Managing Hepatic Cirrhosis in Primary Care Settings

Liver cirrhosis ( CH) is the twelfth most common cause of death worldwide and the eighth most expensive disease to treat worldwide. There are few comprehensive resources available that describe the management of patients with CH in primary care.

Liver cirrhosis (HC) is both a clinical and pathological diagnosis.

It is defined as the histological alteration of the liver architecture due to fibrosis that has replaced normal liver tissue leading to portal hypertension and the end stage of liver disease that is normally irreversible in advanced stages.

Clinically, the diagnosis is made when the patient presents decompensated or with clinical deterioration, with signs of variceal bleeding, renal failure, spontaneous bacterial peritonitis, hepatic encephalopathy or ascites. Early recognition and diagnosis of decompensated CH is essential since, without transplant, it is accompanied by a high mortality rate (up to 26.4% at 2 years and up to 85% at 5 years).

> Demographics

• Male sex

• Race: Asian American and Pacific Islander

• Income < $20,000/year

> Social history

• Current smoker

• Excessive alcohol consumption

• Intravenous drug use

• Not having a partner at home

• Men who have sex with men

> Medical history

• Viral hepatitis (hepatitis B, hepatitis C)

• Autoimmune hepatitis

• Hemochromatosis

• Wilson’s disease

• Mellitus diabetes

• Metabolic syndrome

• Alpha-1 antitrypsin deficiency

• Primary biliary cholangitis

• Primary sclerosing cholangitis

• Alcoholic liver disease

• Non-alcoholic fatty liver disease

• Congestive heart failure

• Chronic biliary disease

> Medications

• Paracetamol

• Anabolic steroids

• lsoniazid

• Methotrexate

• Sulfa medications

• Tetracyclines

• Anti-seizure medications

• Statins

• Amoxicillin-clavulanate

• Opioidsb

In the initial stages, liver cirrhosis (HC) is usually clinically asymptomatic and insidious.

It has been reported that up to 20% of patients with hepatitis C virus infection may develop cirrhosis before the appearance of clinical signs.

Up to 10% of patients with non-alcoholic steatohepatitis may develop cirrhosis without clinical symptoms or signs.

In asymptomatic patients , detection of elevated aminotransferases or imaging suspicious for liver disease should prompt further investigation to determine the likelihood of liver disease. This includes a complete medical history to detect risk factors for cirrhosis.

Furthermore, laboratory tests should be performed to evaluate liver disease. In patients with a high suspicion of liver disease, a lesion test should be ordered. These tests include white blood cell count and platelet count (<150 × 109/L), aspartate aminotransferase, alanine aminotransferase, albumin, alkaline phosphatase, gamma-glutamyl transferase, total bilirubin, prothrombin time, and INR (international normalized ratio).

Once the presence of liver disease is evident, patients should undergo a complete evaluation to determine the evolution of the disease and the possible etiology, as it is essential for prognosis. For example, patients with CH induced by the hepatitis C virus have a lower rate of annual decompensation than those with hepatitis B, that is, 4% vs. 10%. Patients with alcohol-induced CH have higher rates of decompensation than patients with other forms of cirrhosis.

The American College of Gastroenterology recommends that if aminotransferases are elevated during routine laboratory testing, additional testing should be done, including hepatitis B surface antigen and hepatitis B core and surface antibodies, anti-hepatitis virus. C and, iron studies. Because alanine aminotransferase is found in cells other than hepatocytes, creatine kinase testing and determination of the creatine kinase ratio are important.

Age also plays a key role in the interpretation of elevated aminotransferases. For example, in a young individual with significantly elevated aminotransferases, genetic disorders such as Wilson’s disease or hemochromatosis should be ruled out and require additional studies. On the other hand, an abdominal ultrasound should also be requested, especially focused on the right hypochondrium to rule out an acute disease or a structural process.

If laboratory tests are normal and aminotransferases remain elevated after a period of 3 to 6 months, further investigation should be performed with determination of antinuclear and antismooth muscle antibodies, gamma globulin, ceruloplasmin phenotype, and alpha-1 antitrypsin. Evaluation of additional causes is necessary.

The diagnostic test for liver cirrhosis (CH) is liver biopsy.

Non-invasive testing modalities used are vibration-controlled transient elastography and magnetic resonance elastography. It should be noted that noninvasive measures, especially transient elastography, are replacing biopsy as the preferred option for fibrosis staging.

Transient elastography determines liver stiffness by measuring the speed of low-frequency ultrasound waves traveling through the liver. It is both sensitive and specific for establishing the diagnosis of CH. In fact, if elastography is inadequate or inconclusive, the National Institute for Health and Care Excellence (NICE) guidance recommends performing a liver biopsy.

Several classification systems aim to predict the degree of liver injury and prognosis. The most used score is the Child-Pugh-Turcotte, with an excellent predictive value. It is based on albumin, total bilirubin, INR, and the degree of ascites and encephalopathy.

It allows evaluating the severity of cirrhosis. On the other hand, NICE recommends using the model for end-stage liver disease (MELD) every 6 months as it predicts 3-month mortality in patients with end-stage liver disease.

The MELD score, initially created to predict survival of patients with transjugular intrahepatic portosystemic shunt, uses creatinine, bilirubin, and INR. In clinical practice, the Child-Pugh-Turcotte and MELD systems are commonly used together because studies of the discriminative ability of Child-Pugh-Turcotte vs. that of MELD have given variable results.

A systematic review found that Child-Pugh-Turcotte had greater sensitivity than MELD in predicting outcomes in patients with acute or chronic liver failure, but MELD had greater sensitivity. However, the MELD score showed better discriminative ability to predict outcomes in patients treated in intensive care units.

On the other hand, in patients undergoing surgery, the Child-Pugh-Turcotte had greater specificity. It should be noted that no significant difference was found when comparing the sensitivity and specificity for predicting 12-month mortality between the 2 scores. For this reason, it is recommended to use the clinical context to decide which classification system will be used in clinical practice.

One of the most important and deadly complications of liver cirrhosis (CH) is the rupture of gastroesophageal varices secondary to portal hypertension.

The demonstrated cumulative incidence of the development of esophageal varices in patients with cirrhosis is 5% at one year and 28% at 3 years. Progression was 12% at 1 year and 31% at 3 years, and the 2-year risk of bleeding was 12% vs. 2% with small varicose veins versus none at the beginning of the study.

Esophageal varices can be diagnosed by esophagogastroduodenoscopy, which is typically recommended in the presence of high-risk varices.

In patients with compensated CH who are not candidates for treatment with non-selective beta-blockers to prevent decompensation, initial screening can be done using platelet count and liver elastography.

If the measurement of liver stiffness is <20 kPa or the platelet count is <150 × 109/l, they should undergo esophagogastroduodenoscopy to detect varicose veins. For patients who avoid screening endoscopy, transient elastography and platelet counting can be repeated annually. If the liver stiffness measurement increases (<20 kPa) or the platelet count decreases (<150 × 109/L), screening endoscopy should be performed.

For patients without varicose veins or with small varices, controlling the underlying cause and managing the complications of cirrhosis effectively prevent the progression of varicose rupture. For example, keeping hepatitis viral load low to prevent worsening fibrosis may prevent worsening varicose vein engorgement.

For patients with large varices, therapy with nonselective beta-blockers (carvedilol [preferred], nadolol, or propranolol) dramatically reduces the risk of variceal bleeding, from 30% to 14%. To prevent bleeding in those with medium or large varicose veins, NICE recommends endoscopic band ligation.

One of the most feared complications of liver cirrhosis (CH) is the development of hepatocellular carcinoma (HCC), with an annual incidence of up to 8% in patients with CH. Risk factors for HCC are infection with hepatitis B or C viruses, exposure to aflatoxin, alcohol consumption, tobacco use, and obesity. The risk of developing HCC is also higher in patients ≥55 years of age, patients with prothrombin activity ≤75%, and patients with platelet counts <75 × 109/L.

The most commonly used initial imaging for the detection of hepatocellular carcinoma (HCC), due to its relatively low cost, is ultrasound . To detect HCC, current guidelines from NICE and the American Association for the Study of Liver Deseases recommend that patients with CH undergo routine imaging every 6 months. This recommendation is based on low-quality evidence from several studies suggesting a benefit of at least 3 months of life years gained in patients undergoing ultrasound surveillance every 6 months.

Computed tomography ( CT) and magnetic resonance imaging (MRI) are other options as they have greater sensitivity and specificity than ultrasound. However, its availability is limited and the associated cost is higher. Therefore, only in select cases in which ultrasound results are difficult to interpret (morbidly obese patients, those with fatty liver, or those with advanced liver disease), CT and MRI can be done.

Ultrasound only has a sensitivity of 47% when HCC is detected at an early stage in patients with CH, so a negative imaging result does not diminish a high clinical suspicion or replace serial ultrasound.

If the ultrasound detects a mass <10 mm, a repeat ultrasound is justified after 3 months to monitor growth. For lesions >10 mm, the need for further CT or MR imaging and the risks and benefits of a specialist biopsy should be discussed. However, it should be noted that biopsy motivated by suspicion of HCC is usually avoided for fear of tumor seeding, which favors the generalization of localized disease.

In addition to imaging, tumor markers such as serum alpha-fetoprotein can also be used to detect HCC. Generally, alpha-fetoprotein levels >20 ng/ml are considered a positive test.

Patients with evidence of a lesion ≥10 mm and a serum alpha-fetoprotein level >20 ng/ml should undergo diagnostic testing with contrast-enhanced multiphasic CT or MRI.

Furthermore, clinicians should remember that although elevated alpha-fetoprotein levels are expected in patients with CH, even in the absence of HCC, alpha-fetoprotein levels >400 ng/mL warrant further workup to rule out HCC.

To reduce the risk and delay the onset of hepatocellular carcinoma (HCC), chemopreventive strategies and dietary agents have been proposed. Universal immunization and antiviral therapy for patients with hepatitis B and C virus infection reduces the risk of developing HCC.

Aspirin and statins have antineoplastic effects and anti-inflammatory properties that may have a protective effect on the development of HCC. However, there is still a substantial lack of data on this topic. Additional studies are needed to determine benefit in this subset of patients.

Although no specific recommendations have been published on the use of medications in patients with CH, it can be generalized that hepatotoxic medications should be prescribed with caution.

Hepatic encephalopathy ( HPE) refers to cognitive dysfunction resulting from liver disease that is manifested by a broad spectrum of neurocognitive symptoms ranging from subclinical abnormalities to coma.

In the US, CHD is a major cause of morbidity, mortality, and healthcare expenditures. Primary care physicians can play a key role in recognizing the signs and symptoms of CHD and initiating treatment early, before hospitalization is required. The clinical presentation of ECH varies widely. Patients with minimal disease may have few symptoms, such as subtle personality changes or abnormal psychometric tests.

Hepatic encephalopathy ( HPE) is important because it affects 50% of patients with chronic liver disease. Early diagnosis of minimal CHD may help predict the likelihood of developing overt CHD and may allow initiation of treatment and lifestyle modifications to slow or prevent progressive disease.

The International Society for Hepatic Encephalopathy and Nitrogen Metabolism has suggested that patients be tested using 2 separate psychometric tests as each may assess different components of cognitive functioning, while impairment in patients with minimal CCH may vary from patient to patient. other.

Some tests available include Animal Naming Test, Psychometric Hepatic Encephalopathy Score, Critical Flicker Frequency test, Continuous Reaction Time test, Inhibitory Control Test, Stroop Test, Trail Making Test, computerized Scan test, and electroencephalography.

Some of these tests are time-consuming and require specialized equipment and staff training. Therefore, they cannot be performed in a busy outpatient primary care setting. However, the Animal Naming Test has a high degree of accuracy, can be administered quickly, and is feasible in an outpatient setting.

Symptoms of overt CHD are more obvious and include personality changes, irritability, disinhibition, sleep disturbances, altered sleep cycle or excessive daytime sleepiness, disorientation, inappropriate behavior, confusion, stupor, and coma. On the other hand, there are motor symptoms such as hypertonia and hyperreflexia, as well as extrapyramidal signs such as muscle rigidity, bradykinesia, hypokinesia, slower speech, Parkinson-type tremor and dyskinesia. Finally, asterixis is usually observed in the early and middle stages of the disease.

The diagnosis of overt hepatic encephalopathy (HPE) is based primarily on clinical examination findings and is established only after excluding other causes of brain dysfunction. A key test to determine the severity of CHD is the use of the West Haven Criteria which helps stratify patients into the following grades, based on clinical presentation and neuropsychiatric status:

• Intact : normal, without subclinical symptoms or clinical deterioration in mental status

• Covert : minimal encephalopathy and lack of disorientation and asterixis (i.e. grade I)

• Manifest (grades II to IV).

It should be noted that elevated blood ammonia levels are not diagnostic of ECH nor are they useful in determining prognosis or staging. Therefore, they should not be used for ECH monitoring.

It is very important for doctors to ensure that their patients with liver cirrhosis (CH) receive the appropriate vaccines.

According to guidance from the US Centers for Disease Control and Prevention, patients with chronic liver disease should receive the following vaccines: influenza (annual), hepatitis A and B, shingles, Tdap, and 1 dose of pneumococcal conjugate vaccine (PCV15, PCV20) if the patient is ≥65 years old or between 19 and 64 years old, after diagnosis of liver disease. If PCV15 is used, it is followed by administration of one dose of pneumococcal polysaccharide vaccine.

Diet and exercise

The Mediterranean diet , avoiding red meat and processed foods, has been shown to provide the best results in reducing the risk of non-alcoholic fatty liver disease (NAFLD) by improving the progression to non-alcoholic steatohepatitis and eventually CH. In addition, it must contain corn syrup, high fructose content and foods rich in saturated fats.

In a randomized clinical trial, for 6 months patients with NAFLD followed a low-glycemic Mediterranean diet, without caloric restrictions, showing reductions in the NAFLD score determined by liver ultrasound. On the other hand, patients who followed a Mediterranean diet showed more significant weight loss than the control group.

Those who followed a Mediterranean diet and exercised at least 30 minutes a day (e.g., aerobic exercise consisting of brisk walking, slow or fast running, dancing) showed not only more significant weight loss but also aminotransferase levels and liver stiffness not so high compared to controls. It has been postulated that the cause of sarcopenia is hyperammonemia, muscle autophagy, and low levels of branched-chain amino acids. To prevent or reverse this catabolic state, high protein diets can help maintain the nitrogen levels necessary to avoid sarcopenia.

For patients with CHD, the European Association for the Study of the Liver clinical practice guideline recommends 1.2 to 1.5 g/kg/day of protein and at least 35 kcal/kg/day of caloric intake. On the other hand, the European Association for the Study of the Liver recommends avoiding fasting for more than 6 hours, because it increases the risk of entering a catabolic state during the night. Therefore, intakes should be small and frequent, with nighttime snacks containing high amounts of carbohydrates and protein to improve nitrogen balance throughout the night.

For patients with liver cirrhosis (CH) and ascites, an important part of symptom management is sodium restriction.

Sodium intake should be limited to <2 g/day or 88 mEq/day, since the development of ascites has been observed to be secondary to renal sodium retention. In general, patients can meet this recommendation by avoiding added salt and pre-prepared foods, which are often high in sodium. However, extreme restriction <2 g/day is not recommended as it may reduce food intake, worsening the poor nutrition and catabolic state common in CH patients. Furthermore, for patients taking diuretics, a marked reduction in sodium intake may exacerbate hyponatremia.

Fluid restriction of 1 to 1.5L/day should be reserved for patients with clinical hypervolemia and severe hyponatremia (serum sodium <125 mEq/L).

Fluid restriction is most effective when fluid intake is less than urine volume. However, urine volume is usually low in patients with CH, so adequate fluid restriction is almost impossible and therefore not recommended.