemic collateral formation include the following:

Anterior abdominal wall dilated veins: May indicate umbilical epigastric vein shunts

Caput medusa (par umbilical collateral veins)

Rectal hemorrhoids , Ascites , Par umbilical hernia

•Hematemesis or melena: May indicate gastro esophageal variceal bleeding or bleeding from

portal gastropathy

•Mental status changes: May indicate the presence of portosystemic encephalopathy

•Increasing abdominal girth: May indicate ascites formation

•Hematochezia: May indicate bleeding from portal colonopathy

Diagnosis

• HVPG is gradient between the WHVP and the FHVP, estimate of the pressure gradient between the

portal vein and the inferior vena cava.

• An HVPG exceeds 12 mmHg variceal hemorrhaging may occur

WHVP reflecting not the actual hepatic portal vein pressure but the hepatic sinusoidal pressure. It is

determined by wedging a catheter in a hepatic vein, to occlude it

treatment

Management of active variceal bleeding

1. resuscitation, blood transfusion if needed .

2. Hemoglobin values should be maintained at about 7-8 g/dL

3. Non selective beta blocker e.g. [Propranolol ]

4. (somatostatin, octreotide or terlipressin), endoscopic banding ligation, balloon tamponade

The most effective

is the combination of a vasoconstrictor with endoscopic ,continued for 2 to 5 days

Prophylaxis of variceal bleeding

1. Pharmacological if no contraindications (non-specific ß-blockers like Propranolol and isosorbide

mononitrate ®monocord )

2. Propranolol Deralin ® is initiated at a dose of 20 mg orally twice a day, whereas

3. Nadolol Corgard® is initiated at a dose of 20 mg orally every day.

4. The dose should be titrated to produce a resting heart rate of about 50 to 55 beats per minute

5. endoscopic (banding ligation) – more than one session is needed

6. both treatments have similar results.

ligation is a local therapy that has no effect on portal pressure and that can lead to hemorrhage from ligation-induced ulcers

First line is β-blockers if not contraindicated

Second line is ligation

If no varices, β-blockers don’t prevent the development of varices and associated with more side

effects.

Endoscopy should be repeated

1. every 2 to 3 years in patients with no varices,

2. every 1 to 2 years in patients with small varices,3. and sooner in patients with decompensated disease so that effective therapy can be instituted

before the varices grow in size and bleed.

recommended antibiotic 1. oral norfloxacin ® apirol at a dose of 400 mg twice daily for 5 to 7 days,

2. intravenous ceftriaxone at a dose of 1 g/day for 5 to 7 days is preferable in patients with advanced

liver disease or in those already on norfloxacin

Surgery has no role in primary prophylaxis. Its role in acute variceal bleeding is exceedingly limited,

because therapy with endoscopic treatment controls bleeding in 90% of patients

failure is defined as: a single episode of clinically significant rebreeding

(transfusion requirement of 2 U of blood or more within 24 h]

a systolic blood pressure < 100 mm Hg

a postural change of >20 mm Hg, and/or a pulse rate greater than 100 bpm)

Hepatic encephalopathy

1.Pathophysiology

2.Secondary complications

3.clinical manifestations

4.Symptoms

5.Labs and diagnosis

6.treatment

Pathogenesis

The portal system metabolize 80-90% nitrogen-containing compounds through the urea

cycle and/or excreted immediately

The most important is ammonia (NH3).

It crosses the blood–brain barrier

is absorbed and metabolized by the astrocytes, [30% of the cerebral cortex]

Astrocytes use ammonia when synthesizing glutamine from glutamate.

Increases glutamine lead to an increase in osmotic pressure in the astrocytes, which become swollen

Ammonia are elevated but aren’t correlated with the severity of liver disease

Definition :

an alteration in mental status and cognitive function occurring in the presence of liver failure

Ammonia levels are typically elevated in

patients with hepatic encephalopathy, but the correlation between

severity of liver disease and height of ammonia levels is often poor

Causes :

In a small proportion of cases, the encephalopathy is caused directly by liver failure;

more likely in acute liver failure.

More commonly, especially in chronic liver disease,

hepatic encephalopathy is caused or aggravated by an additional cause

accumulation in the bloodstream of toxic substances that are normally removed by the liver.

changes in mental status can occur within weeks to months.

Brain edema mainly the cerebral cortex can be seen in these patients, with severe encephalopathy

Cerebral herniation is a feared complication of brain edema in acute liver failure

Diagnosis

Classification and grading

West Haven Criteria

based on 1. the level of impairment of autonomy2. changes in consciousness3. intellectual function, behavior,4. the dependence on therapy

Grade 1 - lack of awareness; euphoria or anxiety; shortened attention span; impaired Impaired fine motor skills , fine tremor

Grade 2 - Lethargy or apathy; minimal disorientation for time or place; subtle personality change; inappropriate behavior asterexsis, ataxia , slurred speech, Flapping tremor

Grade 3 - Somnolence to semi stupor, but responsive to verbal stimuli; confusion; gross disorientation Clonus , rigor , asterexsis

Grade 4 - Coma (unresponsive to verbal or noxious stimuli) Sing of increased intra cranial pressure .

A classification of hepatic encephalopathy was introduced at the World

Congress of Gastroenterology 1998 in Vienna.

According to this classification, hepatic encephalopathy is subdivided in

type A, B and C depending on the underlying cause.

•Type A (=acute) describes hepatic encephalopathy associated with acute liver failure, typically associated with cerebral oedema

•Type B (=bypass) is caused by portal-systemic shunting withoutassociated intrinsic liver disease

•Type C (=cirrhosis) occurs in patients with cirrhosis - this type is subdivided

in episodic, persistent and minimal encephalopathy

(MHE) is defined as encephalopathy that does not lead to clinically overt cognitive dysfunction, but can be

demonstrated with neuropsychological studies

treatment

Type Causes

Excessive

nitrogen load

1. Consumption of large amounts of protein, gastrointestinal bleeding e.g. from esophageal

varices (blood is high in protein, which is reabsorbed from the bowel)

2. renal failure (inability to excrete nitrogen-containing waste products such as urea)

3. constipation

Electrolyte or

metabolic

disturbance

1. Hyponatraemia and hypokalaemia

2. alkalosis

3. hypoxia

4. dehydration

Drugs and

medications

1. Sedatives [benzodiazepines]

2. Narcotics

3. antipsychotics,

4. alcohol intoxication

Infection Pneumonia, urinary tract infection, spontaneous bacterial peritonitis, other infections

OthersSurgery, progression of the liver disease, additional cause for liver damage (e.g. alcoholic

hepatitis,hepatitis A)

Unknown In 20–30% of cases, no clear cause for an attack can be found

Ammonia level targeted therapy :1. Try to avoid sedative agents and BZD if necessary use propofol.

2. decreasing ammonia production in the gut are lactulose [ less efficient ]

3. no absorbable antibiotics such as neomycin , metronidazole , rifaximin

4. LOLA as combination therapy - preparation of L-ornithine and L-aspartate used to

increase the generation of urea through the urea cycle

Define the grade of the encephalopathy [1-4]

Glasgow coma scale

Consider nasogastric tube

Keep the patient at 30 degrees to maintain perfusion

Intubation required if :

1. Glasgow coma scale < 8

2. Grade 3 /4 encephalopathy

Edema targeted therapy : First monitor the ICP , range 50-60 mmHg

Measure INR before , apply coagulation factors if needed 1. Hyperventilation reduced ICP

2. Hypothermia reduced ICP

3. Osmotherapy if renal function preserved : mannitol , 30% saline [Keep Na+ 140-155]4. Corticosteroids e.g. dexamethasone

Ascites

The most common cause of ascites is cirrhosis, which accounts for 80% of cases

another 15% of cases:

1. Peritoneal malignancy (e.g., peritoneal metastases from GI tumors or ovarian cancer)

2. heart failure (Chapter 58)s

3. peritoneal tuberculosis (Chapter 332)

4. The initial, most cost-effective, and least invasive method to confirm the presence of ascites isabdominal ultrasonography.

Diagnostic paracentesis

Initial tests that should be performed on the ascitic

●Appearance assessment (eg, clear, bloody, cloudy, milky)

●Serum-to-ascites albumin gradient determination (SAAG)

●Cell count and differential

●Total protein concentration

Additional tests that may be performed

●Culture with bedside inoculation of aerobic and anaerobic blood culture

bottles (infection, bowel perforation)

●Glucose concentration (malignancy, infection, bowel perforation)

●LDH concentration (malignancy, infection, bowel perforation)

●Gram stain (suspected bowel perforation)

●Amylase concentration (pancreatic ascites or bowel perforation)

●Tuberculosis smear, culture, and adenosine deaminase activity (tuberculous

peritonitis)

●Cytology and possibly antigen level (malignancy)

●Triglyceride concentration (chylous ascites)

●Bilirubin concentration (bowel or biliary perforation)

●Serum pro-brain natriuretic peptide (heart failure)

Na < 2 g/day.

Spironolactone100

mg/day adjusted

every 3 to 4 days

to a maximal

effective dose of

400 mg/day.

Furosemide, at an

escalated dose from

40 to 160 mg/day

Inadequate response or hyperkalemia

The goal is weight loss

1 kg in the first week

2 kg/week subsequently.

large-volume paracentesis + albumin of 6 to 8 g IV

per liter of ascites removed, Particularly when more than 5 L is removed at once

Refractory ascites 10 to 20%

Reduce the dose or switch protocol if :

weight loss is greater than 0.5 kg/day in patients

without peripheral edema

more than 1 kg/day in patients with peripheral

edema.

Side effects1) electrolyte abnormalities

2) renal dysfunction,

3) Encephalopathy

4) painful gynecomastia (with

spironolactone).

Spontaneous Bacterial Peritonitis

Definition :infection of ascitic fluid occurs in the absence of perforation of a hollow viscus or an intra-abdominal inflammatory

Causes :a) abscess, acute pancreatitis, or cholecystitis. Bacterial translocation,

the main mechanism : migration of bacteria from the intestinal lumen to mesenteric.

b)Mainly gram-negative bacteria

Impaired local and systemicb) Transient bacteremia due to :

1. Shunting of the blood away from kupffer cells collaterals

2. bacterial overgrowth attributed to a decrease in small bowel motility and intestinal transit time.

Infections, particularly from

Hepato-renal syndrome

• Definition :

1. a form of functional renal failure without renal pathology

2. Reduced renal perfusion ,associated with reduced GFR and sodium excretion

3. HRS is often seen in patients with refractory ascites

• Epidemiology: occurs in about 10% of patients with advanced cirrhosis or acute liver failure

• causes :

1. Splanchinc vasodialation , reduced systemic SVR hypoperfusion

2. Local increase in the femoral and renal vascular resistance RAAS and sympathomimetic

agents

Type 1 hepatorenal syndrome –more serious type; a progressive impairment

1. 2 X serum creatinine = 50% reduction in creatinine clearance

2. a level greater than 2.5 mg/dL

3. during a period of less than two weeks.

4. Oliguria may occure

●Type 2 hepatorenal syndrome – is less severe; fairly stable . The major clinical

feature is ascites that is resistant to diuretics.

The best therapy for HRS is liver transplantation;

Terlipressin in combination with albumin

initial treatment with norepinephrine in combination with albumin.

Norepinephrine IV as until mean arterial pressure raise by 10 mmgH

albumin is given for at least two days as an intravenous bolus Midodrine along with octreotide in combination with albumin

Cardiopulmonary Complications

cirrhotic cardiomyopathy

1. The hyper dynamic high-output heart failure with decreased peripheral utilization of

oxygen

2. Cirrhosis increased cholesterol decreased cardiomyocytes membrane fluidity

1. Decreased fluidity causes :

Reduced amount of receptors and channel [ K , beta adrenergic , Ca+2 ]

Impaired signaling

Reduced response

Wong F. Cirrhotic cardiomyopathy. Hepatology International 2009;3(1):294-304.

The hallmark is pulmonary bed vasodilation arterial hypoxemia

More than one RBC at the time reduced oxygenation

which causes the equivalent of a right-to-left shunt.

Hepato-pulmonary

Porto pulmonary hypertension

vasoconstrictive substances that may be produced in the splanchnic circulation and

bypass metabolism by the liver;

the initial result is reversible pulmonary hypertension.

However, irreversible pulmonary hypertension can occur due to :

1. endothelial proliferation

2. Vasoconstriction

3. in situ thrombosis thrombosis

4. obliteration of vessels

Coagulopathy

Coagulopathy is almost universal in patients with cirrhosis.

decreased synthesis of clotting factors

impaired clearance of anticoagulants.

thrombocytopenia from hypersplenism due to portal hypertension.

Decreased hepatic mass reduced synthesis

Vitamin K requires biliary excretion for its absorption;

HypoCoagulable state : Vitamin K–dependent clotting factors are Factors 1972

HyperCoagulable state :

( protein C, protein S, anti-thrombin)

Treatment:

IM or IV vitamin K can quickly correct this abnormality.

Platelet function is often abnormal in patients with chronic liver disease, in addition

to decreases in platelet levels due to hypersplenism

Fresh frozen plasmaCryocepitate

Hematologic abnormalities

Numerous hematologic manifestations of cirrhosis are

present

including anemia from a variety of causes :

1.Hypersplenism

2.Hemolysis e.g. [ HBC , cryo]

3. iron deficiency

4.Bleeding due to portal HTN

5.B12 /folate deficiency from malnutrition.6.neutropenia may be seen as a result of hypersplenism

Definitive treatment Vs best treatment transplantation Vs prevention

Symptom or Sign Possible Cause

Abdominal discomfort

hepatic encephalopathy

Calf pain or swelling, symptoms of pulmonary embolism

Clubbing

Confusion, lethargy

Dyspnea, hypoxia

Fatigue, pallor

Fluid overload, oliguria, symptoms of renal failure

Fragility fracture (due to a fall from standing height or less)

Symptoms of infection

Jaundice

Petechiae, purpura, bleeding

Pruritus, xanthelasmas

Rectal bleeding

Splenomegaly

Steatorrhea