Cirrhosis of Liver and its Complications

  • Clinical Stages of cirrhosis:
  • – Stage 1: No ascites + No varices
  • – Stage 2: No ascites + varices without bleeding
  • – Stage 3: Ascites ±  varices
  • – Stage 4: Variceal bleeding ± ascites

 

  • Management of cirrhosis of Liver
  •            – General management
  •            – Management of complications of cirrhosis
  •            – Management of underlying cause of cirrhosis
  • Nutritional management of cirrhosis:
  • – Small , frequent, high calorie diet with bed time snacks
  • – Monitoring of fat soluble vitamins and zinc with its replacement if required
  • – Protein requirement: 0.8-1.2 g/kg/day
  • Vaccination:
  • – Hepatitis A,B
  • – Influenza
  • – Pneumonia
  •                        Prognosis of cirrhosis
  • – Compensated cirrhosis:
  •                 Median survival 9-12 years
  • – Decompensated cirrhosis:
  •                 Median survival 2 years
  • – If ascites present:
  •                 50% patients die within 2 years
  • – If refractory ascites present :
  •               Median survival 6 months

 

 West Haven Criteria of hepatic encephalopathy

 

Management of Hepatic Encephalopathy

  • -Elimination and correction of precipitating factors
  •          • Bleeding
  •          • Infection
  •          • Hypokalemia
  •           •Medication
  •          •Dehydration
  •          •Reduce ammonia level
  •          •Avoid toxic effect of ammonia on CNS

Side effects of lactulose:

  • – Abdominal cramping
  • – Flatulence
  • – Diarrhea
  • – Electrolyte imbalance

** Lactulose may be given per rectum as enema to patients who are at risk of aspiration

Oral antibiotic:

  • – Rifaximine 550mg 12 hourly
  • – Modify intestinal flora
  • – Lower stool PH → increase ammonia excretion
  • – 2nd line agent after lactulose

Other agents that modify intestinal flora

  • – Acarbose
  • – Probiotics

Agents that enhances ammonia clearance through urine

  • – Sodium Benzoate
  • – Sodium Phenylacetate
  • – Sodium Phenylbutyrate

Other Therapy

  • – Extracoporeal albumin dialysis/ MARs
  • – L-ornithin-L-aspartate (LOLA) →   Activate urea cycle

 

 

1.Pharmacological therapy

  • – Vasopressin and its analogue
  • – Somatostatin and its analogue
  • – β-blocker agents
  • – Combined α, β blocking agents
  • – Nitrates

2.Endoscopic therapy

  • – Sclerotherapy
  • – Variceal ligation
  • – Detachable snare and stents

3.TIPS

4.Balloon occluded retrograde transvenous obliteration (BRTO)

5.Surgical therapy

  • Non shunt procedure
  •          – Esophageal transection
  •          – Devascularisation
  • Porto-systemic shunt
  •          – Selective shunt
  •          – Partial Porto-systemic shunt
  •          – Portacaval shunt
  •         – Rex bypass
  • Liver transplantation

Surgical procedures:

  • – Used as salvage therapy when standard management with pharmacologic/ endoscopic therapy fails in patients with non-cirrhotic portal HTN and CTP-A patients

Esophageal transection:

  • – When 2 session of endoscopic therapy fail to control variceal bleeding within 24 hours

Devascularisation Procedure:

  • – Recurrent variceal bleeding with extensive splenic and portal vein thrombosis when vein is available for portosystemic shunt
  • – Operation is combined with splenectomy

Portosystemic shunt:

  • – Done almost exclusively in children with
  • – Refractory bleeding due to non-cirrhotic portal HTN

 

 

  • – 40% cirrhotic patients have esophageal varices
  • – 60% cirrhotic patients with ascites have esophageal varices
  • – 5% per year new varices will appear who have no varices at initial endoscopy
  • – 25% patients with newly diagnosed varices will experience bleeding within 2 year

Risk of variceal bleeding:

  • – Increase with variceal size
  • – Varices >5 mm → risk bleeding 30% by 2 year
  • – HVPG <12 mm Hg → Risk of bleeding virtually absent

Esophageal variceal bleeding

  • – Initial treatment : Cessation of treatment in 80-90% cases
  • – Spontaneous stoppage of bleeding : 50% cases
  • – Excessive transfusion: increase chance of rebleeding
  • – Patients who have stopped bleeding : 1/3rd will rebleed within 6 weeks
  • – Risk of death in variceal bleeding
  •               • 5-8% at 1 week
  •               • 20% at 6 week

Markers of failure to control bleeding at 5 days

  • – Active bleeding at endoscopy
  • – Lower hematocrit values
  • – Higher CTP score
  • – Increased transaminase
  • – HVPG>20 mmHg
  • – Bacterial infection
  • – Portal vein thrombosis

Highest risk of death on cirrhosis:

  • – Rebleeding early
  • – MELD score 18
  • – Patients requiring 4 units of packed RBC
  • – Renal failure

Treatment of esophageal varices:

  1. Primary prophylaxis (prevention of variceal hemorrhage who never bleed)
  2. Control of variceal bleeding
  3. Secondary prevention of rebleeding

Prevention of esophageal variceal bleeding

  1. Pharmacologic prevention
  2. endoscopic prevention

Beta-Blocker therapy:

  • – HVPG may be measured before starting beta blocker agent
  • – HVPG should be remeasured 1 month after maximum tolerated dose of β-blocker
  • Goal of treatment: HVPG ↓<12 mm Hg or≥ 20%

Who are candidates for β-blocker prophylaxis?

  • – Small varices with CTP score C
  • – All patients with large varices

 

  • – Red wale sign does not influence the decision for prophylaxis
  • – Withdrawal of β-blocker increase the risk of bleeding
  • – 15% patients need to discontinue the drug due to side effects
  • – Base-line parameters should be as follows to continue β-blocker
  •                     •Heart rate: 55-60/min
  •                    • SBP>90mm Hg
  • – Risk of bleeding is more at night
  • – Dose of propranolol can be increased every 3-5 day until target heart rate 25% below baseline or 55-60 /min reached
  • – Patients pharmacologic therapy, F-up endoscopy is unnecessary unless GI bleeding occurs
  • – Patients intolerant of β-blocker  →  Endoscopic therapy should be pursued

Endoscopic prevention of variceal hemorrhage

  • – Prophylactic sclerotherapy for prevention of variceal bleeding is not recommended
  • – Combined β-blocker + EVL as primary prophylaxis is not currently recommended
  • – EVL is the only option for
  •                  • High risk varices who have contraindication to /Not responded to/Intolerant to β-blocker

 

Acute Variceal Bleeding

 

 

Definition of uncontrolled bleeding:

     Any of the following 3 criteria

– Transmission 4 units of RBC or more to maintain hematocrit >25%

– Inability to increase SBP by 20 mm Hg or >70 mm Hg

– Persistent heart rate > 100 beats/min

 

Definition of rebleeding:

  • Recurrence of bleeding after initial control for 24 hours during which vital signs and Hb are stable

Treatment target of variceal bleeding:

  • Resuscitation of the patient
  • Control the bleeding
  • Prevent complications

 

Management steps:

 

ACG Guideline

 

1.Cirrhosis with no varices

  • β- blocker: Not indicated to prevent variceal development
  •         ♦ Compensated cirrhosis + no varices at initial EGD     Repeat EGD in 3 years
  •         ♦ Decompensated cirrhosis + no varices at initial EGD  Repeat EGD annually

 

2.Patients with cirrhosis + small varices that have not bled

  • – Increased risk of hemorrhage in these patients
  • – Add non-selective β- blocker to prevent first variceal bleeding  if CTP: B/C or presence of red wale mark on varices
  • – If there is no criteria for increased risk of bleeding   ⇒   β- blocker can be used, although the long benefit is  not established
  • – Patients with small varices not receiving β- blocker  ⇒  Repeat EGD in 2 yearly
  • – Patients with small varices receiving β- blocker F/Up ⇒     EGD not necessary

 

3.Cirrhosis with non-bleeding medium/large varices

  • Medium/large varices + high risk of hemorrhage (CTP B,C/ red wale mark on endoscopy)
  •                                                 
  • β- Blocker/ EVL may be recommended to prevent first variceal hemorrhage
  • If no high risk of hemorrhage (CTP A, no red wale sign)
  •                                    ↓
  •              –  β- Blocker is preferable
  •              – EVL if β- Blocker contraindicated
  • If patient is on β- Blocker
  •                     – Maximum dose should be adjusted
  •                     –  F-Up surveillance EGD is unnecessary
  • ⇒ If treated by EVL
  •                    – Repeat EVL 1-2 weekly until obliteration with first surveillance EGD performed 1-3 months after obliteration and then 6-12 monthly to check variceal recurrence

 

 

Sarin Classification of Gastric Varices

Type 1 (GOV1):

  • – Varices extends 2-5 cm blow the gastroesophageal junction and are in continuity with esophageal varices. GOV1 comprises 70% of all gastric varices

Type 2 (GOV2):

  • – Varices in the cardia and fundus of the stomach in continuity of esophageal varices

  ** Intrahepatic causes of portal hypertension may be associated with both GOV1 and GOV2

Isolated Gastric Varices 1 (IGV1):

  • Varices occurring in the fundus of the stomach in the absence of esophageal varices. Splenic vein thrombosis usually results in IGV1,but the most common cause of fundal gastric varices may be cirrhosis

  Isolated Gastric Varices 2 (IGV2):

  • Varices that occur in the gastric body, antrum, pylorus in the absence of esophageal varices

 

Figure: Types of Gastric Varices

 

 

                Natural history of gastric varices

 

  • – Gastric varices occur in advanced portal HTN
  • – Gastric varices tend to be larger in diameter than esophageal varices
  • – Bleeding from gastric varices is less common than esophageal varices as gastric varices are supported by gastric mucosa
  • – Gastric varices may bleed at HVPG<12 mm Hg
  • – Gastric varices bleed only when they are large (>20mm diameter)
  • – Bleeding is more common from fundal varices than varices from gastroesophageal junction
  • – Bleeding is more common in GOV2 and IGV1 (Fundal)
  • – 25% patients with of portal HTN have gastric have gastric varices, most commonly GOV1
  • – Gastric varices in continuity with esophageal varices may regress after esophageal variceal obliteration. If the gastric varices persist despite obliteration of esophageal varices, the prognosis is poor because of the severity of liver disease

Prevention of bleeding from gastric varices

  • – β-blocker when in continuity with esophageal varices
  • – Cyanoacrylic glue injection
  • – TIPS
  • – BRTO (Baloon occluded Retrograde Transvenous Obliteration)
  • – Preventive measures are taken when varices >20mm in diameter with MELD>17

 

                                 Management of acute gastric variceal bleeding:

 Approach: (as approach for the management of esophageal variceal bleeding)

  • – Volume resuscitation
  • – Avoidance of over transfusion
  • – Antibiotic prophylaxis with Norfloxacin 400 mg twice daily for 7 days
  • – Endoscopy of upper GIT after volume resuscitation and hemodynamic stabilization
  • – Medical management with vasoactive agent should be started at least 30 minutes before endoscopic therapy
  • Preferred endoscopic therapy: Cyanoacrylate glue
  •          •  The endoscope may be damaged by glue, this risk is minimized by covering the tip of endoscope by silicone gel and suction is avoided 15-29 seconds following injection
  •         •Complications of cyanoacrylate injection
  •                       ♦ Bacteremia
  •                       ♦ Variceal ulceration
  • – Band ligation of varices >10mm in diameter is usually unsafe. Ligation is safest if the varices are in the cardia of the stomach
  • – When bleeding cannot be controlled by medical and endoscopic therapy TIPS will control the bleeding in 90% patients

 

           

 

  • – Whitish mosaic-like gastric erythema
  • – Develops in 51-98% patients with cirrhosis and non-cirrhotic portal HTN
  • – Occurs due to  resistance to portal flow
  • – No linear correlation with level of portal pressure
  • – Correlated with
  •                    • Duration of liver disease
  •                    • Severity of liver disease
  •                    • Presence and size of gastroesophageal varices
  • – Gastric mucosa of PHG bleeds easily on contact, more susceptible to damage by bile acid, aspirin, NSAID
  • – PHG most prominent in gastric body, fundus

Pathogenesis:

  • Not clearly understood
  • May be related to over production of Nitric oxide   → Capillary dilation →    VEGF      Angiogenesis

Endoscopic findings:

– Gastric mucosa

  •            • Erythematous
  •            • Edematous
  •            • Characteristic pattern (Mosaic pattern mucosa/Snake-skin appearance)
  •                         Endoscopic view of Portal Hypertensive Gastropathy

Clinical feature:

  • – Anemia
  • – Rarely acute blood loss

Treatment of PHG:

  • – Decrease blood flow by
  •                   •Beta blocker, Octreotide, Vasopressin
  • – Iron replacement
  • – TIPS if Hb is not stable

 

 

        

 

Hyponatremia in cirrhosis:

when serum Sodium <130 mmol/L, but S.Sodium <135mmol/L should also be considered as hyponatremia

– Hyponatremia in cirrhosis is associated with

  • • Impaired survival
  • • Increased morbidity particularly neurological complications
  • • Reduced survival after transplantation

Hypovolemic hyponatremia:

  • Low sodium concentration in the absence of ascites and edema, usually occurs after a prolonged negative sodium balance with marked loss of extracellular fluid, most frequently after diuretic therapy

Management of hypovolemic hyponatremia

– Administration of normal saline and treatment of the cause (usually diuretic withdrawal)

Hypervolemic hyponatremia:

– Low sodium concentration with expansion of the extracellular fluid volume with ascites and edema

Causes of Hyponatremia in Decompensated Cirrhosis:

  • – Impaired solute-free water excretion secondary to non-osmotic hyper secretion of vasopressin (ADH)
  • – As a consequence of excessive hypotonic (5% dextrose) fluid

Treatment of Hyponatremia in cirrhosis:

  • – Fluid restriction to 1000 ml/day    Effective in a minority of patients but may be effective in preventing a further reduction in serum sodium level
  • – No data to support use of normal/ hypertonic saline
  • – Albumin administration might be effective

Vaptans: Tolvaptan, Conivaptan

  • – Considered in patients with severe hyponatremia (<125 mmol/L)
  • – Na+ should be closely monitored particularly during the first day of treatment and when the dose is increased
  • – Neither fluid restriction nor administration of saline should be used in combination with vaptans to avoid a too rapid increase in serum sodium concentration
  • – Duration of treatment with vaptan is not known
  • – Safety has only been established for short term use (1 month)

 

 

Diagnostic criteria for Hepatorenal syndrome:

  • – Cirrhosis with ascites
  • – Serum creatinine level ≥ 1.5 mg/dL (133 µmol/L)
  • – No or insufficient improvement in serum creatinine level (remains ≥ 1.5 mg/dL) 48 hr after diuretic withdrawal and adequate volume expansion with IV albumin
  • – Absence of shock
  • – No evidence of recent use of nephrotoxic agents
  • – Absence of intrinsic renal disease

Classification of HRS:

      1.Type 1 HRS:

  •        –  Rapidly progressive form of renal dysfunction
  •        – The serum creatinine level doubles to a value higher than 2.5 mg/dL in a period of 2 weeks or less

                     Triggers of type 1 HRS

  •                           • Severe bacterial infections
  •                           • GI bleeding
  •                           • Surgical procedures
  •                           • Acute liver injury
  •                           • SBP is the main bacterial infection that predisposes cirrhotic patients to develop HRS

      2.Type 2HRS:

                  – Slowly progressive than type 1 HRS

                 – Median survival: 6 months

                – Type 2 HRS is observed in patients with severe ascites (diuretic resistant) and is characterized by

   serum creatinine levels lower than 2.5 mg/dL

Type 1 HRS may develop in patients with type 2 HRS following a triggering event

 

 

 

 

 

 

  • – Effusion usually occur in right side of the chest
  • – Usually patients have small defect in the diaphragm
  • – With large  diaphragmatic defect ascites may be undetectable on clinical examination despite large pleural effusion
  • Who develop hepatic hydrothorax?
  •       – Patients least adherent to treatment regimen
  •       – Refractory ascites
  • Treatment of hepatic hydrothorax:
  •        – First line therapy:   Sodium restriction + Diuretics
  •       –  Other therapies:
  •                     • Pleurodesis
  •                    • Peritoneovenous shunt
  •                    • TIPS
  •                    • Surgical repair of the diaphragmatic defect

 

 


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