Liver diseases

Liver diseases are continuous process of inflammation, destruction, and regeneration of liver parenchyma, which may lead to fibrosis and cirrhosis. They are characterized by progressive deterioration of liver functions for which includes synthesis of clotting factors, other proteins, detoxification of harmful products of metabolism, and excretion of bile.

The spectrum of etiologies is broad for chronic liver disease, which includes toxins, alcohol abuse for a prolonged time, infection, autoimmune diseases, genetic and metabolic disorders. Cirrhosis is a final stage of chronic liver disease that results in disruption of liver architecture and is currently the 11th most common cause of death globally and liver cancer is the 16th leading cause of death; combined, they account for 3.5% of all deaths worldwide.

They account for approximately 2 million deaths per year worldwide, 1 million due to complications of cirrhosis and 1million due to viral hepatitis and hepatocellular carcinoma.

Liver transplantation is the second most common solid organ transplantation, yet less than 10% of global transplantation needs are met at current rates.

Epidemiology of liver diseases

Chronic liver disease is one of the frequent causes of death, especially in the developing world. In recent years, there has been a rise in the frequency of chronic liver disease. The majority of liver diseases in the industrialized world include alcoholic liver disease, chronic viral hepatitis, including hepatitis B and C, non-alcoholic fatty liver disease (NAFLD), and hemochromatosis. In the United States, about 4.5 million individuals (1.8 percent of the adult population) had chronic liver disease and cirrhosis.

Chronic liver disease and cirrhosis were responsible for 41,473 fatalities (12.8 deaths per 100,000 people). Cirrhosis is one of the top 20 causes of disability-adjusted life years and lost years of life. Around 2 billion people worldwide drink alcohol, and up to 75 million have alcohol use disorders and are at risk of alcohol-related liver damage.

Over 2 billion persons are obese or overweight, and over 400 million have diabetes; both are risk factors for non-alcoholic fatty liver disease and hepatocellular carcinoma. Globally, the prevalence of viral hepatitis remains high, although drug-induced liver damage is becoming a more common cause of acute hepatitis.

Pathophysiology of liver disease

Liver diseases are characterized by a constant and continuing process of hepatic fibrosis, architectural deformation of liver tissue, and liver cells necrosis. While fibrosis is typically irreversible, it might be reversible in its early stages. If untreated, chronic liver illness typically leads to permanent fibrosis, regeneration nodule formation, and the development of cirrhosis liver.

The rate of fibrosis development is determined by the underlying etiologies, environmental variables, and host factors. Patients with HIV-HCV coinfection had the fastest rate, whereas primary biliary cirrhosis had the slowest. The rate of fibrosis progression increased with age, while females showed a more gradual progression of liver fibrosis in all but alcoholic liver disease. Similarly, genetic polymorphism was identified as an underlying reason for differences in fibrosis rate advancement and the development of more severe illness in certain persons compared to others with the same underlying etiology.

Hepatic fibrosis is defined as the deposition of extracellular matrix in response to persistent liver damage caused by any cause. Hepatic stellate cells (HSC), which are vitamin A-storing latent cells situated in the region between sinusoids and hepatocytes, commence the common route.

In response to chronic liver damage, HSC differentiates into proliferative fibrogenic myofibroblasts, which upregulate the expression of inflammatory receptors such as chemokine receptors, ICAM-1, and other inflammatory mediators by secreting chemokines and other leukocyte chemoattractants. This pro-inflammatory or initiation phase also affects the gene and phenotypic expression of liver cells, making them more susceptible to these inflammatory cytokines, and the persistence of activated HSC cells culminates in extracellular matrix build up and progressive fibrosis.

Histopathology

In pathological situations, stellate cells are assumed to be the source of collagen. Chronic liver damage stimulates hepatic stellate cells, which become activated and convert into myofibroblast-like cells. The extracellular matrix is then laid out. Chronic inflammation, cytokine release by injured parenchymal cells, and extracellular matrix disturbance are all well-known triggers for stellate cells.

Cirrhosis of the biliary system is distinguished by feathery degeneration of periseptal hepatocytes, resulting in the formation of prominent "halos" and irregular-shaped nodules ("jigsaw" micronodular pattern). Fibrosis gradually connects the neighboring central veins and portal tracts, resulting in venous outflow blockage and in veno-portal or veno-centric ("reversed lobulation") cirrhosis.

The etiology has an impact on the patterns of liver fibrosis. Chronic hepatotropic virus infection results in portal expansion, periportal fibrosis, septal (bridging) fibrosis, and cirrhosis. Adult non-alcoholic fatty liver disease and alcoholic liver disease both induce fibrosis, which begins with a centrilobular perivenular distribution and progresses to sinusoidal fibrosis.

Types of liver disease

Acute liver disease

the onset of symptoms does not exceed six months then a patient is deemed to have acute liver disease. Most cases are self-limiting episodes of hepatocyte inflammation or damage, which resolve without causing further complications.

Chronic liver disease

Patients with symptoms of liver disease that persist for more than six months have chronic liver disease. It occurs when permanent structural changes within the liver occur secondarily to longstanding hepatocyte damage.

Causes of liver diseases

Alcoholic Liver Disease-liver disease from drinking.

Alcohol consumption is a major risk factor for the development of liver disease. Alcoholic liver disease is a spectrum of diseases which includes alcoholic fatty liver with or without hepatitis, alcohol hepatitis (reversible because of acute ingestion) to cirrhosis (irreversible). Patients with severe alcohol use disorder mostly develop chronic liver disease; this is the most frequent cause of liver disease.

Non-alcoholic liver Diseases (NAFLD/NASH)

The metabolic syndrome (obesity, hyperlipidemia and diabetes mellitus) is linked to non-alcoholic fatty liver disease (NAFLD). Non-alcoholic steatohepatitis develops in some of these people, resulting in liver fibrosis. All metabolic syndrome risk factors have the potential to exacerbate the illness process.

Chronic Viral Hepatitis

Chronic hepatitis B, C, and D infections are the most common causes of chronic liver disease in East Asia and Sub-Saharan Africa.

There are several viruses that can cause hepatitis:

Hepatitis A: spread via the fecal-oral route and is more common in regions with inadequate hygiene and sanitation. There is no progression of the infection to chronic liver disease or carrier status.
Hepatitis B: can cause acute disease or chronic infection, and despite the availability of highly effective vaccination and advances in antiviral medication, it continues to be a serious public health concern across the world. Contact with contaminated blood or body fluids causes transmission, and it is usually transferred from an infected mother to her baby during birth.

When exposed to the virus as a child, the chance of chronic infection is considerable (90%) compared to fewer than 5–10% for adults who acquire the infection.

Hepatitis C: is a blood-borne virus that is usually spread through the sharing of injectable drug-use equipment. Tattooing, electrolysis, ear piercing, acupuncture, and transfer from mother to infant pose a possible risk of hepatitis C infection.

Patients are normally asymptomatic after being exposed to the hepatitis C virus, while around 20% develop acute hepatitis and may experience lethargy, weakness, and anorexia. Approximately 85 % of those who are infected with the virus acquire chronic illness. Within 20 years, 20–30% of people with chronic hepatitis C infection advance to end-stage liver disease, with a small number developing hepatocellular carcinoma.

Hepatitis D: also known as delta virus and can only replicate in the presence of the hepatitis B virus. The combination of both increases the risk of progression to chronic hepatitis and cirrhosis.
Hepatitis E: transmitted via the fecal-oral route. Unless a patient has pre-existing liver disease the infection is generally mild and lasts only a couple of weeks. Hepatitis E does not cause chronic infection.

Liver disease genetic:

Alpha-1 antitrypsin deficiency: This is the most common genetic cause of chronic liver disease among children.
Hereditary hemochromatosis: an autosomal recessive disorder of iron absorption due to a mutation involving the HFE gene that regulates the iron absorption from the intestine, excessive iron is absorbed from the gastrointestinal tract. As a result, there is a pathological increase in total body iron (such as ferritin and hemosiderin). This process leads to the generation of hydroxyl free radicals, which in turn causes organ fibrosis.
Wilson disease: autosomal recessive disorder leading to copper accumulation in the body (mainly in the liver and brain), which can cause hepatitis, fibrosis and cirrhosis.

Autoimmune Causes

Autoimmune liver disease is an uncommon condition in which autoantibodies destroy the liver tissue. The majority of people who appear with this condition have cirrhosis. Females are more likely to be affected than males.

Primary biliary cirrhosis (PBC): characterized by the destruction of intrahepatic biliary channels, as well as portal inflammation and scarring. It causes cholestatic jaundice and liver parenchyma fibrosis. PBC is more frequent among middle-aged women. PBC's alkaline phosphatase levels rise.
Primary Sclerosing Cholangitis (PSC): commonly associated with ulcerative colitis. This condition is characterized by a decrease in the size of intrahepatic and extrahepatic bile ducts due to inflammation and fibrosis.
Autoimmune hepatitis (AIH): This is a form of chronic inflammatory hepatitis, more common in women than men, and is characterized by elevated autoantibodies such as antinuclear antibodies, anti-smooth muscle antibodies, and hypergammaglobulinemia.

Drug-induced liver injury:

Many medications have been linked to liver dysfunction. This can be due to either direct drug toxicity or toxicity of metabolites. Patients with pre-existing liver illness are not at an elevated risk of drug-induced hepatotoxicity in general (except methotrexate and sodium valproate). Almost all types of acute or chronic liver disease can be caused by drugs. In most situations, discontinuing the medicine will result in the resolution of liver damage.

Idiopathic/cryptogenic, around 15%.

Liver diseases signs and symptoms

Signs and symptoms can be nonspecific, such as lethargy, anorexia, or weight loss, or they can be specific to the condition that the patient has developed. Portal hypertension, hepatocellular insufficiency, and hepatocellular carcinoma are the three major consequences. Decompensated chronic liver disease might manifest as one of the complications listed below:

Portal Hypertension

Portal hypertension is caused by cirrhotic and noncirrhotic causes of resistance to portal blood flow. Portal hypertension is defined as a portal venous pressure of more than seven millimeters of mercury (mmHg); however, clinical characteristics or problems do not appear until the portal pressure exceeds 12 mmHg.

The causes of portal hypertension are classified as prehepatic (e.g., portal vein thrombosis), hepatic (e.g., cirrhosis), and posthepatic (e.g., Budd Chiari syndrome). The most prevalent causes of portal hypertension are cirrhosis and hepatic schistosomiasis, with cirrhosis being more common in industrialized nations. The following are the effects of long-term portal hypertension:

Esophageal varices: manifests as melena or upper GI hemorrhage. Cirrhosis of the liver causes an increase in portal pressure, which can result in esophageal or gastric varices. The most prevalent life-threatening consequence of chronic liver disease is esophageal variceal hemorrhage.
Caput medusa
Rectal hemorrhoids
Ascites: It is an accumulation of fluid in the peritoneal cavity because of raised portal pressure, decreased albumin, and splanchnic vasodilation (due to the release of nitric oxide). Most of the patients develop ascites in the later stages of cirrhosis. Clinical findings in such patients are abdominal distension, shifting dullness, and a fluid wave.

Hepatic Encephalopathy

Hepatic impairment causes this neuropsychiatric illness. In the liver, toxic metabolic products such as ammonia are detoxified. Cirrhosis patients have poor elimination of these chemicals from the body, resulting in an elevated level of ammonia. Ammonia levels above a certain threshold can affect consciousness. Hepatic encephalopathy can occur in almost half of decompensated chronic liver disease patients.

The patient may exhibit variable symptoms such as lethargy, apathy, disorientation to time, personality change, inappropriate behavior, somnolence to semi-stupor, or coma. Infections, GI bleeding, hyperkalemia, TIPS, sedating medications, and alkalosis can all exacerbate hepatic encephalopathy.

Jaundice

Jaundice is a yellowish discoloration of the eyes, skin, and mucous membranes caused by bilirubin overproduction or under. When total bilirubin exceeds 2 mg/dl, jaundice is clinically evident. As with chronic liver disease, the liver parenchyma is destroyed, and bilirubin does not conjugate, causing it to lodge in numerous tissues throughout the body. Because of the bile salt buildup, there is pruritus.

Spontaneous Bacterial Peritonitis (SBP)

It is one of the most severe and agonizing effects of chronic liver disease. Bacteria (E. coli, Klebsiella, Streptococcus pneumonia) infect the ascitic fluid after passing through the gastrointestinal system. Inflammation was caused by the infection spreading via the fluid to the peritoneal membrane. SBP is characterized by fever, generalized abdominal discomfort, soreness, and the absence of bowel sounds.

Hyperestrinism

The catabolism of estrogen is impeded in chronic liver illness, resulting in an accumulation of estrogen in the body. Palmar erythema, spider angiomas, gynecomastia (enlarged sensitive subareolar tissue), and testicular atrophy are all manifestations of hyperestrinism.

Hepatorenal Syndrome (HRS)

Hepatorenal syndrome is a kind of functional renal failure in which the kidneys remain normal but there is a progressive decrease in renal function. It is an exclusionary diagnosis. Chronic liver disease causes the production of vasoconstrictors, which causes the constriction of renal arteries. The following criteria have been described:

Chronic liver disease with portal hypertension or advanced liver failure
Continuous rising in creatinine, usually more than 0.3 mg/dl within 48 hours or doubling from baseline within seven days.
Oliguria with the absence or minimal proteinuria
Urine sodium less than 10 meq/L
Failure to improve with volume expansion and stopping the diuretics.
Absence of shock
No recent use of the nephrotoxic drug
Absence of renal parenchymal disease

Coagulopathy

The liver produces clotting factors, so the patients have coagulopathies and manifest or contribute to easy bruising and bleeding per gastrointestinal tracts.

Diagnosis of liver disease

The diagnosis of chronic liver disease depends upon the etiology and complications of the disease.

Viral hepatitis B and C: Serology, liver function test (AST, ALT),, and PCR with genotype

Alcoholic liver disease: Elevated levels of AST>ALT (3:1) with a history of chronic alcohol intake. An upper endoscopy can diagnose and treat esophageal varices. On endoscopy, we can measure the size of varices. Small varices are less than 5 mm, and large varices are greater than 5 mm.

Hemochromatosis: Raised serum iron, ferritin, decreased TIBC, and liver biopsy. Genetic testing can detect a mutation in the HFE gene.

Wilson disease: Raised urine copper, decreased serum ceruloplasmin, and liver biopsy. Genetic testing for the ATP7B gene.

Non-alcoholic fatty liver disease: Diagnosis of exclusion and ALT>AST. Ultrasonography of the liver is informative.

Autoimmune hepatitis: Raised autoimmune markers anti-nuclear antibodies, anti-smooth muscle antibodies, anti actin antibodies and ANCA.

Alpha 1 antitrypsin deficiency: Decreased levels of alpha-1 antitrypsin

Primary biliary cirrhosis: Markedly raised alkaline phosphatase levels with an antimitochondrial antibody

Budd-Chiari and veno-occlusive disease: CBC, clotting profile, and imaging studies like ultrasound doppler or computed tomography with contrast study can assess the presence of a clot in the hepatic vein (Budd-Chari) and portal vein in portal vein thrombosis.

Cure for liver diseases

Patients with chronic liver disease mostly present with one of the complications:

Esophageal varices: One of the most fatal consequences is varices-related bleeding, and therapy involves aggressive fluid resuscitation, vasopressors (octreotide, terlipressin), and endoscopy. In an emergency, endoscopic band ligation and injectable sclerotherapy are the most often used treatments for variceal hemorrhage.

Propranolol is used for the prevention of both primary and secondary esophageal varices. Ascites requires the use of diuretics (furosemide, spironolactone) and sodium restriction.

Hepatic encephalopathy: The main treatment principle is to address the triggering factors. Patients with hepatic encephalopathy generally improve with the removal of the precipitating factor, as well as rifaximin and lactulose.

Lactulose works by converting ammonia to ammonium ions, which reduces absorption from the gastrointestinal system. Rifaximin is a medication that is used to reduce ammonia generation by gut bacteria. In individuals with hepatorenal syndrome, a liver transplant is a curative therapy.

Hepatorenal syndrome: The primary goal is to correct the underlying cause. Treatment modalities depend on the severity and location of the patient including norepinephrine or terlipressin with albumin infusion or midodrine, octreotide with albumin infusion. TIPS procedure in some patients can help and liver transplantation is the only definite treatment in the patient who fails to respond to all other treatments.

Hepatocellular carcinoma (HCC): Treatment is based on the Barcelona clinic liver cancer staging system in the management of HCC:

Initial stage (single HCC lesion): Resection and ablation.
Intermediate stage: Transarterial chemoembolization and radio-embolization.
Metastatic disease: Sorafenib

Outlines for management of most common liver diseases:

Viral Hepatitis: direct-acting antivirals achieving HCV eradication and Interferon-alpha.

Alcoholic liver disease: Alcohol abstinence.

Non-alcoholic fatty liver disease: Treatment of metabolic syndrome components such as management of diabetes mellitus and dyslipidemia.

Autoimmune hepatitis: Corticosteroids and other immunosuppressive drugs.

Hereditary hemochromatosis: Phlebotomy and iron-chelators.

Wilson disease: Copper-chelators.

Alpha-1-antitrypsin deficiency: liver transplantation.

Drug-induced hepatitis: Identify and stop the offending drug.

Primary biliary cholangitis (PBC): Ursodeoxycholic acid (UDCA).

Primary sclerosing cholangitis (PSC): liver transplantation.

Budd-Chiari syndrome: Anticoagulation, thrombolysis or angioplasty with or without stenting, TIPS, or liver transplant.

Conclusion

Liver diseases are defined as a process of inflammation, destruction, and regeneration of liver parenchyma, which may lead to deterioration of liver functions which includes synthesis of clotting factors, other proteins, detoxification of harmful products of metabolism, and excretion of bile. The spectrum of etiologies is broad which includes toxins, alcohol abuse, infection, autoimmune diseases, genetic and metabolic disorders. Cirrhosis is a final stage of chronic liver disease that results in disruption of liver architecture. Signs and symptoms can be nonspecific, such as lethargy, anorexia, or weight loss, or they can be specific to the condition that the patient has developed such as portal hypertension, hepatocellular insufficiency, and hepatocellular carcinoma. Liver function tests, imaging techniques, and histopathological findings can be used to diagnose the majority of those with liver diseases. Treatment of the underlying cause, management of complications and symptomatic therapy are the main component in the treatment process.