case study of liver function

Case Report: Using basic liver function tests as a guide to suspected Wilson’s disease

Sudeep Adhikari Roles: Conceptualization, Writing – Review & Editing Prashant Kumar Shah Roles: Conceptualization, Writing – Original Draft Preparation Yuba Raj Sharma Roles: Supervision, Writing – Review & Editing

Wilson's disease, liver disease, basic liver function tests, Nepal

Revised Amendments from Version 1

This revised version contains the minor changes as had been suggested by the reviewers, including addition of reticulocyte and indirect bilirubin parameters in Table 1.

See the authors' detailed response to the review by Raffaele Iorio See the authors' detailed response to the review by Jason L. Burkhead

Introduction

Wilson’s disease is an autosomal recessive disorder of copper metabolism that leads to liver disease and neuropsychiatric manifestations. The majority of patients are diagnosed between the ages of five and 35 years. This disease is usually suspected in patients with liver disease of uncertain etiology, especially if accompanied by neuropsychiatric symptoms. But it can also present with liver abnormalities alone. Untreated, this disease is universally fatal, with patients dying from cirrhosis or progressive neurologic disease. 1 Hence its timely recognition is important. It is not usually diagnosed in resource-limited countries as diagnostic tests are not easily available. Here we present a case of Wilson’s disease from Nepal. The patient presented with liver disease (without neuropsychiatric features), and we discuss how basic liver function test parameters can be used as a guide to suspected Wilson’s disease.

A 36-year-old woman from Lalitpur, Nepal presented to the emergency department of Patan Hospital in December 2018, with complaints of abdominal distension and yellowish discoloration of the skin for two months and shortness of breath for the last 10 days. She had no history of fever, cough, abdominal pain, nausea, vomiting, black stools, altered sensorium or abnormal body movement. She had a history of consuming home-made alcohol, almost daily for 12 years, although quantification of the intake could not be done.

On examination she appeared icteric and pale. Blood pressure was 90/60 mm Hg, pulse 78 beats per minute, respiratory rate 20 breaths per minute, temperature 98.7 Fahrenheit and oxygen saturation of 97% at room temperature. Abdomen was distended and non-tender, liver and spleen were not palpable and shifting dullness was present. Chest examination showed decreased air entry. Bilateral pitting pedal edema was noted. Neurological examinations did not reveal any abnormality. She was looked after at another health care center three weeks prior to her admission as a case of alcoholic liver disease. She stopped drinking alcohol, but without improvement in her symptoms. Her investigations are as shown in Table 1 .

Table 1. Laboratory parameters of the patient before and after treatment for Wilson’s disease.

Ultrasound of the abdomen showed hepatosplenomegaly and gross ascites. Ascitic fluid tap was done and sent for analysis, which showed WCC 100 cells/μL (neutrophils 60% and lymphocytes 40%), protein 1 gm/dl and albumin 0.5 gm/dl. Upper gastrointestinal endoscopy showed small sized esophageal varices and mild portal hypertensive gastropathy. Hepatitis B surface antigen (HBsAg) and hepatitis C antibody were nonreactive. Direct Coombs test was negative. Patient was started on furosemide 20 mg once daily, spironolactone 50 mg once daily and thiamine 100 mg once daily.

Slit lamp examination of her eyes showed the presence of Kayser–Fleischer (KF) rings. Twenty-four-hour urinary copper was 85.70 (normal < 60) μg and serum ceruloplasmin level was 23 (normal 20–60) mg/dl. The diagnosis of subacute liver failure with Wilson’s disease was made. We started oral zinc acetate (50 mg elemental zinc thrice daily) along with the above drugs and she was discharged in one week of admission. There was clinical and biochemical improvement as seen during one-month (January 2019) and 11 months (November 2019) follow-up visits ( Table 1 ).

This female patient who presented with features of chronic liver disease had a history of alcohol intake for almost 12 years. Nepal is a low-income country in South Asia, and a full chronic liver disease screening (including tests for Wilson’s disease, autoimmune hepatitis, hemochromatosis) is usually not possible in the Nepali health setup. The limited screen includes alcohol history, history of any drug or toxin use and serologies for hepatitis B and C. 2 However, the people mostly consume home-made alcohol in Nepal, and the exact quantification is usually not possible to estimate whether the amount of intake is significant enough to cause liver disease or not. 3 We usually ascribe liver disease in any patient to the alcohol, no matter the amount of intake by the patient, especially if serologies are nonreactive and there is no drug or toxin exposure. In our patient with a history of alcohol use, we extended the tests beyond the conventional limited screen, which led to a diagnosis of Wilson’s disease.

Basic liver function tests (LFT) including bilirubin, transaminases level and alkaline phosphatase (ALP) are available in most of the health centers in Nepal. In any patient with liver disease who presents with acute liver failure, the combined ratio of ALP/total bilirubin (<4) and aspartate transaminase (AST)/alanine transaminase (ALT) (>2.2) provides sensitivity and specificity of 100% for diagnosing Wilson’s disease. 4 In our patient, ALP/total bilirubin was 3.09 and AST/ALT was 3.4 during the admission ( Table 2 ). Although she did not have acute liver failure during the presentation, we used this pattern of LFT (the ‘Wilson’s pattern’) as a guide to suspect the possibility of Wilson’s disease and ordered slit lamp examination of eyes for KF rings, serum ceruloplasmin level and 24-hour urinary copper tests.

Table 2. Wilson’s pattern of liver function tests of the patient before and after treatment.

(alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT)).

The diagnosis was made using the Leipzig scoring system for Wilson’s disease. 5 Total points obtained were four (two for KF ring, one for Coombs negative hemolytic anemia (anemia with increased reticulocyte percentage and increased indirect fraction of bilirubin), one for high 24-hour urinary copper), which established the diagnosis of Wilson’s disease. However, she had no neurologic symptoms and her serum ceruloplasmin level was normal. Liver copper and mutation analysis were not performed.

The preferred treatment choice for patients with Wilson’s disease with cirrhosis is copper chelator like D-penicillamine or trientene initially, followed by oral zinc therapy in maintenance. However, the treatment with zinc acetate was started in this case because of unavailability of chelating agents. On follow up in one month, she had no abdominal distension and jaundice. LFTs were improved, which continued to improve till 11 months follow up ( Table 1 ). Even the ‘Wilson’s pattern’ of LFTs was resolved with treatment ( Table 2 ).

LFTs are simple and readily available tests even in remote parts of Nepal, done in all patients with liver disease. As screening for rare diseases is not always possible in low-income countries, this case demonstrates the usefulness of the ‘Wilson’s pattern’ LFT as a guide for suspecting Wilson’s disease in patients with liver disease. However, the sensitivity and specificity of this pattern is yet to be studied in patients with subacute liver disease.

Data availability

All data underlying the results are available as part of the article and no additional source data are required.

Written informed consent for publication of the clinical details and/or clinical images was obtained from the patient.

• 1.   Patil M, Sheth KA, Krishnamurthy AC, et al. : A review and current perspective on Wilson disease. J Clin Exp Hepatol. 2013 Dec 1; 3 (4): 321–36. PubMed Abstract | Publisher Full Text | Free Full Text
• 2.   Gautam S, Sigdel KR, Adhikari S, et al. : Case Report: Pulmonary tuberculosis and raised transaminases without pre-existing liver disease-Do we need to modify the antitubercular therapy? Wellcome Open Res. 2020; 5 . PubMed Abstract | Publisher Full Text | Free Full Text
• 3.   Pradhan B, Hadengue A, Chappuis F, et al. : Alcoholic liver disease in Nepal: identifying homemade alcohol as a culprit. Clin Exp Gastroenterol. 2015; 8 : 183. PubMed Abstract | Publisher Full Text | Free Full Text
• 4.   Korman JD, Volenberg I, Balko J, et al. : Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008 Oct; 48 (4): 1167–74. PubMed Abstract | Publisher Full Text | Free Full Text
• 5.   European Association For The Study Of The Liver: EASL clinical practice guidelines: Wilson’s disease. J Hepatol. 2012 Mar 1; 56 (3): 671–85. PubMed Abstract | Publisher Full Text

Comments on this article Comments (0)

Open Peer Review

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Liver disease, Wilson' disease, pediatric liver disease

• Respond or Comment
• COMMENT ON THIS REPORT

Is the background of the case’s history and progression described in sufficient detail?

Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?

Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?

Is the case presented with sufficient detail to be useful for other practitioners?

Reviewer Expertise: Expertise in basic biology of Wilson Disease and working knowledge of diagnostic procedures.

• Author Response 03 Mar 2022 Sudeep Adhikari , Department of Internal Medicine, Pyuthan Hospital, Pyuthan, 22300, Nepal 03 Mar 2022 Author Response Thank you for the review, and the constructive feedback. Competing Interests: none Thank you for the review, and the constructive feedback. Thank you for the review, and the constructive feedback. Competing Interests: none Close Report a concern
• Author Response 03 Mar 2022 Sudeep Adhikari , Department of Internal Medicine, Pyuthan Hospital, Pyuthan, 22300, Nepal 03 Mar 2022 Author Response Thank you for the constructive feedback. Changes have been made in the revised version regarding the issues raised. Regarding Coombs negative hemolytic anemia, details regarding indirect bilirubin and ... Continue reading Thank you for the constructive feedback. Changes have been made in the revised version regarding the issues raised. Regarding Coombs negative hemolytic anemia, details regarding indirect bilirubin and reticulocyte count have been added, however haptoglobin level was not tested. Regarding choice of therapy with zinc acetate instead of d-penicillamine, the fact that the d-penicillamine was not available for use has been acknowledged in the revised manuscript. Thank you for the constructive feedback. Changes have been made in the revised version regarding the issues raised. Regarding Coombs negative hemolytic anemia, details regarding indirect bilirubin and reticulocyte count have been added, however haptoglobin level was not tested. Regarding choice of therapy with zinc acetate instead of d-penicillamine, the fact that the d-penicillamine was not available for use has been acknowledged in the revised manuscript. Competing Interests: none Close Report a concern

Reviewer Status

Alongside their report, reviewers assign a status to the article:

Reviewer Reports

• Raffaele Iorio , University of Naples Federico II, Naples, Italy
• Jason L. Burkhead , University of Alaska Anchorage, Anchorage, USA

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Case Report: Using basic liver function tests as a guide to suspected Wilson’s disease

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Interpretation of Liver Function Tests (LFTs)

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Introduction

Liver function tests (LFTs) are among the most commonly ordered blood tests and include:

• Alanine transaminase (ALT)
• Aspartate aminotransferase (AST)
• Alkaline phosphatase (ALP)
• Gamma-glutamyltransferase  (GGT)

This guide gives an overview of LFTs   and a structured approach to their interpretation.

Why check LFTs?

LFTs can be requested for multiple reasons: 1

• To investigate patients with suspected liver disease
• To monitor patients with confirmed liver disease (e.g. cirrhosis)
• To monitor the effects of potentially hepatotoxic medications

LFTs are often sent as part of a ‘ baseline ’ screening panel of investigations for patients presenting with a wide range of symptoms, even where none of the above criteria is met. 

Reference ranges

Table 1 . Liver function test reference ranges

These reference ranges can vary between laboratories, so always check local guidelines. 

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are enzymes found within liver cells at high concentrations.

Raised ALT / AST levels in the blood occur in pathologies that cause liver cell (hepatocyte) inflammation or damage. Therefore, raised ALT / AST levels are a marker of hepatocellular injury .

Common causes of hepatocellular injury include:

• Hepatitis (viral, alcoholic, ischaemic)
• Liver cirrhosis
• Drug / toxin-induced liver injury (e.g. paracetamol overdose)
• Malignancy (hepatocellular carcinoma)

Hint : The AST:ALT ratio can help determine the aetiology of hepatocellular injury, with a >2:1 ratio classical of alcoholic liver disease. 2

Serum alkaline phosphatase (ALP) is derived from biliary epithelial cells (cells lining the biliary tract) and bones . 3 Raised ALP levels can therefore be caused by cholestasis or bone disease .

• Cholestasis

Cholestasis describes an interruption in the bile flow from hepatocytes to the small intestine. Common causes include gallstone disease , external compression of the biliary tract (e.g. pancreatic malignancy ) or medication side effects. Bilirubin may or may not be raised depending on the severity of cholestasis.

Gamma-glutamyltransferase (GGT) is found in hepatocytes and also biliary epithelial cells. 2 It is a non-specific but highly sensitive marker of liver damage and cholestasis.

ALP and GGT are interpreted together to localise the source of raised ALP in the blood:

• An ALP rise with normal GGT suggests bone disease (e.g. Paget’s disease, vitamin D deficiency, bony metastases)
• An ALP rise with associated GGT rise is more suggestive of cholestasis

Hint : An isolated GGT rise is classically associated with alcohol excess .

Bilirubin is a waste product of haemoglobin breakdown . It is predominantly metabolised and excreted by the liver . Raised levels of bilirubin in the blood will lead to a yellowing of the skin, known as jaundice .

Hint : Jaundice is usually absent until the bilirubin level exceeds 50 micromol/L .

Bilirubin metabolism

To understand the significance of raised bilirubin levels, it is essential to consider the bilirubin metabolism/excretion pathway:4

• When red blood cells are broken down, unconjugated (insoluble) bilirubin is created as a waste product and binds to albumin in the bloodstream
• Hepatocytes take up unconjugated bilirubin and metabolise it to form conjugated (soluble) bilirubin
• Hepatocytes excrete conjugated bilirubin into the biliary tract, where it flows into the bowel lumen as bile
• Gut bacteria further metabolise bilirubin in bile to form urobilinogen , which is eventually excreted in the stools as stercobilinogen
• A small amount of urobilinogen is reabsorbed from the intestine into the portal venous system, and as urobilinogen is water-soluble, the kidney is able to excrete some of this into the urine.

Stercobilinogen gives stools their dark colour . Urobilinogen is colourless in the urine. However, if the urine is left exposed to the air, oxidation will occur, creating a dark colour. Under normal physiological conditions, urobilinogen will be present in the urine, however conjugated bilirubin will not be present.

Raised levels of bilirubin in the blood can be caused by:

• Excess bilirubin production ( pre-hepatic jaundice )
• A breakdown in bilirubin metabolism ( hepatocellular jaundice )
• A blockage in the bile excretion pathway ( cholestatic jaundice )

Pre-hepatic jaundice

Pre-hepatic jaundice occurs when increased red blood cell breakdown produces excess bilirubin . This can overwhelm metabolism/excretion pathways, leading to jaundice .

The most common cause of increased red blood cell breakdown is haemolysis . Bilirubin is unconjugated in the blood, as the hepatocytes have not yet metabolised it. The remainder of LFTs are generally normal , as the liver is otherwise working well.

Hint : In pre-hepatic jaundice, patients are often anaemic due to excess red blood cell breakdown. The diagnosis may be Gilbert’s syndrome if no anaemia is present.

Gilbert’s syndrome

Gilbert’s syndrome is a congenital disorder present in up to 5% of the population. It results from a deficiency of glucosyltransferase , the enzyme responsible for the conjugation of bilirubin within hepatocytes.

Gilbert’s syndrome classically presents following viral infection with raised bilirubin but normal LFTs/ full blood count. The disease is benign and requires no specific management.

Hepatocellular jaundice

Hepatocellular jaundice occurs when hepatocytes are damaged and dysfunctional, leading to an inability to metabolise unconjugated bilirubin from the bloodstream. This leads to high levels of unconjugated bilirubin in the blood. There will generally also be very high ALT / AST levels , marking hepatocyte damage.

Hint : Common causes of hepatocellular injury are covered above (hepatitis, cirrhosis, malignancy, drug or toxin insult). When liver injury is severe, there are not enough functioning hepatocytes to metabolise bilirubin, and jaundice will develop.

Cholestatic (obstructive) jaundice

Cholestasis is an interruption in bile flow from hepatocytes to the gut. When this interruption is severe, bilirubin levels will build up in the blood. The bilirubin has been metabolised in the liver, and thus the bilirubin in the blood is predominantly conjugated bilirubin. There will generally also be high ALP levels with associated high GGT , marking dysfunction of the biliary system.

Obstructive jaundice will classically lead to dark urine and pale stools . Bilirubin cannot enter the gastrointestinal tract due to cholestasis, leading to low stercobilinogen excretion in stools .

The bilirubin in the blood is conjugated and can be filtered by the kidneys. The presence of conjugated bilirubin gives the urine a very dark colour .

Hint : Stools may also be pale in hepatocellular jaundice, as there is decreased bilirubin metabolism/excretion, however as the bilirubin in the blood is unconjugated, it will not be able to pass into the urine. Therefore, the urine should remain a normal colour.

Causes of cholestasis

Cholestasis can occur due to either intrahepatic or extrahepatic biliary obstruction.

Causes of intrahepatic obstruction (obstruction of the hepatic bile canaliculi):

• Drugs (e.g. antibiotics, oral contraceptive pills, anabolic steroids)

Causes of extrahepatic obstruction (obstruction of hepatic ducts, or distal biliary tree):

• Primary sclerosing cholangitis
• Intraluminal malignancy: cholangiocarcinoma
• Extraluminal malignancy causing duct compression: head of pancreas tumours

Split bilirubin

The split of conjugated/unconjugated bilirubin in the blood can be requested to give further clues as to the aetiology of jaundice.

Causes of predominantly unconjugated hyperbilirubinaemia :

• Pre-hepatic jaundice (e.g. haemolysis)
• Gilbert syndrome

Causes of predominantly conjugated hyperbilirubinaemia :

• Hepatocellular jaundice*

*Hepatocellular jaundice can initially cause a mixed conjugated/unconjugated jaundice, but at its most severe, unconjugated hyperbilirubinaemia is seen.

Albumin is synthesised in the liver and helps to bind water, cations, fatty acids and bilirubin. It also plays a crucial role in maintaining the oncotic pressure of blood. Albumin is used as a non-specific marker of the  synthetic function of the liver.

Albumin levels can fall due to:

• Decreased albumin production: malnutrition , severe liver disease
• Increased albumin loss: protein-losing enteropathies, nephrotic syndrome

Hint : A decrease in the synthetic function of the liver indicates severe liver disease.

Albumin has a half-life of 20 days , so it will take time to decrease, even in severe liver disease. Further assessment of the synthetic function of the liver can be gained by ordering a coagulation screen , as the liver is also responsible for the synthesis of clotting factors .

Severe liver disease leads to decreased production of clotting factors and an increased prothrombin time (PT) / INR in the absence of other causes of coagulopathy.

The liver is also responsible for gluconeogenesis , and serum blood glucose assessment can also indirectly assess the liver’s synthetic function. However, gluconeogenesis tends to be one of the last functions to become impaired in liver failure.

LFT interpretation method

Determine the pattern of lft derangement.

The pattern of ALT to ALP rise can indicate whether the pathology is primarily cholestatic or hepatocellular:

• A greater than 10-fold increase in ALT and a less than 3-fold increase in ALP suggests a predominantly hepatocellular injury
• A less than 10-fold increase in ALT and a more than 3-fold increase in ALP suggests cholestasis
• It is possible to have a mixed picture involving both hepatocellular injury and cholestasis

An isolated ALP rise without a GGT rise should raise your suspicion of bony pathology .

Assess the bilirubin

Bilirubin is a marker of severity in acute cholestatic pathology and acute hepatocellular liver injuries. The presence of clinical jaundice is generally an indication of severe disease requiring urgent referral to secondary care for prompt assessment and management.

An isolated bilirubin rise without further LFT derangement suggests pre-hepatic jaundice or Gilbert’s disease.

Assess synthetic function

In severe hepatocellular injuries, the synthetic functions of the liver also become impaired , leading to decreased albumin .

Coagulation studies may show prolonged prothrombin time, and in very severe disease, serum blood glucose may be low due to impaired gluconeogenesis.

Hint : In chronic hepatocellular pathology (e.g. cirrhosis), the ALT / AST may return to within the normal range, however synthetic function of the liver can be markedly impaired.

Summary table

The table below compares the typical LFT patterns associated with acute hepatocellular damage and cholestasis . A single arrow (↑) refers to a mild impairment, and a double arrow (↑↑) refers to severe impairment.

Further investigations

Once the pattern of LFT derangement has been established, it is essential to determine the underlying cause .

If cholestasis is suspected, an ultrasound should be arranged to assess the biliary tree for a potential site/cause of biliary obstruction .

If hepatocellular injury is suspected, a liver ultrasound is generally arranged to assess for any structural lesions that may give clues as to the diagnosis. If the cause is unclear, a ‘ liver screen’ may be ordered to investigate further.

Liver screen

A ‘liver screen’ is a batch of blood investigations to identify a wide range of potential causes of liver disease:

• Hepatitis serology (A/B/C)
• Epstein-Barr Virus (EBV)
• Cytomegalovirus (CMV)
• Anti-mitochondrial antibody (AMA)
• Anti-smooth muscle antibody (ASMA)
• Anti-liver/kidney microsomal antibodies (Anti-LKM)
• Anti-nuclear antibody (ANA)
• Immunoglobulins  –  IgM/IgG
• Alpha-1 Antitrypsin (to rule out alpha-1 antitrypsin deficiency)
• Serum Copper (to rule out Wilson’s disease)
• Ceruloplasmin (to rule out Wilson’s disease)
• Ferritin (to rule out haemochromatosis)

Dr Chris Jefferies

• Coates P. Liver Function Tests. Australian Family Physician. March 2011. Available at [ LINK ].
• UpToDate. Approach to the patient with abnormal liver biochemical and function tests. May 2023. Available at [ LINK ].
• Patient.info Professional. Abnormal Liver Function Tests. July 2019. Available at [ LINK ].
• UpToDate. Bilirubin metabolism. October 2022. Available at [ LINK ].

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Case Study: A Patient With Elevated Liver Enzymes

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I recently saw a 47 year old woman named Martha who was found to have abnormal liver function (elevated liver enzymes) on a blood test. Her ultrasound scan revealed a fatty liver. Increasing nausea, bloating and abdominal discomfort prompted her doctor to conduct these tests.

Past history

Onset of severe inflammatory and infective lung disease (affecting the small bronchial tubes in the lungs) beginning 18 months ago. Type 2 diabetes, high blood pressure, high cholesterol and triglycerides, osteoporosis and the autoimmune skin disease psoriasis.

Martha’s own doctor had prescribed the following medication:

• Multiple courses of antibiotics to treat infection in her lungs
• Prednisone, which is a steroid to lower inflammation in the lungs
• Glicazide to lower blood sugar
• Risedronate and vitamin D to increase bone density
• Irbesartan/hydrochlorothiazide to lower blood pressure
• Pravastatin to lower cholesterol
• Esomeprazole to reduce stomach acid and relieve reflux

So at any one time this patient’s liver had to metabolize and deal with the waste products of seven different drugs. That’s hard work even for a healthy non-fatty liver!

Since starting these drugs, Martha has experienced rapid weight gain from 154 pounds to 191 pounds and yet her diet had not changed. This is incredibly common in patients of mine who begin taking several medications. Martha also experienced increasing fatigue and her blood sugar had risen so that she now required insulin. Because she is so tired, she no longer feels inclined to exercise. Just getting through each day is hard enough.

My recommendations for my patient

• The thiazide diuretic (hydrochlorothiazide) that she was given to treat her blood pressure is known to worsen diabetes and can promote magnesium deficiency. Therefore a magnesium supplement is necessary.
• For the osteoporosis I recommended a high strength vitamin D supplement, a good mineral supplement and an exercise program.
• Cholesterol and triglycerides can usually be reduced with a lower carbohydrate diet. The diet is in my book called I Can’t Lose Weight and I Don’t Know Why .
• Acid reflux is almost always caused by food intolerance and small intestinal bacterial overgrowth, which causes fermentation in the gut and  hydrogen and methane production. I asked Martha to remove gluten, dairy products and sugar from her diet. I put her on my 15 Day Cleanse , which is a comprehensive program that improves liver, gut and immune function. In 15 days, the supplements and eating plan help to increase energy, reduce bloating and all patients are able to lose some weight. After the 15 days I asked Martha to continue with the liver and gut maintenace program, to continue her progress.
• To reduce her elevated blood sugar and blood fats, I gave my patient Berberine capsules .

I also referred Martha for physiotherapy on her lungs and taught her deep breathing and coughing exercises.

In my practice I work with naturopaths and nutritionists who are passionate and highly skilled and enable me to treat my patients holistically. This provides the ideal model for primary care medicine and is a paradigm that I believe modern medicine needs to embrace.

The above statements have not been evaluated by the FDA and are not intended to diagnose, treat or cure any disease.

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• Adaptive clinical trial
• Risk factors

Instructions for Salvia miltiorrhiza polyphenol injections indicate abnormal liver function as an occasional adverse reaction, but the incidence of this adverse drug reaction (ADR) has increased in recent years. We assessed S . miltiorrhiza polyphenol ADRs by performing a nested case-control study(NCCS) and meta-analysis. In the NCCS, 2633 patients receiving this treatment in the First Affiliated Hospital of Bengbu Medical College were enrolled. Logistic regression models found that in 58 (2.2%) patients experiencing abnormal liver function, the risk for liver dysfunction was associated with sulfa drug allergy (OR = 7.874, 95%CI (1.280, 48.447), P = 0.026), payment methods (OR = 0.106, 95%CI (0.012, 0.934), P = 0.043), duration of administration (OR = 0.922, 95%CI (0.862, 0.986), P = 0.017), cefathiamidine (OR = 0.441, 95%CI (0.216, 0.900), P = 0.025), human serum albumin (OR = 1.958, 95%CI (1.011, 3.789), P = 0.046), Dazhu Rhodiola injection (OR = 2.599, 95%CI (1.112, 6.070), P = 0.027), or reduced glutathione (OR = 0.394, 95%CI (0.188, 0.826), P = 0.014). Meta-analysis of reports on S . miltiorrhiza polyphenol ADRs in controlled trials and other observational studies included 676 patients, of which 17 (2.17%; 95%CI (0.0105, 0.0358)) presented with liver dysfunction; associated ADR risk factors included co-administration of other drugs. Our NCCS and meta-analysis had similar ADR incidence rates, which were higher than the rate in the drug instructions. This study provides guidance for assessing liver dysfunction risks associated with S . miltiorrhiza polyphenol injections.

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Introduction.

An injectable formulation of Salvia miltiorrhiza polyphenols prepared as a multi-effect antioxidant freeze-dried powder was jointly developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Shanghai Green Valley (Group) Co., Ltd. Its main active component is magnesium lithospermate B (Fig.  1 ), a salvianolic acid B salt extracted from the traditional Chinese medicinal herb Danshen (S . miltiorrhiza) . The injectable formulation, which exerts anti-arrhythmic and antioxidant effects and protects the endothelium, is used to treat coronary heart disease, angina pectoris, and ischemic stroke 1 , 2 , 3 , 4 , 5 , 6 , 7 .

Chemical structure of Salvia miltiorrhiza magnesium lithospermate B.

The abnormal liver function indicated in the Salvia miltiorrhiza polyphenols injection instructions is an occasional adverse reaction. It is clinically manifested mainly as elevated glutamine-pyruvate transaminase activity, which can be improved after drug withdrawal. This is based on early research conducted under normal and reasonable use. The probability of occurrence of occasional adverse reactions ranges from 0.1% to 1% according to the Council for International Organizations of Medical Sciences (CIOMS) 8 . However, with the increasing use of S . miltiorrhiza polyphenol injections, especially when used in combination with other drugs, the clinical manifestation and severity of liver dysfunction have far exceeded the ones known during their launch 9 . Case reports, randomized placebo-controlled clinical studies, and literature analyses describe abnormal glutamic-pyruvic transaminase, alanine aminotransferase, and total bilirubin adverse reactions detected by liver function monitoring during treatment 10 , 11 , 12 , 13 , 14 , 15 . However, the incidence, outcome, and severity of the adverse reactions were not systematically analysed.

Therefore, we conducted both a NCCS and an meta-analysis to investigate the influencing factors and incidence of adverse reactions to S . miltiorrhiza polyphenol injection. We aimed to develop an approach for reducing adverse reactions to S . miltiorrhiza polyphenols, methods for its safety risk assessment, and directions for future research.

Study design

This NCCS protocol was approved by the First Affiliated Hospital of Bengbu Medical College and the Research Institute of the State Administration of Traditional Chinese Medicine. This study was carried out in accordance with an invention patent for a method and system of re-evaluating drugs after market launch. The research protocol had been used for the safety re-evaluation of other drugs and had previously been published elsewhere. In addition, CHPS software had obtained the copyright from the National Copyright Administration of the People’s Republic of China.

Nested case-control study(NCCS) design

We performed a prospective, large-sample nested case-control study (NCCS) based on liver function monitoring of S . miltiorrhiza polyphenol injection. From June 1st, 2017 to December 31st, 2018, patients receiving S . miltiorrhiza polyphenol injection in the First Affiliated Hospital of Bengbu Medical College were automatically included the study via the hospital pharmacovigilance system (HPS). We set the alert threshold for liver function abnormality in the HPS. If the value of a patient’s liver function triggers an alert signal, the patient’s liver function abnormality is automatically assigned into the case group. We used the patient’s age and gender as the matching conditions, and the control group was determined according to the principle of NCCS design in the remaining untriggered patient population. The design of the NCCS is shown in Fig.  2 .

Flowchart of inpatient selection and processing.

Alert thresholds for abnormal liver function

The HPS, which collects real-world clinical data, is an information system established to support sentinel surveillance, record and evaluate ADRs, conduct drug monitoring and re-evaluation, and obtain drug warning information 16 , 17 , 18 . The following ADR alert thresholds for abnormal liver function during S . miltiorrhiza polyphenol treatment or within 24 h of its withdrawal were used as settings in the HPS: glutamic-pyruvic transaminase or glutamic oxaloacetic transaminase values above 40 U/L or alkaline phosphatase values exceeding the normal range of 40–110 U/L; the total bilirubin exceeding the normal range of 1.71–17.1 μmol/L, the indirect bilirubin exceeding the normal range of 1.7–13.7 μmol/L, or the direct bilirubin exceeding the normal range of 1.71–7 μmol/L; the total serum protein, serum albumin, or serum globulin values exceeding the normal range of 60–80 g/L, 40–55 g/L, or 20–30 g/L, respectively; the prothrombin time, cholinesterase, and total serum bile acid values exceeding the normal range of 12–14 s, 130–310 U/L, and 10 μmol/L, respectively. Patients who triggered the alert during medication were categorized as suspected abnormal liver function. The HPS contained basic information about medications administered to all inpatients during hospitalization.

Case and control group

The case group included all patients who triggered a alert signal in the HPS to indicate abnormal liver function. Patients were matched for age (±5 years age difference) and sex. The patients who were randomly selected from the remaining untriggered signals were assigned to the control group. The ratio of the case to the control group was 1:4. In addition, the causal relationship between S . miltiorrhiza polyphenol injection and abnormal liver function ADR was evaluated according to the Naranjo evaluation scale 19 , 20 . A patient’s score of >5 points indicated a significant relationship. The specific grouping situation was as follows:

Case group. A total of 58 patients were included based on a signal for potential abnormal liver function ADR during S . miltiorrhiza polyphenol injection treatment or within 24 h of its withdrawal.

Control group. A total of 232 control group patients were randomly selected using the case-to-control ratio of 1:4. Patients had not developed abnormal liver function ADR during S . miltiorrhiza polyphenol injections and had discontinued the injections for >7 d.

Meta-analysis design

Inclusion criteria. (1) Randomized controlled trials (RCTs) and other observational studies written in Chinese or English were included. (2) The subjects were patients who received S . miltiorrhiza polyphenol treatment, regardless of age, sex, or disease type. (3) The test drug was the S . miltiorrhiza polyphenol injection, administered as an intravenous drip and used alone or in combination with other drugs. 4) Outcome measures reported the incidence and rate of abnormal liver function.

Exclusion criteria. (1) The description of the intervention involving drugs was unclear, and the ADR could not be evaluated. 2) ADRs were not previously described. (3) The data was incomplete and could not be analysed. (4) Short reports. (5) Reviews. (6) Animal or cell experiments. (7) Basic medical research.

We used the Cochrane System Evaluator Manual v. 5.1.0 offset risk assessment tool 21 and MOOSE guidelines 22 to assess the quality of the RCTs and observations. Each of seven quality criteria was counted as one point, and a total score of ≥4 was indicative of high-quality literature 23 . Quality score evaluation and basic data extraction from the literature were conducted independently by two evaluators, and their results were cross-checked for accuracy. When an inconsistency occurred, the research team determined whether to include the study or not.

Data source

NCCS data were obtained from the medical records in the Hospital Information System (HIS) of the First Affiliated Hospital of Bengbu Medical College. Meta-analysis data were obtained from PubMed, Embase, the Cochrane Library, Web of Science, Clinical Trials, CNKI, VIP, and Wanfang Data. The retrieval time to build our database lasted until June 15th, 2019. The search was performed by combining the subject and the free words, then, the results were screened according to the inclusion and exclusion criteria. The PubMed search strategy was as follows:

“ Salvia miltiorrhiza polyphenols for injection” [Title/Abstract] OR “Dan Shen Duo Fen Suan Yan” [Title/Abstract]

“Coronary heart disease” [Title/Abstract] OR “Angina pectoris” [Title/Abstract] OR “Myocardial infarction” [Title/Abstract] OR “Cerebral infarction” [Title/Abstract] OR “Thrombosis” [Title/Abstract] OR “Adverse drug reaction” [Title/Abstract]

(1) AND (2)

Data extraction

NCCS data were extracted by a professional data expert. The data included patient’s sex, age, drug allergy history, admission condition, payment method, comorbidities, combined medication, and drug information (including specifications, usage and dosage, solvent, duration of administration). The data of 2633 patients who received S . miltiorrhiza polyphenol injections were uniformly standardized before analysis 24 . Meta-analysis data included author names, study title, publication date, study type, observation object, intervention measures, and quality evaluation scores. Possible offsets were avoided during data extraction, but if unavoidable, a sensitivity analysis was performed.

Statistical analyses

NCCS data were analysed by χ 2 test, Wilcoxon test, and univariate and multivariate conditional logistic regression analyses. Abnormal liver function ADR was the dependent variable, while possible causes like admission condition, allergy history, payment method, comorbidities, solvent type, dosage, duration of administration, and top 43 frequently combined drugs were independent variables(Supplementary Table  1 ). Statistical analysis was performed using SPSS V21.0 statistical software. Meta-analysis data were processed using R3.5.0 software. The confidence interval for each effect variable was expressed as 95% CI. Homogeneity test (Q test) was used to evaluate heterogeneity. The test level was α = 0.1, and the size of heterogeneity was quantitatively determined by combining I 2 (judgment criterion P  ≥ 0.1 or I 2  ≤ 50%) 25 , 26 . Heterogeneity was considered significant when p  < 0.1 and I 2  > 50%. When P  ≥ 0.1 and I 2  ≤ 50%, the fixed-effect model was used for the meta-analysis; otherwise, a random-effect model was used.

Ethics approval

Ethics approval was obtained from the Clinical Medicine Research Ethics Committee of the First Affiliated Hospital of Bengbu Medical College. The patient data used in this study were approved by the Ethics Committee of the First Affiliated Hospital of Bengbu Medical College. Before enrolment, each patient was full explained about the study and signed an informed consent form.

Nested case-control study results

Demographic characteristics.

The NCCS included a total of 2633 patients who received S . miltiorrhiza polyphenol injection according to their medical records. During the study, 58 patients who triggered an alert singal during treatment had a Nangjo score of more than 5 points. Thus, the incidence rate of abnormal liver function was 2.2% (58/2633). Among the 58 patients were 30 patients with increased glutamic aminotransferase, 19 with increased aspartate aminotransferase, 5 with increased total bilirubin, and 4 with other ADRs related to liver function. Fifty patients with general ADRs improved after discontinuation. Eight patients were cured after treatment with reducible glutathione and other prophylactin.

Based on the NCCS design, 290 patients were included in the study. The case group had 58 patients with an average age of 64.12 ± 16.28 years, and the control group had 232 patients with an average age of 64.41 ± 16.86 years. Patients were 16–94 years of age. The Wilcoxon test did not indicate significant age differences between the groups (P  =  0.745). The sex ratio was similar within each group and did not significantly differ between both groups (P = 0.594). Thus, age and sex distribution were similar in both groups (Table  1 ).

Factors affecting abnormal liver function

Univariate conditional logistic regression analysis showed that sulfa drug allergy, admission condition, payment methods, duration of administration, hypertension and combined use with 10% potassium chloride, cefathiamidine, human serum albumin, Dazhu Rhodiola injection, ambroxol oral solution, reduced glutathione, mannitol injection, and vitamin B6 are associated with ADRs of S . miltiorrhiza polyphenol injections (P < 0.05) (Table  2 ). These statistically significant factors were used as candidate variables to establish a multivariate conditional logistic regression model. The experimental variables were gradually screened backward using P < 0.05 as test level. The results showed sulfa drug allergy, payment methods, duration of administration, and combined use with cefotaxime, human serum albumin, Dazhu Rhodiola injection, and reduced glutathione were statistically significant risk factors (Table  3 ).

Meta-analysis results

Literature search.

Our literature search identified 3109 relevant studies. Chinese databases contributed 3051 studies, including 899 from VIP, 1066 from Wanfang Data, and 1086 from the China National Knowledge Infrastructure. Fifty-eight studies were retrieved from English databases, including 7 from the Cochrane Library, 51 from PubMed, but 0 from other databases. All studies were screened based on the inclusion and exclusion criteria, yielding 9 studies for the meta-analysis, including 3 RCTs, 4 non-RCTs, and 2 observational studies.

Basic research information

A total of 676 patients from 9 studies were selected, including 676 patients who received S . miltiorrhiza polyphenol injections. In 17 patients who presented with abnormal liver function, the main manifestations were alanine aminotransferase, aspartate aminotransferase, and total bilirubin elevation. A single daily dose contained 100–200 mg/d, using 5% glucose or 0.9% sodium chloride as solvents. Main indications for treatment were cardiovascular and cerebrovascular diseases. Eight articles had a quality score greater than or equal to 3, which was the threshold score for a high-quality study. The basic information derived from these articles is summarized (Table  4 ).

Incidence of abnormal liver function determined by meta-analysis

Among 676 patients receiving S . miltiorrhiza polyphenol injections, 17 exhibited abnormal liver function. Thus, the incidence rate of abnormal liver function in the treatment group was 2.17% by meta-analysis. A forest plot for abnormal liver function in our meta-analysis was created (Fig.  3 ).

Forest plot to assess incident distribution in meta-analysis.

Publishing bias and sensitivity analysis

We used a funnel plot method to evaluate potential publication bias because the number of studies was too small for performing the Egger regression or Begg correlation test. There was no symmetric distribution of the data, probably due to the small study number (Fig.  4 ). The meta-analysis was performed after removing literature items showing poor quality and high specificity. However, there was no significant change in the incidence rate of abnormal liver function, indicating that the meta-analysis generated a robust result.

Funnel plot to assess publication bias in meta-analysis.

Comparison of the ADR incidence rates derived from the NCCS and meta-analysis

We performed a χ2 test on the incidence rate of liver dysfunction in patients treated with S . miltiorrhiza injection using the patient data from the NCCS and the meta-analysis. There was no statistically significant difference in the ADR incidence rates of S . miltiorrhiza treatment between the NCCS data on liver dysfunction and the meta-analysis (P = 0.627).

Post-marketing clinical research on drugs is mainly focused on re-evaluating their safety and effectiveness. RCTs are the gold standard for drug efficacy studies, but there are shortcomings in re-evaluating post-marketing drug safety 27 . Recently, satisfactory results were obtained by applying NCCS and meta-analysis in safety re-evaluation studies of Chinese medicine injections 23 , 28 , 29 . An NCCS requires large-sample clinical data and uses broad inclusion criteria and epidemiological research methods to assess the clinical application of drugs or other interventions (including diagnosis, treatment, and prognosis) in a truly unbiased or less biased population 30 . An NCCS has one cohort of all disease cases that meet specific inclusion criteria; typically, the disease onset occurred within a certain period. Further criteria are applied within the cohort to establish one or more controls along with the treatment group. The groups are matched based on factors such as age, sex, address, and/or ethnicity, and the relevant patient information is subjected to statistical analyses 31 . An NCCS is often used for safety risk assessments 32 , 33 , 34 .

The NCCS design is economical and has the advantage that it avoids potential selective and recall biases of classic case-control studies incurred when collecting data. It reduces the interference of confounding factors by relying on comparable, well-balanced case and control groups, which allows a good extrapolation of study results.

Meta-analysis requires extensive RCTs and other observational studies, which prevents selective migration, ensures comparability between groups, generates highly authentic results, and has a high evidence level. A meta-analysis of widely used RCT research data enables objective evaluation of the evidence and a more accurate and objective assessment of effect indicators.

The innovation of this study is that it evaluated the incidence rate of abnormal liver function for S . miltiorrhiza polyphenol injections based on a meta-analysis and a logistic regression analysis of real-world data. This approach provides a new method that can be used for further studies on the adverse effects of S . miltiorrhiza polyphenol injections. Both NCCS and meta-analysis can be used as a basis for prospective clinical studies. The methods complement each other and generate comparable results. They can innovatively evaluate the safety of S . miltiorrhiza polyphenol injections in clinical practice, providing an evidence-based and rigorous reference for clinicians.

With the wide clinical application of S . miltiorrhiza polyphenol injections, the adverse reaction reports have gradually increased 10 , 35 , 36 , 37 . The NCCS determined an incidence rate of 2.2% for abnormal liver function adverse reactions to S . miltiorrhiza polyphenol injections, and the meta-analysis derived the incidence rate of 2.17%. There was no significant difference in the incidence rate of abnormal liver function adverse reactions between our two studies, although the two methods were quite different. The abnormal liver function described in the S . miltiorrhiza polyphenols injection for instructions is an occasional adverse reaction with a probability range form 0.1% to 1% 8 . The clinical manifestations described in the drug instructions were similar to those identified in our two studies, although the corresponding incidence rate was much lower than in our studies. This may be due to the limited sample size of studies conducted before the drug was approved for the market, and the clinical irrational use of drugs after the market had led to an increase in the incidence of abnormal liver function. Moreover, the subjects in the earlier studies were also strictly screened, while our study included all patients who received S . miltiorrhiza polyphenols within the same period, and our inclusion criteria were broader. There were 9 earlier studies, including 4 non-randomized controlled studies, 2 observational studies, and 3 randomized controlled studies, which had also relatively broad inclusion criteria. In our NCCS and meta-analysis, we found that the abnormal liver function adverse reactions to S . miltiorrhiza polyphenols were closely associated with the combined use of drugs. We know that due to the complex condition of patients, the effect of single-agent treatment is often poor, and treatment with combination therapy is very common in modern medicine. However, the study of the combination therapy before market launch is strictly limited.

Previous studies have shown that factors affecting ADRs of S . miltiorrhiza polyphenol injections might be age, sex, solvent, and concurrent medications 13 , 14 , 15 , 38 , 39 , 40 , 41 , 42 . In this study, univariate and multivariate conditional logistic regression analysis showed that the sulfa drug allergy, payment methods, and duration of administration were also risk factors for abnormal liver function associated with S . miltiorrhiza polyphenol injections. Moreover, administration of S . miltiorrhiza polyphenol injections in combination with cefathiamidine, human serum albumin, Dazhu Rhodiola injection, or reduced glutathione increased the risk of abnormal liver function ADRs.

In previous studies, Lv et al . 41 reported that factors affecting ADRs of S . miltiorrhiza polyphenol injections were age, sex, and concurrent medications. Liao et al . 42 reported that admission condition, solvent, and concurrent medications were risk factors for allergic reactions to S . miltiorrhiza polyphenols. However, these studies did not focus on the risk factors associated with liver dysfunction caused by S . miltiorrhiza polyphenol injections. We identified sulfa drug allergy, payment methods, duration of administration, and concurrent medications as risk factors for abnormal liver function ADRs associated with S . miltiorrhiza polyphenol treatment. Our results varied from earlier reports 41 , 42 . Our case data source, the range of confounding factors, and the research methods differed from those in previous studies 41 , 42 . This study was an NCCS and meta-analysis of re-evaluating the safety of liver function of S . miltiorrhiza polyphenol injections, which included a broader analysis of confounding factors.

Since S . miltiorrhiza polyphenol injections are covered by the national medical insurance in China, the patient can pay the treatment through medical insurance, thereby reducing the economic pressure. Because of this, clinicians may be more inclined to prescribe S . miltiorrhiza polyphenol injections. However, frequent use of the same drug may increase the risk of ADRs. Therefore, this study used the payment method as an independent variable for logistic regression analysis and concluded that payment method was a risk factor for abnormal liver function adverse reactions to S . miltiorrhiza polyphenol injections. This may be a new finding that complements the results of previous studies and provides a new reference for clinical use.

This study combined NCCS methods and meta-analysis to generate a more scientific and reliable reference for the rational clinical use of S . miltiorrhiza polyphenol injections and the prevention and control of adverse reactions. Although all clinical data in this study were derived from the HIS database, our results were more robust, evidence-based, and extrapolated, compared with those of previous studies 13 , 14 , 15 , 42 , 43 . Due to limited data availability, it was impossible to make a comprehensive judgment on symptoms and clinical manifestation in patients. In future studies, it will be necessary to increase the sample size, expand the scope of the cases, and establish a multi-centre, large-sample study to obtain more reliable results.

In conclusion, the incidence rate of abnormal liver function adverse reactions to S . miltiorrhiza polyphenols was approximately 2.0%, which was higher than the value indicated in the drug instruction. This study showed that the risk factors for abnormal liver function adverse reactions to S . miltiorrhiza polyphenol injections were sulfa drug allergy, payment methods, duration of administration, along with co-administration of cefathiamidine, human serum albumin, Dazhu Rhodiola injection, and reduced glutathione. Therefore, when S . miltiorrhiza polyphenol injections are used in a clinical setting, attention should be paid to the indications of the medication, drug allergy history, payment methods and duration of administration. Especially, when combined with other drugs, preventive measures should be taken to limit the risk of compatibility changes. Clinicians can minimise the risk of adverse reactions associated with frequent use by intermittently prescribing other drugs with the same indication.

Data availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request. The current study of trial registration number from the Chinese Clinical Trial Registration Centre is ChiCTR1900024340.

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Acknowledgements

We would like to express our appreciation for assistance provided by the professors of the First Affiliated Hospital of Be ngbu Medical College. We would like to thank Editage for English language editing ( http://www.editage.cn ). This study was supported by the Talent Project of Higher Education Revitalization Program 2014 of the Department of Education of Anhui Province (Wanjiao Miren (2014) No. 181), and Beijing Medical Health Public Welfare Fund (YWJKJJHKYJJ-B17402-B02).

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Jin-quan Cheng, Qing-ping Shi, Feng Ding, Ling-ti Kong & Mei-ling Yu

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Jin-quan Cheng, Qing-ping Shi, Ling-ti Kong, Mei-ling Yu & Can Wang

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J.C. and Q.S. designed the study and wrote the manuscript; F.D. and C.W. were responsible for the data extraction; L.K. and M.Y. participated in the data analysis and reviewed the manuscript. All authors read and approved the final manuscript.

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Cheng, Jq., Shi, Qp., Ding, F. et al. Liver function monitoring: a prospective nested case-control study of Salvia miltiorrhiza polyphenol injection. Sci Rep 10 , 3538 (2020). https://doi.org/10.1038/s41598-020-60608-z

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Pseudo-allergic reactions induced by chinese medicine injections: a review.

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Lupus and the Liver: A Case Study

Affiliations.

• 1 Miscellaneous, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA.
• 2 Immunology, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA.
• 3 Rheumatology, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA.
• PMID: 31646136
• PMCID: PMC6805037
• DOI: 10.7759/cureus.5477

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a wide range of systemic manifestations. Though skin, renal, joint, and hematologic involvement are often associated with SLE, hepatitis is not a common manifestation. While clinically significant hepatopathy in SLE is rare, asymptomatic hypertransaminasemia has been seen in up to 60 percent of SLE patients during the course of their disease and is generally attributed to viral hepatitis, hepatotoxic drugs, or alcohol use. A diagnosis of lupus hepatitis is largely considered a diagnosis of exclusion. There has been a correlation between the presence of ribosomal P autoantibodies with the incidence of lupus hepatitis. Generally, lupus hepatitis responds well to therapy with prednisone, although cases refractory to corticosteroids and conventional immunosuppressants have been described. In these cases, treatment with mycophenolate mofetil has been shown to be effective. Here, we present the case of a 15-year old female who presented with a new diagnosis of SLE with an incidental elevation of her liver function tests (LFTs) and a subsequent finding of hepatomegaly with fatty infiltration.

Keywords: lupus; lupus hepatitis; systemic lupus erythematosus (sle).

Copyright © 2019, Patel et al.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figure 1. Ultrasound Image of Liver, Right…

Figure 1. Ultrasound Image of Liver, Right Side Transverse View

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Case Study: A Teacher With Signs Liver Problems

We present this case study to provide guidance on how best to utilize medical calculators to assist with diagnosis and treatment for this patient.  In the discussion section, we recommend specific medical calculators that will help physicians with clinically appropriate decision making.

Laurie is a 56 year old high school teacher. She is overweight with a history of diabetes, hypertension, peptic ulcer disease, and chronic arthritis. Because of the stress of teaching she often unwinds at night with a drink or two (or three). For her arthritis she takes an herbal medicine recommended by a co-worker as a Chinese wonder drug. She also takes medication for her diabetes and hypertension together with a proton pump inhibitor (PPI).

She went to her doctor because she noted that her belly was expanding and her clothes were no longer fitting. The doctor noted signs suspicious for portal hypertension. Her liver function tests were elevated.  Markers for viral hepatitis were negative. She did not have any known exposures to infectious diseases or chemicals.

The patient was referred to a gastroenterologist who expanded the workup. The serum ANA and filamentous actin (F-actin) were both mildly elevated. The antimitochondrial antibodies were negative. The gastroenterologist decided that a liver needle biopsy might help to establish a diagnosis.

An image-guided needle biopsy of the liver was performed by a radiologist without complications. The radiologist noted some ascites fluid during the procedure. The radiologist did not see abnormalities of the bile ducts or evidence of sclerosing cholangitis, although it was noted that gallbladder showed several large gallstones.

The liver biopsy showed bridging fibrosis but no clear evidence of cirrhosis. A striking change was an interface hepatitis with numerous plasma cells. Moderate steatosis was present. No excess of iron was seen on iron stain.

The gastroenterologist took a careful medication history and excluded potential hepatotoxic drug exposures. He reviewed the herbal remedy and did not think that it was likely to be hepatotoxic based on its reported ingredients. In light of the patient’s history and findings the gastroenterologist made the diagnosis of autoimmune hepatitis.

There are many conditions that can adversely affect the liver. The differential diagnosis in this patient includes:

• Alcoholic liver disease
• Non-alcoholic steatohepatitis (NASH) with evidence of metabolic syndrome
• Autoimmune hepatitis
• Herbal remedy related hepatitis
• Biliary cirrhosis

The challenge is to determine which of these are present and to what extent. Once the causes are known then steps can be taken:

• To stop the sources of hepatic injury
• To reverse existing damage so that the liver (and patient) can recover.

Fortunately the liver can recover from many types of injury.

Role of Liver Biopsy

Liver biopsy can be helpful in identifying a cause for liver disease, especially when the clinical findings are ambiguous or overlapping. Generally, a liver biopsy should only be performed if it will change treatment or management of the patient. In nonalcoholic liver disease (NAFLD), chronic hepatitis, or other liver disease, it can be used to determine the extent of liver damage and fibrosis. Liver biopsies are also useful for unexplained liver function tests or liver disease.

Autoimmune Hepatitis (AI)

Autoimmune (AI) hepatitis is a chronic disease of often unknown etiology. Several possible inciting events, such as viral infections, drugs, environmental exposures, have been linked to development of autoimmune hepatitis. Women develop AI hepatitis more often than men, 7-8 to 1. AI Hepatitis is seen most often among two age groups, late pediatric (10y-20y) and again in middle age (45y-70y). Cases have been diagnosed in infants as well as the elderly.

Alcoholic Liver Disease

Alcohol abuse may lead to a variety of pathology in the liver including steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Clinical manifestations of the disease will depend on severity, but patients are typically asymptomatic until developing hepatitis or cirrhosis (presenting with signs of hepatic decompensation). Classic laboratory findings in alcoholic liver disease is moderately elevated transaminases, with the asparate aminotransferase (AST) to alanine aminotransferase (ALT) typically greater than 1.5.

Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic fatty liver disease is divided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NASH is characterized by hepatic inflammation and histologically is not able to be differentiated from alcoholic steatohepatitis. Factors associated with disease progression include older age, diabetes, and body mass index. Hepatocellular carcinoma is often associated with cirrhosis stemming from nonalcoholic fatty liver disease.

Drugs-induced Liver Disease

Drug-induced liver disease in the most common cause of acute liver failure in the United States. Over a thousand drugs have been known to cause drug-induced liver injury, with the most common drug in the United States being acetaminophen. Amoxicillin is also a common cause worldwide. Many patients present asymptomatic with disease only detected because of abnormalities in laboratory testing. Patients may, however, present with symptoms including malaise, nausea, vomiting, right upper quadrant pain, jaundice, or dark urine. Diagnosis can often be difficult and relies on a detailed history and ruling out other causes of liver disease. Primary treatment is stopping the offending agent.

Of concern for patients who abuse alcohol and who have pain is the use of acetaminophen which can be toxic to the liver in high doses.

Herbal Remedies

Many people take an herbal remedy and because they are “natural” they are assumed to be safe. One of the first recognized examples proving how wrong this can be is the Veno-Occlusive Disease (VOD) caused by pyrrolizidine alkaloids in bush teas.

When evaluating an herbal remedy for toxicity it is important to know if there are any unstated additives.

Take Home Points

• In practice many people have more than one cause for a clinical or laboratory finding, and the challenge is to separate them out. A complete workup and evaluation of laboratory data along with detailed history can often identify the cause.
• Patient Evaluation
• Temporal Course and Activity
• Causes of Hepatitis
• Additional Concerns
• Differential Diagnosis of Hepatitis
• Management of Viral Hepatitis
• Patient Concerns
• Using Medal Packs can improve diagnostic accuracy and reduce risk for incomplete workup. In turn, Medal Packs may be able to reduce hospital stay and overall healthcare costs while improving patient care.
• Medal Packs are available on our website and via our iOS and Android app, and can serve as handy reference to physicians both in and out of the office.
• The medical algorithms highlighted in this case study are available at The Medical Algorithms Company and also on the apervita health analytics platform.

About the Authors

Adam Vohra is a Health Innovation Fellow at Apervita. He is currently a dual-degree MD/MBA student in his final year at The University of Chicago Pritzker School of Medicine and Booth School of Business. He plans to pursue a residency in internal medicine next year. Adam is interested in issues related to health care quality and delivery and has published research on predictors of intensive care unit admission for pneumonia. He is currently working on research to create analytics to predict heart failure readmissions. Adam is also involved heavily in health care policy and currently serves on the Board of Trustees of the Illinois State Medical Society as the sole medical student member. In the past, Adam has also represented medical students in the American Medical Association House of Delegates. Prior to coming to The University of Chicago, Adam completed his undergraduate studies at Northwestern University where he studied biology and political science.

Dr. Chad Rudnick, MD, FAAP is a board-certified pediatrician in Boca Raton, FL. He is the Medical Director of The Medical Algorithms Company. A proponent of incorporating medical technology into his practice, Dr. Rudnick uses telemedicine and medical algorithms from The Medical Algorithms Company in his daily practice to better serve his patients and their families. An accomplished medical writer, he maintains a popular pediatric blog, All Things Pediatric, and has written for numerous online and print publications including KevinMD.com.

John Svirbely, MD is a founder and Chief Medical Officer of The Medical Algorithms Company and the primary author of its medical algorithms. John is a co-founder of the Medical Algorithms Project and has developed its medical content for nearly 20 years. He has a BA degree from the Johns Hopkins University and his MD from the University of Maryland. He is a board-certified pathologist with a fellowship in medical microbiology and biomedical computing at Ohio State University. Currently he is in private practice in Cincinnati, Ohio. He has authored multiple books and articles on medical algorithms.

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Case report of acute liver injury caused by the eszopiclone in a patient with chronic liver disease

Eszopiclone, sold under the brand name Lunesta, is a new type of non-benzodiazepine hypnotic. Eszopiclone is a zopiclone dextrorotation, which is classified as a cyclopyrrolone. It functions by binding gamma-aminobutyric acid (GABA) receptors. Compared with benzodiazepines hypnotics, eszopiclone has higher selectivity for certain subunits of the GABA(A) receptor. So far, there are no reports about the elevation of serum enzymes or severe liver injury caused by eszopiclone. Here, we present a case report of acute liver injury following eszopiclone treatment in a patient with chronic hepatitis B virus (HBV).

Patient concerns:

The patient was a 53-year-old female with a 36-year history of positive HBV markers. Due to poor sleep, the patient took trazodone hydrochloride orally for 1 year. After hospital admission for positive hepatitis B pathogenic markers, abdominal distension, fatigue, and aggravation, she was treated with eszopiclone under the guidance of the mental health department.

Her transaminase levels increased abnormally after eszopiclone treatment and rapidly decreased after drug withdrawal. This was determined to be an acute liver injury event. liver-protecting treatment was maintained. Considering the patient's anxiety and depression, the patient's family members refused a liver biopsy.

Transaminase levels decreased rapidly within one week, and the patient continued to take trazodone hydrochloride after discharge. No adverse events occurred in the follow-up period.

Sleep disorders are more common in patients with chronic diseases, especially patients with chronic liver disease. Recently, it has become common for patients with hepatitis B and C to use antidepressants along with antiviral treatment. Patients with chronic hepatitis B or C may have a threefold risk of liver dysfunction after receiving antituberculosis treatment. [ 1 , 2 ] A proinflammatory environment induced by actively replicating the hepatitis virus may alter the detoxication process and increase drug toxicity. [ 3 ] At this time, the safety of other drugs should be reevaluated. Although hepatitis and liver injury are listed as rare adverse reactions of eszopiclone, this case is the first to report the eszopiclone-involved acute liver injury.

1. Introduction

Eszopiclone is a fast-acting sedative and hypnotic drug commonly used to prolong sleep time, improve sleep quality, and reduce the number of awakenings after the onset of sleep. Studies have shown that the effective doses of eszopiclone for elderly patients and non-elderly patients to achieve efficient sleep induction and maintenance are 2 and 3 mg, respectively. [ 4 ] A systematic review and meta-analysis of a randomized, double-blind, and placebo-controlled trial of eszopiclone in the treatment of primary insomnia showed that eszopiclone is a safe choice for the treatment of primary insomnia, including in elderly patients, and it was also ranked the optimal therapy for prolonging objective total sleep time. Thus far, no reports have been published regarding the elevation of serum enzymes or severe liver injury caused by eszopiclone. The patient in this case report uses eszopiclone in a special disease state. Eszopiclone may aggravate the hepatotoxicity of trazodone through the following mechanisms, which prompted us to pay attention to a series of special populations who also have this risk.

Drug-induced liver injury (DILI) refers to liver disease caused by drugs or metabolites. In Western patients with DILI, antibacterial antibiotics, and psychoactive drugs are the most frequently implicated therapeutic drug classes. [ 5 ] Studies have shown that specific patient populations may have an increased risk of DILI. For example, women who use diclofenac [ 6 ] and older patients who use isoniazid [ 7 ] and amoxicillin-clavulanic [ 8 ] both have an increased risk of developing liver damage. Additionally, certain disease states have also been shown to be among the risk factors that can contribute to DILI. These include diabetes and obesity, which are risk factors for methotrexate-induced liver damage, and pre-existing chronic liver disease (CLD), which increases the risk of severe acute liver injury. [ 9 ] Therefore, we believe that the special disease state of CLD may also be related to the increased risk of liver damage from certain drugs, although this remains controversial.

In this article, we report a case of acute DILI, determined by acute and transient transaminase elevation, in a 53-year-old woman who was taking drugs for chronic moderate viral hepatitis B, anxiety, depression, and sleep disorders. The cytochrome P450 (CYP) iso-zymes CYP3A4 and CYP2E1 are involved in the bio-transformation of eszopiclone; therefore, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone.

2. Case report

A 53-year-old woman was admitted to our hospital because of positive hepatitis B pathogenic markers (36 years), abdominal distension, fatigue (1 year), and aggravation (7 days). The patient had a family history of hepatitis B and her mother was an hepatitis B virus (HBV) carrier. For 36 years prior to hospital admission, the patient had taken no hepatitis B medication. In 2001, the patient was diagnosed with “neurosis” due to “anxiety and poor sleep.” She intermittently treated sleep disorders with zolpidem tartrate and other drugs. In May 2018, due to the aggravation of symptoms, the patient began oral administration 150 mg of trazodone hydrochloride until after admission. The patient was monitored for markers related to liver function, including aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase, and albumin (ALB). Hepatitis B antigens and HBV-DNA levels were also measured. On November 12, liver function tests showed AST 211.2 U/L, ALT 171.4 U/L, ALP 41.9 U/L, γ-GT 44.7 U/L, and ALB 38.5 g/L (Table ​ (Table1); 1 ); HBsAg (+), HBeAg (+), HBeAb (+), and HBcAb (+); HBV-DNA 4.67 × 10 6 IU/mL; liver transient elastography 8.0 kpa, fat attenuation value 211 db-m; and abdominal computed tomography showed mild fatty liver. Autoimmune antibodies were negative and immunoglobulin levels were normal. The clinical diagnosis was “chronic moderate viral hepatitis B; neurosis.” Each day, the patient was given 15 mL polyene phosphatidylcholine intravenously, 0.5 mg entecavir orally, and continued 150 mg trazodone hydrochloride orally. Re-examination of liver function on November 16 showed AST 197.6 U/L, ALT 91.9 U/L, ALP 39.5 U/L, γ-GT 51.2 U/L, and ALB 31.8 g/L (Table ​ (Table1 1 ).

Laboratory test results upon patient readmission.

Provides the laboratory test results of liver function after admission. The test date is selected based on the improvement of the patient's symptoms, such as fatigue and loss of appetite.

γ-GT = γ-glutamyl transpeptidase, ALB = albumin, ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase.aspartate aminotransferase.alanine aminotransferase.γ-glutamyl transpeptidase.alkaline phosphatase.albumin.

On November 22, the patient's sleep disorder worsened, and the Department of Mental Health recommended adding 3 mg eszopiclone orally each day. Re-examination of liver function on November 24 showed AST 2969 U/L, ALT 203.7 U/L, ALP 54U/L, γ-GT 204.7 U/L, and ALB 32.2 g/L (Table ​ (Table1). 1 ). We immediately stopped administering eszopiclone and applied hepatoprotective drugs, which maintain the previous treatment plan, that is,15 mL of polyene phosphatidylcholine is given daily by intravenous infusion. Another liver function test on December 2 showed AST 194.2 U/L, ALT 80.1 U/ L, ALP 88 U/L, γ-GT 415.3 U/L, ALB 26.9 g/L, and HBV-DNA 2.76 × 10 4  IU/mL (Table ​ (Table1). 1 ). The liver enzyme index decreased significantly by December 2. In the process of the increase and decrease of transaminase, the patient has no obvious symptom changes. Table ​ Table1 1 provides the laboratory test results of liver function after admission. The test date is selected based on the improvement of the patient's symptoms, such as fatigue and loss of appetite.

3. Discussion

Eszopiclone, a new type of non-benzodiazepine hypnotic, is a zopiclone dextrorotation, which is classified as a cyclopyrrolone. Its affinity for non-benzodiazepine receptors is much stronger than that of zopiclone levorotatory. Additionally, it is more efficient at inducing sleep, reducing arousal, and reducing anxiety compared with zopiclone. It is a gamma-aminobutyric acid/BZI receptor complex, which can achieve sedative and hypnotic effects by inhibiting the excitatory center. The peak blood concentration occurs at about 1 hour, and the half-life is only about 6 hours. Compared with other types of sedative-hypnotics, it has a more rapid onset and fewer side effects. It improves sleep quality without damaging psychomotor function, generally without drug dependence, and it can significantly shorten the patient's sleep latency, prolong the patient's sleep time, and improve sleep quality. [ 10 ] Although hepatitis and liver injury are listed as rare adverse reactions on the product label, since the approval and widespread use of eszopiclone, there has been no relevant report on clinically obvious liver disease caused by eszopiclone.

This patient in this case report had preexisting CLD (viral hepatitis B). Before admission, she took trazodone regularly for 1 year. During hospitalization, she was given antiviral therapy; 10 days later, eszopiclone was added. Following treatment with eszopiclone, transaminase increased significantly and then decreased rapidly after drug withdrawal. Based on ALT ≥3 times the upper limit of normal (ULN) and R value [(ALT/ULN)/(ALP/ULN)] ≥5, the patient was diagnosed with the hepatocellular injury. [ 11 , 12 ] Furthermore, the Roussel Uclaf Causality Assessment Method (RUCAM) was used to evaluate the case. The RUCAM score is was 6 points after applying eszopiclone, meaning that eszopiclone was categorized as the probable cause of liver injury. [ 13 ] Due to the poor condition of the patients themselves and the high transaminase levels during hospitalization, the re-drug reaction test could not be performed. The score was affected by various factors without further examination and verification.

The difficulty of this case is that the patient had basic liver disease, and acute liver function injury often occurs in the active stage of chronic hepatitis. The incidence of CLD in the general population is on the rise, presenting challenges for clinicians diagnosing DILI in these patients. In this case report, the liver injury was very likely related, either directly or indirectly, to the patient's use of eszopiclone. However, due to the patient's anxiety, it was impossible to obtain a liver biopsy for pathological auxiliary diagnosis.

This also reminds us that patients with liver disease are in a special immune state, and the related medication safety requires our close attention. A systematic review and meta-analysis of symptoms, morbidity, and quality of life of end-stage liver disease show that the incidence of depression, anxiety, and sleep disorders in these patients is 4.5% to 64%, 14% to 45%, and 26% to 77%, respectively. [ 14 ] The incidence of these disorders correlates with the economic burden of liver disease patients and the deterioration of social and occupational function. Some studies have shown that metabolic disorders of melatonin and glucose, changes in thermoregulation, and secretion characteristics of ghrelin may be related to sleep disorders in patients with CLD, [ 15 ] and compared with chronic hepatitis B patients, patients with cirrhosis and acute-on-chronic liver failure have a higher proportion of insomnia, which may be attributed to the more serious physical symptoms of these diseases. [ 16 , 17 ] At present, new drugs for the treatment of anxiety, depression, and sleep disorders emerge continually, which makes it challenging to ascertain the safety and efficacy of these drugs used by patients with liver disease.

The patient, in this case, used trazodone long-term use for anxiety and depression. Trazodone is a triazole pyridine derivative, which is a new type of antidepressant used to treat depression, aggressive behavior, and panic disorder. Trazodone can be associated with transient, usually asymptomatic, elevated serum transaminase levels. The injury usually occurs after several months of continuous ingestion and it usually manifests as elevated transaminase. It is also associated with rare cases of acute liver injury in clinical practice. [ 18 , 19 ] Studies have shown that CYP3A4 and CYP2D6 inhibitors can affect the cytotoxicity of trazodone, suggesting that trazodone-induced liver cytotoxicity is at least partially induced by its metabolites. [ 20 , 21 ] The cytochrome P450 CYP3A4 is exclusively involved in the metabolism of trazodone in the human body. [ 22 ] This enzyme plays a key role in the metabolic activation of trazodone, [ 21 ] and eszopiclone is also metabolized by cytochrome P450s (mainly CYP3A4 and CYP2E1). [ 23 ] The effect of eszopiclone or its metabolites on CYP3A4 may be an important reason for the aggravation of trazodone hepatotoxicity by eszopiclone. It is worth noting in this case that the patient had chronic HBV infection and had not received standard treatment for many years. After hospitalization, the patient has prescribed the antiviral entecavir. Some studies have shown that HBV infection and the use of antiviral drugs can inhibit the activities of CYP2C9 and CYP3A4, cause abnormal drug metabolism, and change the blood drug concentration, which can also cause acute liver injury. [ 24 ]

The treatment of various types of liver diseases has recently made great progress, but there are still many patients with end-stage liver disease who need our attention, especially regarding the improvement of quality of life and drug safety. At present, there is no comprehensive study of antidepressant and anxiety drugs in the treatment of sleep disorders in such patients. It is critical to understand these drugs in the context of liver disease to best care for these patients.

Author contributions

Funding acquisition: Ge Yu, Guijie Xin.

Investigation: Zhaoxia Li.

Resources: Guijie Xin.

Supervision: Ge Yu, Guijie Xin.

Validation: Guijie Xin.

Writing – original draft: Tong Wu.

Writing – review & editing: Tong Wu.

Abbreviations: ALB = albumin; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; ATT = antituberculosis treatment; CYP450 = cytochrome P450; DILI = drug-induced liver injury; GABA = gamma-aminobutyric acid; HBV = hepatitis B virus; ULN = upper limit of normal.

How to cite this article: Wu T, Yu G, Li Z, Xin G. Case report of acute liver injury caused by the eszopiclone in a patient with chronic liver disease. Medicine . 2021;100:25(e26243).

Informed written consent was obtained from the patient for publication of this case report and accompanying images.

This study was supported by the Health and Health Innovation Program of Jilin Province under Grant no 2018J043. This study was supported by the Youth Development Foundation of the First Hospital of Jilin University under Grant no JDYY102019005.

The authors have no conflicts of interest to disclose.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

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Case Presentation: 63-Year-Old Man With Advanced HCC

Michael A. Morse, MD, FACP: This is a 63-year-old man who is known to have chronic hepatitis B and he&rsquo;s being appropriately screened. At that time, he&rsquo;s found to have 2 hepatic lesions. Laboratory tests suggest that he has Child-Pugh A liver function, and he is now presented with the question of how to manage the disease.

On further evaluation he&rsquo;s found to have an AFP [alpha-fetoprotein] of about 300, and that he does have Child-Pugh A liver function. The question at that point is regarding the best management of the disease. Appropriately here with a high AFP, the imaging finding, this is clearly a hepatocellular carcinoma. So he went to a surgical resection. The things we look for at the time of surgery are whether there&rsquo;s vascular invasion—there was none&mdash;and how many lesions&mdash;there were 2. The sizes were 5 cm and 2 cm. There is no known benefit from adjuvant therapy in these patients, so he was monitored. Unfortunately, he was found to have recurrent disease. He had 1 new liver lesion and then also had pulmonary metastasis as well. His AFP, which had normalized after the surgery, had increased again. Clearly, he&rsquo;s having a recurrence of disease. I don&rsquo;t think this is something that needs to have a biopsy to prove recurrence with the rising AFP at this point.

Then, since he still had Child-Pugh A disease, he was offered the opportunity to take systemic therapy given there was extrahepatic spread. He proceeded to lenvatinib. In terms of lenvatinib, we&rsquo;ll talk about some of the adverse effects of this whole class of drugs later. He tolerated it with some fatigue and some diarrhea, but he initially did have a response with some decrease in his tumor marker and also in the extent of disease. But unfortunately, as is often the case, he began to have more progression with further pulmonary metastasis and rising AFP, now above 400.

He still had a good performance status, PS 0, his Child-Pugh classification was still A, and so the opportunity for second-line therapy was discussed with him. Cabozantinib was started at the standard dose of 60 mg, which he did tolerate but eventually developed some diarrhea. Because of that, had a dose reduction to 40 mg. He continued on it and was noted to have partial response. As is often the case, eventually he had progression of disease after the initial clinical benefit.

I&rsquo;m often asked about what the prognosis is after people have had surgery and then certainly if they have recurrent disease, what the future&rsquo;s going to look like for them. After surgery, the most important feature is whether there&rsquo;s vascular invasion. Also, the size of the tumor is important as well. In his case, although the range is quoted to be about a 40% to 70% 5-year survival, in reality his is about a 60% 5-year survival. Unfortunately, he had progression of disease, and at the point we&rsquo;re now talking about him getting cabozantinib, the median survivals are about 8 to 11 months.

Transcript edited for clarity.

Case: 63-Year-Old Male with R/R mHCC

February 2018: Initial presentation

• A 63-year-old man with chronic HBV infection referred for further imaging studies based on suspicious findings during routine ultrasound for HCC

Initial Clinical Workup

• AFP: 300 IU/mL
• Platelets: 210,000 cells/mcL
• Bilirubin: 1.2 mg/dL
• Albumin: 3.6 g/dL
• No hepatic encephalopathy
• Ascites not present
• Imaging: CT revealed 2 lesions in right hepatic lobe (2cm, 5cm); no extrahepatic disease; no cirrhosis; no portal hypertension
• Patient underwent right hepatectomy; negative margins; no vascular invasion

December 2018

• On routine follow-up, imaging showed new lesion in left hepatic lobe (~2.3cm)
• Chest CT showed 3 small lesions (<1cm) in upper left lobe of lung
• Patient started on lenvatinib 12 mg QD; experienced moderate diarrhea and fatigue
• Imaging at 3 and 6 months showed partial response
• AFP: 100 IU/mL

August 2019

• Routine follow-up blood sample reveals AFP 450 IU/mL
• CT scan showed progression in the lung and 2 new liver lesions; remains Child-Pugh A
• Patient started on cabozantinib 60 mg QD
• Patient developed grade 2 diarrhea; dose-reduction to 40 mg QD
• Imaging at 3 months showed stable disease
• Imaging at 6 months showed partial response

Tailoring Treatments to Better Outcomes in Liver Cancer

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Gholam Analyzes Treatment Outcomes for Advanced HCC in Child-Pugh B Population

During a live Community Case Forum event in partnership with the Tennessee Oncology Practice Society, Pierre Gholam, MD, examined the current state of treatment for patients with hepatocellular carcinoma, looking in particular at what data is available for those with Child-Pugh B and C status who have poorer outcomes and have limited data from prospective clinical trials.

Addressing irAEs Limits Interruption or Discontinuation in HCC

In a retrospective study in patients with hepatocellular carcinoma, 40% of patients developed irAEs after receiving the first and second doses of immunotherapy.

BMI Affects Survival Probability With Atezolizumab Plus Bevacizumab in HCC

In the frontline, patient body mass index plays a prognostic role when using atezolizumab plus bevacizumab vs lenvatinib for patients with advanced hepatocellular carcinoma.

Lenvatinib Is Effective, Regardless of Age in HCC

No differences in efficacy and safety were seen in a study cohort of 1325 patients undergoing frontline treatment with lenvatinib for unresectable hepatocellular carcinoma.

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