What is the diagnosis and treatment approach for a patient with cirrhosis, potentially due to hepatitis B or C, or alcohol abuse, presenting with symptoms such as fluid buildup and portal hypertension?

Cirrhosis: Comprehensive Diagnosis and Management

Definition and Epidemiology

Cirrhosis is the end-stage form of chronic liver disease characterized by progressive fibrosis that destroys liver architecture and blocks intrahepatic portal blood flow, leading to portal hypertension and hepatic dysfunction. 1

• Affects approximately 2.2 million adults in the United States, with age-adjusted mortality increasing from 14.9 per 100,000 in 2010 to 21.9 per 100,000 in 2021 2
• Approximately 90% of cases result from chronic alcohol abuse, chronic viral hepatitis (hepatitis B and C), and nonalcoholic fatty liver disease/metabolic syndrome 1
• In the US specifically: alcohol use disorder accounts for approximately 45% of cases, hepatitis C for 41%, and nonalcoholic fatty liver disease for 26% 2
• Only one in three people with cirrhosis knows they have it, and approximately 40% are diagnosed only when presenting with complications 2, 3

Diagnostic Approach

Clinical Presentation

Most patients remain asymptomatic until decompensation occurs, making early detection challenging. 3

Common symptoms when present include:

• Muscle cramps (approximately 64% prevalence) 2
• Pruritus (39%) 2
• Poor-quality sleep (63%) 2
• Sexual dysfunction (53%) 2

Initial Laboratory Workup

When clinical signs, abnormal liver function tests, or symptoms are discovered, pursue the following immediately: 3

• Complete blood count, comprehensive metabolic panel, liver function tests (AST, ALT, alkaline phosphatase, bilirubin, albumin) 3
• Prothrombin time/international normalized ratio 3
• Viral hepatitis serologies (hepatitis B surface antigen, anti-HBc antibodies, anti-HBs antibodies, anti-HCV antibodies) 1
• Ferritin and transferrin saturation (to assess for hemochromatosis) 3
• Additional testing based on demographics: anti-nuclear antibody, anti-smooth muscle antibody, ceruloplasmin, alpha-1 antitrypsin level 3

Noninvasive Fibrosis Assessment

Noninvasive methods should be used instead of liver biopsy to assess liver disease severity prior to therapy. 1

Validated noninvasive tests include: 1, 3

• Transient elastography (vibration-controlled): Cirrhosis typically confirmed at ≥15 kPa 2
• Aspartate aminotransferase to platelet ratio index (APRI) 1
• Fibrosis-4 (FIB-4) score 1
• FibroTest/FibroSure 3
• Nonalcoholic fatty liver fibrosis score 3

The most efficient approach combines direct serum biomarkers with transient elastography. 1

Important caveat: These tests perform well identifying cirrhosis versus no fibrosis but less well for intermediate stages; factors like obesity, elevated ALT, and post-prandial testing can adversely affect liver stiffness measurements 1

Severity Scoring Systems

The Child-Pugh score and Model for End-Stage Liver Disease (MELD) score are essential for assessing cirrhosis severity and prognosis. 1

For ICU patients, the CLIF-SOFA score better predicts outcomes than MELD or Child-Pugh scores by identifying acute-on-chronic liver failure (ACLF) grades based on organ failures 1

Management of Underlying Etiology

Alcohol-Related Cirrhosis

Alcohol cessation is the single most effective treatment for alcoholic liver disease, with approximately 75% 3-year survival in patients who stop drinking compared to 0% 3-year survival in those who continue drinking. 4, 5

• Even with advanced disease (Child-Pugh class C), stopping alcohol can dramatically improve liver function and reduce complications 4
• Nutritional support is crucial as many patients are malnourished 1, 4
• Periods of excessive alcohol intake can lead to superimposed alcoholic steatohepatitis requiring specific management 1

Viral Hepatitis Management

For hepatitis C: Antiviral treatment is recommended for all patients with chronic HCV infection except those with limited life expectancy due to nonhepatic causes. 1

• Direct-acting antiviral regimens achieve sustained virological response in nearly all infected patients 1
• Treatment priority should be given to those with advanced fibrosis (F3-F4), extrahepatic manifestations, or risk of transmission 1
• Protease inhibitor-containing regimens are contraindicated in Child-Pugh B or C cirrhosis due to toxicity risk 1

For hepatitis B: Antiviral treatment can lead to dramatic improvement even in decompensated cirrhosis. 6

Metabolic Dysfunction-Associated Steatotic Liver Disease

Address modifiable risk factors: 3

• Weight loss through caloric restriction and exercise
• Control of diabetes mellitus
• Management of dyslipidemia
• Avoidance of hepatotoxic medications

Management of Portal Hypertension Complications

Ascites Management

First-line therapy combines dietary sodium restriction (2,000 mg/day or 88 mmol/day) with diuretic therapy. 5, 6

Initial Diuretic Regimen

• Start with spironolactone 100 mg once daily 5, 6
• Add furosemide 40 mg once daily if needed 5, 6
• Maximum doses: spironolactone 400 mg/day and furosemide 160 mg/day 5, 6
• Combination therapy (starting both simultaneously) is more effective than sequential initiation, resolving ascites in 76% versus 56% with lower hyperkalemia rates (4% versus 18%) 2

Monitoring Response

• Daily weight measurement at the same time each day is essential 6
• Target weight loss: 0.5 kg/day without peripheral edema, up to 1 kg/day with edema 6
• Measure 24-hour urinary sodium excretion if weight loss inadequate; >78 mmol/day indicates adequate response 6
• Random spot urine sodium-to-potassium ratio >1 correlates with adequate 24-hour sodium excretion with approximately 90% accuracy 6
• Monitor serum electrolytes, creatinine, and weight regularly 5, 6

Tense Ascites

For tense, uncomfortable ascites, perform large-volume paracentesis for rapid relief. 5, 6

• Administer intravenous albumin 8 g per liter of fluid removed to prevent circulatory dysfunction 5, 6
• Resume diuretic therapy after paracentesis to prevent rapid reaccumulation 6

Refractory Ascites

Defined as fluid overload unresponsive to sodium restriction and high-dose diuretics (400 mg/day spironolactone and 160 mg/day furosemide) or rapid recurrence after therapeutic paracentesis 5

Management options: 5

• Serial therapeutic paracenteses with albumin replacement
• Transjugular intrahepatic portosystemic shunt (TIPS) in selected patients
• Liver transplantation evaluation (should be prioritized)

Critical pitfall: Nonsteroidal anti-inflammatory drugs should be avoided as they reduce urinary sodium excretion, induce azotemia, and convert diuretic-sensitive patients to refractory. 5, 6

Spontaneous Bacterial Peritonitis

Bacterial infections occur in 60-80% of patients with acute liver failure and are common precipitants of ACLF. 1

• Annual incidence in patients with ascites is 11% 2
• Perform diagnostic paracentesis with ascitic fluid cell count, differential, total protein, and culture when infection suspected 6
• Empirical broad-spectrum antibiotics should cover enterobacteria, staphylococcal, and streptococcal species 1
• Antibiotic prophylaxis indicated in high-risk patients 3

Hepatorenal Syndrome

Hepatorenal syndrome-acute kidney injury (HRS-AKI) has an annual incidence of 8% in patients with ascites and median survival less than 2 weeks without treatment. 2

Management approach: 1

• Albumin (20-40 g/day) plus vasoconstrictors recommended for Stage 2 or greater HRS-AKI 1
• Terlipressin (0.5-2.0 mg IV q6h or continuous infusion 2 g/24h IV) is indicated in hospitalized patients with Stage 2 or greater HRS-AKI without ACLF-3 or major cardiopulmonary/vascular disease 1
• In a randomized trial of 300 patients, terlipressin improved reversal rate from 18% to 39% 2
• Norepinephrine can be used as alternative, particularly in patients with shock 1
• Renal replacement therapy should be individualized; generally recommended for patients who failed pharmacotherapy and are listed or being considered for liver transplantation 1

Variceal Bleeding Prevention

In a 3-year randomized trial of 201 patients with portal hypertension, nonselective β-blockers (carvedilol or propranolol) reduced risk of decompensation or death compared to placebo (16% versus 27%). 2

• Regular endoscopic screening needed to monitor for varices and assess bleeding risk 4
• High-risk varices require prophylaxis with nonselective beta-blockers or endoscopic band ligation 4, 3
• Patients with acute gastrointestinal bleeding should be monitored in intensive care unit with endoscopy within 24 hours 7

Hepatic Encephalopathy

Lactulose is the first-line treatment for hepatic encephalopathy. 8

• In meta-analyses of 705 patients, lactulose reduced mortality relative to placebo (8.5% versus 14%) 2
• In trials involving 1,415 patients, lactulose reduced recurrent overt hepatic encephalopathy (25.5% versus 46.8%) 2
• Usual adult oral dosage: 30-45 mL (20-30 g lactulose) three or four times daily, adjusted to produce 2-3 soft stools daily 8
• For rapid laxation in acute portal-systemic encephalopathy: hourly doses of 30-45 mL until laxative effect achieved 8
• Rifaximin can be added for recurrent episodes 3

Important: The use of osmotic laxatives or non-absorbable antibiotics to lower ammonia levels is NOT recommended in acute liver failure. 1

Precipitating factors to identify and manage: 7

• Constipation
• Infection
• Gastrointestinal bleeding
• Certain medications
• Electrolyte imbalances
• Noncompliance with medical therapy

Hepatocellular Carcinoma Screening

Approximately 1-4% of patients with cirrhosis develop hepatocellular carcinoma annually, with 5-year survival of approximately 20%. 2

• Ultrasound screening every 6 months is recommended for all patients with cirrhosis 3, 7
• Incidence ranges from 7-16% after 5 years to 29% after 10 years in alcoholic cirrhosis 1

Management of Acute-on-Chronic Liver Failure (ACLF)

ACLF is a dynamic syndrome combining acute decompensation of cirrhosis with one or several extrahepatic organ failures and high short-term mortality. 1

Key management principles: 1

• Diagnosis and grading using CLIF-SOFA score predicts outcomes better than MELD or Child-Pugh scores
• Infection is the most common precipitant (48% prevalence) 1
• High suspicion for sepsis needed in all patients presenting to emergency room with new or worsening decompensation 1
• Cirrhotic ICU patients have 30-50% in-hospital mortality 1

Infection Management in ACLF

Patients with ACLF and infection have more severe systemic inflammation and higher probability of death than those without infection. 1

• Most common infections: spontaneous bacterial peritonitis, urinary tract infections, skin/soft-tissue infections 1
• Multi-drug resistant organisms increase risk of ACLF and death 1
• Empirical broad-spectrum antibiotics should be administered if signs of sepsis and/or worsening encephalopathy 1
• Fungal infections occur in one-third of acute liver failure patients; nosocomial and fungal infections carry 30% mortality at 30 days 1

Critical Care Considerations

Electrolyte management: 1

• Target serum sodium 140-145 mmol/L (correlation between hyponatremia and intracranial pressure)
• Corrections should not exceed 10 mmol/L per 24 hours
• Serum sodium above 150 mmol/L is deleterious and should be avoided

Supportive care: 1

• Stress ulcer prophylaxis usually recommended despite lack of data
• No specific nutritional guidelines; energy expenditure similar to other ICU patients
• Monitor and correct electrolyte disturbances including serum phosphate

Symptom Management

Muscle Cramps

• Pickle brine and taurine have demonstrated efficacy 2

Sleep Dysfunction

• Hydroxyzine has shown efficacy 2

Sexual Dysfunction

• Tadalafil improves sexual dysfunction in men 2

Pruritus

• Affects 39% of patients; specific antipruritic therapy may be needed 2

Liver Transplantation

Liver transplantation is the definitive treatment for end-stage cirrhosis and should be considered for all patients with decompensated cirrhosis, preferably before development of renal dysfunction. 1, 5

Indications for evaluation: 5

• Development of ascites (20% mortality within first year)
• Refractory ascites
• Hepatorenal syndrome
• Recurrent variceal bleeding
• Progressive hepatic encephalopathy
• Hepatocellular carcinoma within Milan criteria

Prognosis

The development of ascites indicates poor prognosis with approximately 20% mortality within the first year of diagnosis. 5, 6

Median survival after onset of complications: 2

• Hepatic encephalopathy: 0.92 years
• Ascites: 1.1 years
• Hepatorenal syndrome: less than 2 weeks without treatment

Without alcohol abstinence in alcohol-related cirrhosis, portal hypertension complications typically worsen progressively. 4, 5

Medications to Avoid

Critical contraindications: 5, 6

• Nonsteroidal anti-inflammatory drugs (reduce urinary sodium excretion, induce azotemia, convert diuretic-sensitive to refractory ascites)
• Angiotensin-converting enzyme inhibitors (worsen hypotension)
• Proton pump inhibitors (increase infection risk; use only when clearly indicated) 1

Screening for Other Organ Damage

In alcoholic cirrhosis specifically, screen for: 1

• Alcoholic cardiomyopathy
• IgA-induced nephropathy
• Central and peripheral nervous system involvement (alcoholic dementia, withdrawal syndrome, Wernicke's encephalopathy)
• Chronic pancreatitis