Does liver disease cause itching?

Definition of pruritus

Pruritus is a medical term that means itching, it causes irritation and discomfort to the skin. Depending on the cause of your itching, your skin may not look any different than usual, or it may be inflamed, rough, or bumpy. Repeated scratching can cause raised, thickened areas of skin that can bleed or become infected.

Overview of liver disease

• The severity of liver disease can vary from mild to severe itching
• If your itching is due to liver problems, there is no rash or bug bite. The liver helps your body digest food, store energy and get rid of toxins.

There are many types of liver diseases:

• Illnesses caused by viruses, such as hepatitis A, B and C
• Illnesses caused by drugs, poisons or others who drink, examples include fatty liver disease and cirrhosis
• Liver cancer
• Inherited diseases such as hemochromatosis and Wilson's disease

Causes of pruritus in liver disease

Cholestasis

Cholestasis is a bile secretion which is disturbed. The presence of pruritus in cholestasis is linked to changes in the genes that encode transporters in liver cells and inflammatory liver diseases. More than 70% of patients are affected by primary biliary cholangitis (PBC), and up to 56% have chronic pruritus. The diagnosis of severe pruritus due to liver disease is necessary for a liver transplant, even in cases where liver failure is not present, as a result the presence of itching is a common reaction. Cholestasis of pregnancy goes away by itself after childbirth; If this does not happen, it is appropriate to exclude liver disease.

Bilirubin metabolism disruption

Normally Bilirubin is transported from the liver sinusoids to liver cells through passive diffusion and receptor-mediated endocytosis. The passive diffusion process follows a concentration gradient bidirectionally without the use of energy. Carrier proteins facilitate the uptake of unconjugated bilirubin by hepatic sinusoids, primarily in the periportal region of hepatocytes. 

Organic anions transporting polypeptides, encoded by genes SLCO1B1 and SLCO1B3, mediate the uptake of bilirubin. Conjugated bilirubin not recaptured in hepatocytes is excreted in urine while binding to glutathione S-transferases minimises the efflux of internalised bilirubin.

The inherited disorders of bilirubin metabolism are syndromes where the cause of hyperbilirubinemia is related to a genetic disorder of bilirubin transport and metabolism. 

Gilbert syndrome is the most common familial hyperbilirubinemia, while the others are rare.

Bilirubin monoglucuronide initially forms through the transfer of a glucuronic acid molecule to a carboxyl group of bilirubin through the enzyme UDP-glucuronosyltransferase, which is located in the endoplasmic reticulum. One more molecule of glucuronic acid is subsequently added to a second carboxyl group of bilirubin to form bilirubin diglucuronide. 

Disorders of impaired bilirubin conjugation fundamentally arise from the impaired activity of the UGTA1A enzyme.

Drugs such as protease inhibitors like Indinavir can also cause disorders of bilirubin metabolism by competitively inhibiting the UGT1A1 enzyme.

Neurological and systemic factors

Possible mechanisms include central/peripheral pruritus, mast cell hyperactivity leading to the development of pruritus, or intrahepatic cholestasis during pregnancy. Evidence suggests that central pruritus, which is caused by an upregulation of opioidergic tone, is a significant issue. Pruritus complicating neurological diseases, including cerebrovascular disease and multiple sclerosis, is also considered central. With regards to a centrally mediated itch, it has been suggested that conditions associated with chronic itch may also be associated with central pruritus sensitisation.

In studies of patients with pruritus secondary to atopic dermatitis, noxious stimuli such as heat and pressure, as well as electrical and chemical stimulation, were observed as pruritus, as opposed to pain in control subjects. Microneurographic recordings of a patient with chronic pruritus and nodular pruritus from chronic scratching showed active itch fibres spontaneously. In addition to central opioid-mediated pruritus in cholestasis, it is possible that chronicity of pruritus, such as in liver disease and uremia, results in central sensitisation to pruritus leading to non-pruritic stimuli resulting from continuous stimulation. Primary biliary cholangitis (PBC), affects more than 70% of patients, with up to 56% suffering from chronic pruritus which affects the small bile ducts.

Clinical manifestations of pruritus in liver disease

Common non-dermatologic causes of pruritus include renal, hepatobiliary, oncologic, neuropathic, and psychogenic causes.

Risk factors suggesting that pruritus is related to malignancy include pruritus lasting less than 12 months and more than 60 years. The most common risk factors are males, previous liver diseases and smoking.

Symptom presentation

• Inflamed skin
• Scratch marks
• Bumps, spots or blisters
• Dry, cracked skin
• Leathery or scaly patches

Physical exam findings

1. Skin changes and lesions
2. Scratching and excoriations

Treatment options for pruritus in liver disease

Management of underlying liver disease

Antihistamines and cholestyramine are usually not well tolerated and effective. The role of Sadenylosyl methionine in the treatment of Intrahepatic cholestasis of pregnancy is debatable, although it alleviates pruritus, the foetal /neonatal outcome needs to be studied. 

Women with Intrahepatic cholestasis of pregnancy are most successfully treated with ursodeoxycholic acid, which provides subjective improvement, or even complete resolution of pruritus, and does not show any adverse side effects in mothers or babies.

Cholestyramine, rifampicin, bezafibrate, naltrexone, and sertraline, pruritus is often adequately manageable. KOR agonists and IBAT inhibitors are currently the most promising anti-pruritic drugs for cholestatic pruritus in development.

Symptomatic relief

1. Topical treatments
2. Antihistamines and other systemic medications
3. Non-pharmacological interventions (e.g., cool baths)

Summary

Liver diseases are associated with itching, which was first linked to jaundice in the 2nd century BC.

• Inherited liver diseases, such as hemochromatosis and Wilson's disease, can lead to liver cancer.
• Severe itching due to liver disease is crucial for diagnosing the need for liver transplantation, even without liver failure
• Studies suggest that stimuli like heat, pressure, and chemicals can trigger itching in patients with liver diseases
• Chronic itching may lead to central sensitisation, causing continuous itching even in response to non-pruritic stimuli
• Non-dermatological causes of itching in liver disease include renal, hepatobiliary, oncological, neuropathic, and psychogenic factors
• Risk factors for itching linked to malignancy include duration and age