Jennifer A. Scott and Peter C. Hayes

Royal Infirmary of Edinburgh, Edinburgh, UK


Abnormal LFTs could be identified in dermatology as part of new patient assessment either in an acute setting or outpatient appointment, or during routine monitoring of drug therapies. Further investigation and management of abnormal LFTs are summarized in Figure 13.1.

Dermatological Drugs and Liver Function Tests

Transient changes in LFTs are frequently observed after commencing new drug therapies and are often improved when the medication is stopped. Some drugs, including methotrexate, can cause liver fibrosis. These drugs require regular monitoring of LFTs while on treatment. Table 13.1 summarizes the impact that common dermatological therapies may have on LFTs, discussed in more detail below.

Schematic illustration of flowchart to investigate abnormal liver function tests (LFTs) in dermatology setting.

Figure 13.1 Flowchart to investigate abnormal liver function tests (LFTs) in dermatology setting. Ab, antibodies; ALP (IU/l), alkaline phosphatase; ALT (IU/l), alanine amino transferase; AMA, anti‐mitochondrial antibody; AST (IU/l), aspartate amino transferase; FBC, full blood count; FIB‐4, Fibrosis‐4 Index for Liver Fibrosis; GGT, gamma‐glutamyl transferase; HbA1c, hemoglobin A1c; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; INR, international normalized ratio; NAFLD, non‐alcoholic fatty liver disease; SMA, smooth muscle antibody; tTG, tissue transglutaminase; U+Es, urea and electrolytes;

* Fibrosis scores:

  • ALT/AST ratio > 1 (in the absence of alcohol‐related liver disease),
  • FIB‐4

    • excluding advanced fibrosis was < 1.3 for patients ≤ 65 years and < 2.0 for age > 65 years
    • to predict advanced fibrosis was > 3.25 for both age groups

  • NAFLD fibrosis score:

    • < −1.455: predictor of absence of significant fibrosis (F0–F2 fibrosis)
    • ≥ −1.455 to ≤ 0.675: indeterminate score
    • > 0.675: predictor of presence of significant fibrosis (F3–F4 fibrosis)


Methotrexate is used in the treatment of severe psoriasis [13]. It is an antifolate and anti‐metabolite drug that blocks dihydrofolic acid reductase, inhibiting purine and pyrimidines synthesis, and depleting intracellular stores of folate reducing synthesis of DNA and RNA causing cellular arrest. Moreover, there are increased levels of intracellular adenosine secondary to 5‐aminoimidazole‐4‐carboxamide ribonucleotide formyltransferase inhibition. Adenosine stimulates hepatic stellate cells (liver‐specific mesenchymal cells) to release pathological collagen fibers promoting liver fibrosis. Methotrexate has also been shown to promote proliferation of hepatic stellate cells.

Table 13.1 Drugs used in dermatology and patterns of LFTs.

Pattern Drug
Cholestatic (↑ ALP/GGT) Co‐amoxiclav


Estrogen (oral contraceptives)









Cholestatic pattern (↑ALP/GGT) Cytotoxic pattern (↑ ALT)






ALP, alkaline phosphatase; ALT, alanine amino transferase; GGT, gamma‐glutamyl transferase.

The resultant liver damage can range from mild hepatitis to, very rarely, fulminant hepatic failure. Elevation in serum aminotransferase is common. High‐dose methotrexate can increase alanine amino transferase (ALT) to 10–20 times the upper limit of normal (ULN). These levels often improve within 12–48 hours of treatment. Moderate methotrexate doses can cause elevation in serum aminotransferase in 15–50% of the population, but this is often mild and self‐limiting. The fluctuation seen in LFTs could also be dependent on timings of blood tests taken before or after the dose of methotrexate. Studies have demonstrated that concurrent folic acid replacement reduces the rate of ALT elevation in patients on low‐dose methotrexate. Acute jaundice or liver failure secondary to drug induce liver injury with methotrexate is very rare. With high rates of coexistent fatty liver, low level changes in serum liver tests are very commonly encountered coincidentally.

Hepatitis B can be reactivated by low‐dose methotrexate, even in those with normal ALT, no detectable hepatitis B virus (HBV) DNA and no hepatitis B e antigen. This acute reactivation can result in hepatic failure, liver transplantation, and death. It is therefore important to complete a viral hepatology screen prior to methotrexate therapy. Patients with detectable HBsAg should be reviewed by a gastroenterologist/hepatologist, and are usually treated with antivirals when immunosuppressed. Patients with prior exposure to hepatitis B (cAb positive, sAg negative) are usually monitored every three months.

Liver fibrosis is the result of deposition of pathologic collagen‐rich extracellular matrix, in response to continuing chronic liver injury. End‐stage liver disease or cirrhosis causes portal hypertension, resulting in varices, ascites, and encephalopathy, for which the only curative therapy is liver transplantation. The risk of methotrexate‐induced liver fibrosis is heightened by the presence of obesity, diabetes, increased age, and intake of more than 10 units of alcohol per week. With such a high prevalence of fatty liver, methotrexate is not usually the culprit.

Around 30% of patients treated with methotrexate will develop mild to moderate histological changes, including fatty deposition and mild inflammation. Up to 15% of patients treated with methotrexate will develop mild fibrosis and 1% will have moderate fibrosis or cirrhosis often within 2–10 years of commencing therapy. Some patients will develop portal hypertension without significant fibrosis, suggesting that methotrexate could result in nodular regeneration of the liver. Hepatocellular carcinoma in patients treated with methotrexate is rare and the evidence is limited to case reports.

Liver biopsy has been considered the gold standard to diagnose liver fibrosis. Previously, patients would undergo biopsy after 1, 4, and 8 g of cumulative methotrexate. However, diagnostic accuracy is impeded by sampling error and inter‐pathologist variation in interpretation. Moreover, liver biopsy is invasive and associated with morbidity including pain, bleeding, infection, and damage to nearby organs.

In modern hepatic clinical practice fibrosis scores and measurement of transient elastography (TE) using a FibroScan® (Echosens) have become well established for diagnosing liver fibrosis without biopsy. Box 13.1 shows our recommendations for their use in patients on methotrexate.


Retinoids are used in the management of acne, psoriasis, and Darier’s disease. A rise in serum aminotransferases is seen in around 20% of patients but its significance is uncertain. Retinoids can cause acute hepatitis but rarely cause chronic liver disease. Monitoring for retinoids [5] consists of monitoring LFTs at the start of therapy. If they are persistently abnormal, reduce and potentially stop treatment.


Azathioprine is used to treat various dermatological conditions including pemphigus, pemphigoid, eczema, systemic lupus erythematosus, and dermatomyositis. Elevation of liver enzymes and cholestasis are not uncommon, but are usually reversible on withdrawal of azathioprine. A hypersensitivity reaction to azathioprine is rare, but can result in cholestatic jaundice, portal fibrosis, nodular regenerative hyperplasia, hepatocellular necrosis, fever, and shock. LFTs should be monitored every three months.

Dec 15, 2022 | Posted by in GASTROENTEROLOGY | Comments Off on Dermatology
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